Nutrient chapter

Metformin

Metformin Independent substance, clinical endpoint or measured readout; study context is retained with each finding.

108 recorded mechanisms · 12 availability situations · 1 preserved sources. Draft and verified records are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

What the sources say this nutrient does, one relationship at a time. Plain wording comes first; the technical statement follows.

Rat Oct1 expression produced time-dependent and saturable metformin uptake in CHO cells, with a Km of 377 microM.
Rat organic cation transporter 1 / Oct1 → Metformin source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/12130709.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b", "start_char": 0, "end_char": 1411, "text_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b"}
experimental_model
Rat Oct1-transfected CHO uptake kinetics and Oct1-knockout mouse tissue distribution
exposure
Intravenous metformin in Oct1(-/-) and Oct1(+/+) mice; buformin and phenformin compared in vitro
limitations
Transporter assignment in rodents. Affinities are assay values, not human tissue concentrations, and renal handling was governed by other transporters in this model.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat transporter in CHO cells; mouse in vivo
plain_language
The drug does not simply diffuse into a cell; a named transporter carries it.
primary_references
[metformin-p12130709] Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. (2002). https://pubmed.ncbi.nlm.nih.gov/12130709/ DOI: 10.1124/jpet.102.034140
tissue_or_cell_type
Liver, small intestine and kidney
transport_effect
raises Time-dependent saturable metformin uptake in CHO cells with a Km of 377 micromolar.
transport_pool
the expressing cell Time-dependent saturable metformin uptake in CHO cells with a Km of 377 micromolar.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 60–71
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat Oct1-transfected CHO uptake kinetics and Oct1-knockout mouse tissue distribution · source_derived_draft · unverified_draft
### metformin-rat-oct1-uptake Rat Oct1 expression produced time-dependent and saturable metformin uptake in CHO cells, with a Km of 377 microM. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug does not simply diffuse into a cell; a named transporter carries it. organism: Rat transporter in CHO cells; mouse in vivo tissue_or_cell_type: Liver, small intestine and kidney experimental_model: Rat Oct1-transfected CHO uptake kinetics and Oct1-knockout mouse tissue distribution limitations: Transporter assignment in rodents. Affinities are assay values, not human tissue concentrations, and renal handling was governed by other transporters in this model. exposure: Intravenous metformin in Oct1(-/-) and Oct1(+/+) mice; buformin and phenformin compared in vitro evidence_span: {"source_cache": "artifacts/metformin-research/12130709.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b", "start_char": 0, "end_char": 1411, "text_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b"} [metformin-p12130709] Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. (2002). https://pubmed.ncbi.nlm.nih.gov/12130709/ DOI: 10.1124/jpet.102.034140
Complete structured claim and evidence
Rat Oct1 also transported buformin with a Km of 49 microM, a higher affinity than for metformin.
Rat organic cation transporter 1 / Oct1 → Buformin source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/12130709.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b", "start_char": 0, "end_char": 1411, "text_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b"}
experimental_model
Rat Oct1-transfected CHO uptake kinetics and Oct1-knockout mouse tissue distribution
exposure
Intravenous metformin in Oct1(-/-) and Oct1(+/+) mice; buformin and phenformin compared in vitro
limitations
Transporter assignment in rodents. Affinities are assay values, not human tissue concentrations, and renal handling was governed by other transporters in this model.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat transporter in CHO cells; mouse in vivo
plain_language
Other biguanides use the same carrier, and they bind it more tightly than metformin does.
primary_references
[metformin-p12130709] Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. (2002). https://pubmed.ncbi.nlm.nih.gov/12130709/ DOI: 10.1124/jpet.102.034140
tissue_or_cell_type
Liver, small intestine and kidney
transport_effect
raises Buformin transported into the expressing cell with a Km of 49 micromolar.
transport_pool
the expressing cell Buformin transported into the expressing cell with a Km of 49 micromolar.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 73–84
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat Oct1-transfected CHO uptake kinetics and Oct1-knockout mouse tissue distribution · source_derived_draft · unverified_draft
### metformin-rat-oct1-buformin Rat Oct1 also transported buformin with a Km of 49 microM, a higher affinity than for metformin. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Other biguanides use the same carrier, and they bind it more tightly than metformin does. organism: Rat transporter in CHO cells; mouse in vivo tissue_or_cell_type: Liver, small intestine and kidney experimental_model: Rat Oct1-transfected CHO uptake kinetics and Oct1-knockout mouse tissue distribution limitations: Transporter assignment in rodents. Affinities are assay values, not human tissue concentrations, and renal handling was governed by other transporters in this model. exposure: Intravenous metformin in Oct1(-/-) and Oct1(+/+) mice; buformin and phenformin compared in vitro evidence_span: {"source_cache": "artifacts/metformin-research/12130709.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b", "start_char": 0, "end_char": 1411, "text_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b"} [metformin-p12130709] Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. (2002). https://pubmed.ncbi.nlm.nih.gov/12130709/ DOI: 10.1124/jpet.102.034140
Complete structured claim and evidence
Rat Oct1 also transported phenformin with a Km of 16 microM, a higher affinity than for metformin.
Rat organic cation transporter 1 / Oct1 → Phenformin source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/12130709.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b", "start_char": 0, "end_char": 1411, "text_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b"}
experimental_model
Rat Oct1-transfected CHO uptake kinetics and Oct1-knockout mouse tissue distribution
exposure
Intravenous metformin in Oct1(-/-) and Oct1(+/+) mice; buformin and phenformin compared in vitro
limitations
Transporter assignment in rodents. Affinities are assay values, not human tissue concentrations, and renal handling was governed by other transporters in this model.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat transporter in CHO cells; mouse in vivo
plain_language
Other biguanides use the same carrier, and they bind it more tightly than metformin does.
primary_references
[metformin-p12130709] Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. (2002). https://pubmed.ncbi.nlm.nih.gov/12130709/ DOI: 10.1124/jpet.102.034140
tissue_or_cell_type
Liver, small intestine and kidney
transport_effect
raises Phenformin transported into the expressing cell with a Km of 16 micromolar.
transport_pool
the expressing cell Phenformin transported into the expressing cell with a Km of 16 micromolar.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 86–97
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat Oct1-transfected CHO uptake kinetics and Oct1-knockout mouse tissue distribution · source_derived_draft · unverified_draft
### metformin-rat-oct1-phenformin Rat Oct1 also transported phenformin with a Km of 16 microM, a higher affinity than for metformin. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Other biguanides use the same carrier, and they bind it more tightly than metformin does. organism: Rat transporter in CHO cells; mouse in vivo tissue_or_cell_type: Liver, small intestine and kidney experimental_model: Rat Oct1-transfected CHO uptake kinetics and Oct1-knockout mouse tissue distribution limitations: Transporter assignment in rodents. Affinities are assay values, not human tissue concentrations, and renal handling was governed by other transporters in this model. exposure: Intravenous metformin in Oct1(-/-) and Oct1(+/+) mice; buformin and phenformin compared in vitro evidence_span: {"source_cache": "artifacts/metformin-research/12130709.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b", "start_char": 0, "end_char": 1411, "text_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b"} [metformin-p12130709] Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. (2002). https://pubmed.ncbi.nlm.nih.gov/12130709/ DOI: 10.1124/jpet.102.034140
Complete structured claim and evidence
Liver distribution of metformin in Oct1(-/-) mice was more than 30-fold lower than in Oct1(+/+) mice and was accounted for by the extracellular space.
Experimental Oct1-null mouse genotype → Hepatic metformin accumulation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/12130709.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b", "start_char": 0, "end_char": 1411, "text_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b"}
experimental_model
Rat Oct1-transfected CHO uptake kinetics and Oct1-knockout mouse tissue distribution
exposure
Intravenous metformin in Oct1(-/-) and Oct1(+/+) mice; buformin and phenformin compared in vitro
limitations
Transporter assignment in rodents. Affinities are assay values, not human tissue concentrations, and renal handling was governed by other transporters in this model.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat transporter in CHO cells; mouse in vivo
plain_language
Without the transporter the drug stays outside the liver cells rather than inside them.
primary_references
[metformin-p12130709] Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. (2002). https://pubmed.ncbi.nlm.nih.gov/12130709/ DOI: 10.1124/jpet.102.034140
tissue_or_cell_type
Liver, small intestine and kidney
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 99–110
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat Oct1-transfected CHO uptake kinetics and Oct1-knockout mouse tissue distribution · source_derived_draft · unverified_draft
### metformin-oct1-null-liver Liver distribution of metformin in Oct1(-/-) mice was more than 30-fold lower than in Oct1(+/+) mice and was accounted for by the extracellular space. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Without the transporter the drug stays outside the liver cells rather than inside them. organism: Rat transporter in CHO cells; mouse in vivo tissue_or_cell_type: Liver, small intestine and kidney experimental_model: Rat Oct1-transfected CHO uptake kinetics and Oct1-knockout mouse tissue distribution limitations: Transporter assignment in rodents. Affinities are assay values, not human tissue concentrations, and renal handling was governed by other transporters in this model. exposure: Intravenous metformin in Oct1(-/-) and Oct1(+/+) mice; buformin and phenformin compared in vitro evidence_span: {"source_cache": "artifacts/metformin-research/12130709.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b", "start_char": 0, "end_char": 1411, "text_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b"} [metformin-p12130709] Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. (2002). https://pubmed.ncbi.nlm.nih.gov/12130709/ DOI: 10.1124/jpet.102.034140
Complete structured claim and evidence
Distribution of metformin to the small intestine was also decreased in Oct1(-/-) mice, whereas renal distribution and urinary excretion differed only minimally.
Experimental Oct1-null mouse genotype → Small-intestinal tissue metformin accumulation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/12130709.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b", "start_char": 0, "end_char": 1411, "text_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b"}
experimental_model
Rat Oct1-transfected CHO uptake kinetics and Oct1-knockout mouse tissue distribution
exposure
Intravenous metformin in Oct1(-/-) and Oct1(+/+) mice; buformin and phenformin compared in vitro
limitations
Transporter assignment in rodents. Affinities are assay values, not human tissue concentrations, and renal handling was governed by other transporters in this model.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat transporter in CHO cells; mouse in vivo
plain_language
The same carrier matters in the gut wall, while the kidney uses different routes.
primary_references
[metformin-p12130709] Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. (2002). https://pubmed.ncbi.nlm.nih.gov/12130709/ DOI: 10.1124/jpet.102.034140
tissue_or_cell_type
Liver, small intestine and kidney
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 112–123
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat Oct1-transfected CHO uptake kinetics and Oct1-knockout mouse tissue distribution · source_derived_draft · unverified_draft
### metformin-oct1-null-intestine Distribution of metformin to the small intestine was also decreased in Oct1(-/-) mice, whereas renal distribution and urinary excretion differed only minimally. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The same carrier matters in the gut wall, while the kidney uses different routes. organism: Rat transporter in CHO cells; mouse in vivo tissue_or_cell_type: Liver, small intestine and kidney experimental_model: Rat Oct1-transfected CHO uptake kinetics and Oct1-knockout mouse tissue distribution limitations: Transporter assignment in rodents. Affinities are assay values, not human tissue concentrations, and renal handling was governed by other transporters in this model. exposure: Intravenous metformin in Oct1(-/-) and Oct1(+/+) mice; buformin and phenformin compared in vitro evidence_span: {"source_cache": "artifacts/metformin-research/12130709.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b", "start_char": 0, "end_char": 1411, "text_sha256": "2bd4b1f58d2b0b30807a1a521298f4713a86049a53f62cfc5d6463927644d82b"} [metformin-p12130709] Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. (2002). https://pubmed.ncbi.nlm.nih.gov/12130709/ DOI: 10.1124/jpet.102.034140
Complete structured claim and evidence
Seven non-synonymous OCT1 polymorphisms showed reduced metformin uptake, including OCT1-420del, which has normal activity for model substrates.
Human OCT1 reduced-function coding variants in the 2007 and 2015 studies → Human OCT1-mediated cellular metformin uptake source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/17476361.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1", "start_char": 0, "end_char": 1361, "text_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1"}
experimental_model
Oct1-knockout mouse hepatocytes and mice, human variant uptake assays, and human glucose-tolerance studies
exposure
Metformin in Oct1-deficient mice; seven non-synonymous human OCT1 variants; clinical glucose tolerance tests
limitations
Pharmacogenetic association with drug response, not proof that OCT1 genotype should guide prescribing.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse and human, stated per record
plain_language
A transporter can look normal on a test substrate and still handle this drug poorly.
primary_references
[metformin-p17476361] Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. (2007). https://pubmed.ncbi.nlm.nih.gov/17476361/ DOI: 10.1172/jci30558
tissue_or_cell_type
Hepatocytes and whole body
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 125–136
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oct1-knockout mouse hepatocytes and mice, human variant uptake assays, and human glucose-tolerance studies · source_derived_draft · unverified_draft
### metformin-oct1-variants-uptake Seven non-synonymous OCT1 polymorphisms showed reduced metformin uptake, including OCT1-420del, which has normal activity for model substrates. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: A transporter can look normal on a test substrate and still handle this drug poorly. organism: Mouse and human, stated per record tissue_or_cell_type: Hepatocytes and whole body experimental_model: Oct1-knockout mouse hepatocytes and mice, human variant uptake assays, and human glucose-tolerance studies limitations: Pharmacogenetic association with drug response, not proof that OCT1 genotype should guide prescribing. exposure: Metformin in Oct1-deficient mice; seven non-synonymous human OCT1 variants; clinical glucose tolerance tests evidence_span: {"source_cache": "artifacts/metformin-research/17476361.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1", "start_char": 0, "end_char": 1361, "text_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1"} [metformin-p17476361] Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. (2007). https://pubmed.ncbi.nlm.nih.gov/17476361/ DOI: 10.1172/jci30558
Complete structured claim and evidence
In mouse hepatocytes, deletion of Oct1 reduced the effect of metformin on AMPK phosphorylation and on gluconeogenesis.
Experimental Oct1-null mouse genotype → AMP-activated protein kinase complexes source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/17476361.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1", "start_char": 0, "end_char": 1361, "text_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1"}
experimental_model
Oct1-knockout mouse hepatocytes and mice, human variant uptake assays, and human glucose-tolerance studies
exposure
Metformin in Oct1-deficient mice; seven non-synonymous human OCT1 variants; clinical glucose tolerance tests
limitations
Pharmacogenetic association with drug response, not proof that OCT1 genotype should guide prescribing.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse and human, stated per record
plain_language
If the drug cannot get in, the energy sensor inside is not switched on.
primary_references
[metformin-p17476361] Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. (2007). https://pubmed.ncbi.nlm.nih.gov/17476361/ DOI: 10.1172/jci30558
tissue_or_cell_type
Hepatocytes and whole body
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 138–149
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oct1-knockout mouse hepatocytes and mice, human variant uptake assays, and human glucose-tolerance studies · source_derived_draft · unverified_draft
### metformin-oct1-null-ampk In mouse hepatocytes, deletion of Oct1 reduced the effect of metformin on AMPK phosphorylation and on gluconeogenesis. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: If the drug cannot get in, the energy sensor inside is not switched on. organism: Mouse and human, stated per record tissue_or_cell_type: Hepatocytes and whole body experimental_model: Oct1-knockout mouse hepatocytes and mice, human variant uptake assays, and human glucose-tolerance studies limitations: Pharmacogenetic association with drug response, not proof that OCT1 genotype should guide prescribing. exposure: Metformin in Oct1-deficient mice; seven non-synonymous human OCT1 variants; clinical glucose tolerance tests evidence_span: {"source_cache": "artifacts/metformin-research/17476361.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1", "start_char": 0, "end_char": 1361, "text_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1"} [metformin-p17476361] Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. (2007). https://pubmed.ncbi.nlm.nih.gov/17476361/ DOI: 10.1172/jci30558
Complete structured claim and evidence
In Oct1-deficient mice the glucose-lowering effects of metformin were completely abolished.
Experimental Oct1-null mouse genotype → Serum glucose concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/17476361.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1", "start_char": 0, "end_char": 1361, "text_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1"}
experimental_model
Oct1-knockout mouse hepatocytes and mice, human variant uptake assays, and human glucose-tolerance studies
exposure
Metformin in Oct1-deficient mice; seven non-synonymous human OCT1 variants; clinical glucose tolerance tests
limitations
Pharmacogenetic association with drug response, not proof that OCT1 genotype should guide prescribing.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse and human, stated per record
plain_language
The whole glucose effect depended on the drug reaching the liver in this model.
primary_references
[metformin-p17476361] Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. (2007). https://pubmed.ncbi.nlm.nih.gov/17476361/ DOI: 10.1172/jci30558
tissue_or_cell_type
Hepatocytes and whole body
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 151–162
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oct1-knockout mouse hepatocytes and mice, human variant uptake assays, and human glucose-tolerance studies · source_derived_draft · unverified_draft
### metformin-oct1-null-glucose In Oct1-deficient mice the glucose-lowering effects of metformin were completely abolished. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The whole glucose effect depended on the drug reaching the liver in this model. organism: Mouse and human, stated per record tissue_or_cell_type: Hepatocytes and whole body experimental_model: Oct1-knockout mouse hepatocytes and mice, human variant uptake assays, and human glucose-tolerance studies limitations: Pharmacogenetic association with drug response, not proof that OCT1 genotype should guide prescribing. exposure: Metformin in Oct1-deficient mice; seven non-synonymous human OCT1 variants; clinical glucose tolerance tests evidence_span: {"source_cache": "artifacts/metformin-research/17476361.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1", "start_char": 0, "end_char": 1361, "text_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1"} [metformin-p17476361] Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. (2007). https://pubmed.ncbi.nlm.nih.gov/17476361/ DOI: 10.1172/jci30558
Complete structured claim and evidence
In clinical studies the effects of metformin in glucose tolerance tests were significantly smaller in people carrying reduced-function OCT1 polymorphisms.
Human OCT1 reduced-function coding variants in the 2007 and 2015 studies → Serum glucose concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/17476361.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1", "start_char": 0, "end_char": 1361, "text_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1"}
experimental_model
Oct1-knockout mouse hepatocytes and mice, human variant uptake assays, and human glucose-tolerance studies
exposure
Metformin in Oct1-deficient mice; seven non-synonymous human OCT1 variants; clinical glucose tolerance tests
limitations
Pharmacogenetic association with drug response, not proof that OCT1 genotype should guide prescribing.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse and human, stated per record
plain_language
People who carry a weaker version of the transporter responded less to the drug.
primary_references
[metformin-p17476361] Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. (2007). https://pubmed.ncbi.nlm.nih.gov/17476361/ DOI: 10.1172/jci30558
tissue_or_cell_type
Hepatocytes and whole body
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 164–175
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oct1-knockout mouse hepatocytes and mice, human variant uptake assays, and human glucose-tolerance studies · source_derived_draft · unverified_draft
### metformin-oct1-variants-response In clinical studies the effects of metformin in glucose tolerance tests were significantly smaller in people carrying reduced-function OCT1 polymorphisms. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: People who carry a weaker version of the transporter responded less to the drug. organism: Mouse and human, stated per record tissue_or_cell_type: Hepatocytes and whole body experimental_model: Oct1-knockout mouse hepatocytes and mice, human variant uptake assays, and human glucose-tolerance studies limitations: Pharmacogenetic association with drug response, not proof that OCT1 genotype should guide prescribing. exposure: Metformin in Oct1-deficient mice; seven non-synonymous human OCT1 variants; clinical glucose tolerance tests evidence_span: {"source_cache": "artifacts/metformin-research/17476361.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1", "start_char": 0, "end_char": 1361, "text_sha256": "e8d05affc6b49c7273e21804d2ad9092ca826c8d81431ee093c6215f18f0bce1"} [metformin-p17476361] Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. (2007). https://pubmed.ncbi.nlm.nih.gov/17476361/ DOI: 10.1172/jci30558
Complete structured claim and evidence
Human and rat OCT2 had roughly 10-fold and 100-fold greater capacity to transport metformin than OCT1 in the transfected-cell comparison.
Human organic cation transporter 2 / OCT2 / SLC22A2 → Metformin source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/16272756.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9da4317752d37da62129139affd33016e879d367c4cf58cfefb9200c663fe4ed", "start_char": 0, "end_char": 1284, "text_sha256": "9da4317752d37da62129139affd33016e879d367c4cf58cfefb9200c663fe4ed"}
experimental_model
Human and rat transporter cDNA transfection into HEK293 cells with rat tissue distribution
exposure
Metformin uptake across five renal organic ion transporters and tissue accumulation in male rats
limitations
Relative capacities are transfection-dependent; the study itself notes that plasmid amount changes the apparent kinetics.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human and rat transporters; rat in vivo
plain_language
The kidney transporter moves far more of the drug than the liver one does.
primary_references
[metformin-p16272756] Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. (2005). https://pubmed.ncbi.nlm.nih.gov/16272756/ DOI: 10.2133/dmpk.20.379
tissue_or_cell_type
Kidney and liver
transport_effect
raises A transfected-cell capacity comparison, measured as metformin carried into the cell.
transport_pool
the expressing cell A transfected-cell capacity comparison, measured as metformin carried into the cell.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 177–188
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human and rat transporter cDNA transfection into HEK293 cells with rat tissue distribution · source_derived_draft · unverified_draft
### metformin-oct2-capacity Human and rat OCT2 had roughly 10-fold and 100-fold greater capacity to transport metformin than OCT1 in the transfected-cell comparison. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The kidney transporter moves far more of the drug than the liver one does. organism: Human and rat transporters; rat in vivo tissue_or_cell_type: Kidney and liver experimental_model: Human and rat transporter cDNA transfection into HEK293 cells with rat tissue distribution limitations: Relative capacities are transfection-dependent; the study itself notes that plasmid amount changes the apparent kinetics. exposure: Metformin uptake across five renal organic ion transporters and tissue accumulation in male rats evidence_span: {"source_cache": "artifacts/metformin-research/16272756.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9da4317752d37da62129139affd33016e879d367c4cf58cfefb9200c663fe4ed", "start_char": 0, "end_char": 1284, "text_sha256": "9da4317752d37da62129139affd33016e879d367c4cf58cfefb9200c663fe4ed"} [metformin-p16272756] Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. (2005). https://pubmed.ncbi.nlm.nih.gov/16272756/ DOI: 10.2133/dmpk.20.379
Complete structured claim and evidence
Renal OCT2 expression was the key factor controlling concentrative accumulation of metformin in the rat kidney.
Human organic cation transporter 2 / OCT2 / SLC22A2 → Kidney metformin concentration source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/16272756.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9da4317752d37da62129139affd33016e879d367c4cf58cfefb9200c663fe4ed", "start_char": 0, "end_char": 1284, "text_sha256": "9da4317752d37da62129139affd33016e879d367c4cf58cfefb9200c663fe4ed"}
experimental_model
Human and rat transporter cDNA transfection into HEK293 cells with rat tissue distribution
exposure
Metformin uptake across five renal organic ion transporters and tissue accumulation in male rats
limitations
Relative capacities are transfection-dependent; the study itself notes that plasmid amount changes the apparent kinetics.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat
plain_language
Kidney tissue concentrates the drug because of this transporter.
primary_references
[metformin-p16272756] Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. (2005). https://pubmed.ncbi.nlm.nih.gov/16272756/ DOI: 10.2133/dmpk.20.379
tissue_or_cell_type
Kidney and liver
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 190–201
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human and rat transporter cDNA transfection into HEK293 cells with rat tissue distribution · source_derived_draft · unverified_draft
### metformin-oct2-kidney-accumulation Renal OCT2 expression was the key factor controlling concentrative accumulation of metformin in the rat kidney. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Kidney tissue concentrates the drug because of this transporter. organism: Rat tissue_or_cell_type: Kidney and liver experimental_model: Human and rat transporter cDNA transfection into HEK293 cells with rat tissue distribution limitations: Relative capacities are transfection-dependent; the study itself notes that plasmid amount changes the apparent kinetics. exposure: Metformin uptake across five renal organic ion transporters and tissue accumulation in male rats evidence_span: {"source_cache": "artifacts/metformin-research/16272756.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9da4317752d37da62129139affd33016e879d367c4cf58cfefb9200c663fe4ed", "start_char": 0, "end_char": 1284, "text_sha256": "9da4317752d37da62129139affd33016e879d367c4cf58cfefb9200c663fe4ed"} [metformin-p16272756] Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. (2005). https://pubmed.ncbi.nlm.nih.gov/16272756/ DOI: 10.2133/dmpk.20.379
Complete structured claim and evidence
MATE1 transported metformin in a proton-gradient-dependent manner, with a Michaelis-Menten constant of 0.78 mM.
Human multidrug and toxin extrusion protein 1 / MATE1 / SLC47A1 → Metformin source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/17509534.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2660dd67050133c958e8aa13cf2ac6b574bd56fcefa116d3a73c3db4a7cea44", "start_char": 0, "end_char": 1841, "text_sha256": "d2660dd67050133c958e8aa13cf2ac6b574bd56fcefa116d3a73c3db4a7cea44"}
experimental_model
MATE1 and MATE2-K cDNA transfection into HEK293 cells with kinetic analysis
exposure
Oppositely directed proton gradient; Michaelis-Menten constants for ten substrates
limitations
Millimolar affinities in a transfected system. Substrate overlap describes a shared route, not a predicted clinical interaction.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human transporters
plain_language
A proton-driven pump moves the drug out of the cell into urine.
primary_references
[metformin-p17509534] Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. (2007). https://pubmed.ncbi.nlm.nih.gov/17509534/ DOI: 10.1016/j.bcp.2007.04.010
tissue_or_cell_type
Renal brush-border membrane transport
transport_effect
depends Recorded as proton-gradient-dependent transport. MATE carriers run either way with the proton gradient, and the assay's pool and the extrusion role move opposite ways.
transport_pool
the renal tubular cell interior Recorded as proton-gradient-dependent transport. MATE carriers run either way with the proton gradient, and the assay's pool and the extrusion role move opposite ways.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 203–214
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · MATE1 and MATE2-K cDNA transfection into HEK293 cells with kinetic analysis · source_derived_draft · unverified_draft
### metformin-mate1-metformin MATE1 transported metformin in a proton-gradient-dependent manner, with a Michaelis-Menten constant of 0.78 mM. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: A proton-driven pump moves the drug out of the cell into urine. organism: Human transporters tissue_or_cell_type: Renal brush-border membrane transport experimental_model: MATE1 and MATE2-K cDNA transfection into HEK293 cells with kinetic analysis limitations: Millimolar affinities in a transfected system. Substrate overlap describes a shared route, not a predicted clinical interaction. exposure: Oppositely directed proton gradient; Michaelis-Menten constants for ten substrates evidence_span: {"source_cache": "artifacts/metformin-research/17509534.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2660dd67050133c958e8aa13cf2ac6b574bd56fcefa116d3a73c3db4a7cea44", "start_char": 0, "end_char": 1841, "text_sha256": "d2660dd67050133c958e8aa13cf2ac6b574bd56fcefa116d3a73c3db4a7cea44"} [metformin-p17509534] Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. (2007). https://pubmed.ncbi.nlm.nih.gov/17509534/ DOI: 10.1016/j.bcp.2007.04.010
Complete structured claim and evidence
MATE2-K transported metformin in a proton-gradient-dependent manner, with a Michaelis-Menten constant of 1.98 mM.
Human kidney-specific multidrug and toxin extrusion protein 2 / MATE2-K / SLC47A2 → Metformin source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/17509534.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2660dd67050133c958e8aa13cf2ac6b574bd56fcefa116d3a73c3db4a7cea44", "start_char": 0, "end_char": 1841, "text_sha256": "d2660dd67050133c958e8aa13cf2ac6b574bd56fcefa116d3a73c3db4a7cea44"}
experimental_model
MATE1 and MATE2-K cDNA transfection into HEK293 cells with kinetic analysis
exposure
Oppositely directed proton gradient; Michaelis-Menten constants for ten substrates
limitations
Millimolar affinities in a transfected system. Substrate overlap describes a shared route, not a predicted clinical interaction.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human transporters
plain_language
A proton-driven pump moves the drug out of the cell into urine.
primary_references
[metformin-p17509534] Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. (2007). https://pubmed.ncbi.nlm.nih.gov/17509534/ DOI: 10.1016/j.bcp.2007.04.010
tissue_or_cell_type
Renal brush-border membrane transport
transport_effect
depends Recorded as proton-gradient-dependent transport. MATE carriers run either way with the proton gradient, and the assay's pool and the extrusion role move opposite ways.
transport_pool
the renal tubular cell interior Recorded as proton-gradient-dependent transport. MATE carriers run either way with the proton gradient, and the assay's pool and the extrusion role move opposite ways.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 216–227
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · MATE1 and MATE2-K cDNA transfection into HEK293 cells with kinetic analysis · source_derived_draft · unverified_draft
### metformin-mate2k-metformin MATE2-K transported metformin in a proton-gradient-dependent manner, with a Michaelis-Menten constant of 1.98 mM. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: A proton-driven pump moves the drug out of the cell into urine. organism: Human transporters tissue_or_cell_type: Renal brush-border membrane transport experimental_model: MATE1 and MATE2-K cDNA transfection into HEK293 cells with kinetic analysis limitations: Millimolar affinities in a transfected system. Substrate overlap describes a shared route, not a predicted clinical interaction. exposure: Oppositely directed proton gradient; Michaelis-Menten constants for ten substrates evidence_span: {"source_cache": "artifacts/metformin-research/17509534.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2660dd67050133c958e8aa13cf2ac6b574bd56fcefa116d3a73c3db4a7cea44", "start_char": 0, "end_char": 1841, "text_sha256": "d2660dd67050133c958e8aa13cf2ac6b574bd56fcefa116d3a73c3db4a7cea44"} [metformin-p17509534] Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. (2007). https://pubmed.ncbi.nlm.nih.gov/17509534/ DOI: 10.1016/j.bcp.2007.04.010
Complete structured claim and evidence
MATE1 and MATE2-K together mediate tubular secretion of intracellular ionic compounds across the kidney brush-border membranes.
Human multidrug and toxin extrusion protein 1 / MATE1 / SLC47A1 → MATE-mediated metformin efflux across brush-border membranes source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/17509534.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2660dd67050133c958e8aa13cf2ac6b574bd56fcefa116d3a73c3db4a7cea44", "start_char": 0, "end_char": 1841, "text_sha256": "d2660dd67050133c958e8aa13cf2ac6b574bd56fcefa116d3a73c3db4a7cea44"}
experimental_model
MATE1 and MATE2-K cDNA transfection into HEK293 cells with kinetic analysis
exposure
Oppositely directed proton gradient; Michaelis-Menten constants for ten substrates
limitations
Millimolar affinities in a transfected system. Substrate overlap describes a shared route, not a predicted clinical interaction.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human transporters
plain_language
Entry and exit are separate steps handled by different proteins.
primary_references
[metformin-p17509534] Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. (2007). https://pubmed.ncbi.nlm.nih.gov/17509534/ DOI: 10.1016/j.bcp.2007.04.010
tissue_or_cell_type
Renal brush-border membrane transport
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 229–240
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · MATE1 and MATE2-K cDNA transfection into HEK293 cells with kinetic analysis · source_derived_draft · unverified_draft
### metformin-mate-detoxication MATE1 and MATE2-K together mediate tubular secretion of intracellular ionic compounds across the kidney brush-border membranes. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Entry and exit are separate steps handled by different proteins. organism: Human transporters tissue_or_cell_type: Renal brush-border membrane transport experimental_model: MATE1 and MATE2-K cDNA transfection into HEK293 cells with kinetic analysis limitations: Millimolar affinities in a transfected system. Substrate overlap describes a shared route, not a predicted clinical interaction. exposure: Oppositely directed proton gradient; Michaelis-Menten constants for ten substrates evidence_span: {"source_cache": "artifacts/metformin-research/17509534.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2660dd67050133c958e8aa13cf2ac6b574bd56fcefa116d3a73c3db4a7cea44", "start_char": 0, "end_char": 1841, "text_sha256": "d2660dd67050133c958e8aa13cf2ac6b574bd56fcefa116d3a73c3db4a7cea44"} [metformin-p17509534] Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. (2007). https://pubmed.ncbi.nlm.nih.gov/17509534/ DOI: 10.1016/j.bcp.2007.04.010
Complete structured claim and evidence
hMATE2-K is expressed predominantly in the kidney and localises to the brush-border membranes of proximal tubules, where it transports metformin with a Km of 1.05 mM.
Human kidney-specific multidrug and toxin extrusion protein 2 / MATE2-K / SLC47A2 → Renal tubular secretion of metformin source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/16807400.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "681a4ea4ae958690a5a707397ee3a2b254ebeaab832292f14beea5716e58a9b2", "start_char": 0, "end_char": 1742, "text_sha256": "681a4ea4ae958690a5a707397ee3a2b254ebeaab832292f14beea5716e58a9b2"}
experimental_model
Cloning, expression and kinetic characterisation of hMATE2-K from human kidney
exposure
Proton-gradient-dependent antiport; ammonium-chloride-induced intracellular acidification
limitations
Kidney-specific expression and substrate list from a transfected system; thiamine appears in the same substrate list, which is an observation about the transporter, not a drug-nutrient competition measurement.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human transporter
plain_language
The exit route sits on the urine-facing side of the kidney tubule.
primary_references
[metformin-p16807400] Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. (2006). https://pubmed.ncbi.nlm.nih.gov/16807400/ DOI: 10.1681/asn.2006030205
tissue_or_cell_type
Renal proximal-tubule brush-border membrane
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 242–253
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cloning, expression and kinetic characterisation of hMATE2-K from human kidney · source_derived_draft · unverified_draft
### metformin-mate2k-kidney hMATE2-K is expressed predominantly in the kidney and localises to the brush-border membranes of proximal tubules, where it transports metformin with a Km of 1.05 mM. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The exit route sits on the urine-facing side of the kidney tubule. organism: Human transporter tissue_or_cell_type: Renal proximal-tubule brush-border membrane experimental_model: Cloning, expression and kinetic characterisation of hMATE2-K from human kidney limitations: Kidney-specific expression and substrate list from a transfected system; thiamine appears in the same substrate list, which is an observation about the transporter, not a drug-nutrient competition measurement. exposure: Proton-gradient-dependent antiport; ammonium-chloride-induced intracellular acidification evidence_span: {"source_cache": "artifacts/metformin-research/16807400.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "681a4ea4ae958690a5a707397ee3a2b254ebeaab832292f14beea5716e58a9b2", "start_char": 0, "end_char": 1742, "text_sha256": "681a4ea4ae958690a5a707397ee3a2b254ebeaab832292f14beea5716e58a9b2"} [metformin-p16807400] Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. (2006). https://pubmed.ncbi.nlm.nih.gov/16807400/ DOI: 10.1681/asn.2006030205
Complete structured claim and evidence
Intracellular acidification stimulated hMATE2-K-dependent transport of organic cations including metformin and thiamine.
Human kidney-specific multidrug and toxin extrusion protein 2 / MATE2-K / SLC47A2 → Thiamine (vitamin B1) source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/16807400.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "681a4ea4ae958690a5a707397ee3a2b254ebeaab832292f14beea5716e58a9b2", "start_char": 0, "end_char": 1742, "text_sha256": "681a4ea4ae958690a5a707397ee3a2b254ebeaab832292f14beea5716e58a9b2"}
experimental_model
Cloning, expression and kinetic characterisation of hMATE2-K from human kidney
exposure
Proton-gradient-dependent antiport; ammonium-chloride-induced intracellular acidification
limitations
Kidney-specific expression and substrate list from a transfected system; thiamine appears in the same substrate list, which is an observation about the transporter, not a drug-nutrient competition measurement.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human transporter
plain_language
The same exit pump also handles vitamin B1, so the drug and the vitamin share a route.
primary_references
[metformin-p16807400] Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. (2006). https://pubmed.ncbi.nlm.nih.gov/16807400/ DOI: 10.1681/asn.2006030205
tissue_or_cell_type
Renal proximal-tubule brush-border membrane
transport_effect
lowers Intracellular acidification stimulated the transport, which is the extrusion direction.
transport_pool
the renal tubular cell interior Intracellular acidification stimulated the transport, which is the extrusion direction.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 255–266
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cloning, expression and kinetic characterisation of hMATE2-K from human kidney · source_derived_draft · unverified_draft
### metformin-mate2k-thiamine-substrate Intracellular acidification stimulated hMATE2-K-dependent transport of organic cations including metformin and thiamine. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The same exit pump also handles vitamin B1, so the drug and the vitamin share a route. organism: Human transporter tissue_or_cell_type: Renal proximal-tubule brush-border membrane experimental_model: Cloning, expression and kinetic characterisation of hMATE2-K from human kidney limitations: Kidney-specific expression and substrate list from a transfected system; thiamine appears in the same substrate list, which is an observation about the transporter, not a drug-nutrient competition measurement. exposure: Proton-gradient-dependent antiport; ammonium-chloride-induced intracellular acidification evidence_span: {"source_cache": "artifacts/metformin-research/16807400.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "681a4ea4ae958690a5a707397ee3a2b254ebeaab832292f14beea5716e58a9b2", "start_char": 0, "end_char": 1742, "text_sha256": "681a4ea4ae958690a5a707397ee3a2b254ebeaab832292f14beea5716e58a9b2"} [metformin-p16807400] Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. (2006). https://pubmed.ncbi.nlm.nih.gov/16807400/ DOI: 10.1681/asn.2006030205
Complete structured claim and evidence
Renal clearance and renal secretory clearance of metformin in Mate1(-/-) mice were approximately 18% and 14% of those in wild-type mice.
Experimental Mate1-null mouse genotype → Renal tubular secretion of metformin source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/19332510.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "79d5ec9a2d5c447e349d0e00742a2f2a05a3c9f9581199c4dde1f9b7910c029c", "start_char": 0, "end_char": 1536, "text_sha256": "79d5ec9a2d5c447e349d0e00742a2f2a05a3c9f9581199c4dde1f9b7910c029c"}
experimental_model
Targeted disruption of the murine Mate1 gene with metformin pharmacokinetics
exposure
Single intravenous metformin 5 mg/kg in Mate1(-/-) and Mate1(+/+) mice
limitations
Mouse pharmacokinetics; it does not establish a human exposure threshold or a clinical toxicity risk.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse
plain_language
Removing the exit pump left most of the drug in the body.
primary_references
[metformin-p19332510] Targeted disruption of the multidrug and toxin extrusion 1 (mate1) gene in mice reduces renal secretion of metformin. (2009). https://pubmed.ncbi.nlm.nih.gov/19332510/ DOI: 10.1124/mol.109.056242
tissue_or_cell_type
Kidney and liver
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 268–279
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Targeted disruption of the murine Mate1 gene with metformin pharmacokinetics · source_derived_draft · unverified_draft
### metformin-mate1-null-clearance Renal clearance and renal secretory clearance of metformin in Mate1(-/-) mice were approximately 18% and 14% of those in wild-type mice. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Removing the exit pump left most of the drug in the body. organism: Mouse tissue_or_cell_type: Kidney and liver experimental_model: Targeted disruption of the murine Mate1 gene with metformin pharmacokinetics limitations: Mouse pharmacokinetics; it does not establish a human exposure threshold or a clinical toxicity risk. exposure: Single intravenous metformin 5 mg/kg in Mate1(-/-) and Mate1(+/+) mice evidence_span: {"source_cache": "artifacts/metformin-research/19332510.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "79d5ec9a2d5c447e349d0e00742a2f2a05a3c9f9581199c4dde1f9b7910c029c", "start_char": 0, "end_char": 1536, "text_sha256": "79d5ec9a2d5c447e349d0e00742a2f2a05a3c9f9581199c4dde1f9b7910c029c"} [metformin-p19332510] Targeted disruption of the multidrug and toxin extrusion 1 (mate1) gene in mice reduces renal secretion of metformin. (2009). https://pubmed.ncbi.nlm.nih.gov/19332510/ DOI: 10.1124/mol.109.056242
Complete structured claim and evidence
Mate1(-/-) mice showed a two-fold increase in the area under the blood metformin concentration-time curve.
Experimental Mate1-null mouse genotype → Plasma metformin exposure source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/19332510.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "79d5ec9a2d5c447e349d0e00742a2f2a05a3c9f9581199c4dde1f9b7910c029c", "start_char": 0, "end_char": 1536, "text_sha256": "79d5ec9a2d5c447e349d0e00742a2f2a05a3c9f9581199c4dde1f9b7910c029c"}
experimental_model
Targeted disruption of the murine Mate1 gene with metformin pharmacokinetics
exposure
Single intravenous metformin 5 mg/kg in Mate1(-/-) and Mate1(+/+) mice
limitations
Mouse pharmacokinetics; it does not establish a human exposure threshold or a clinical toxicity risk.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse
plain_language
Blood levels rise when the exit route is gone.
primary_references
[metformin-p19332510] Targeted disruption of the multidrug and toxin extrusion 1 (mate1) gene in mice reduces renal secretion of metformin. (2009). https://pubmed.ncbi.nlm.nih.gov/19332510/ DOI: 10.1124/mol.109.056242
tissue_or_cell_type
Kidney and liver
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 281–292
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Targeted disruption of the murine Mate1 gene with metformin pharmacokinetics · source_derived_draft · unverified_draft
### metformin-mate1-null-exposure Mate1(-/-) mice showed a two-fold increase in the area under the blood metformin concentration-time curve. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Blood levels rise when the exit route is gone. organism: Mouse tissue_or_cell_type: Kidney and liver experimental_model: Targeted disruption of the murine Mate1 gene with metformin pharmacokinetics limitations: Mouse pharmacokinetics; it does not establish a human exposure threshold or a clinical toxicity risk. exposure: Single intravenous metformin 5 mg/kg in Mate1(-/-) and Mate1(+/+) mice evidence_span: {"source_cache": "artifacts/metformin-research/19332510.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "79d5ec9a2d5c447e349d0e00742a2f2a05a3c9f9581199c4dde1f9b7910c029c", "start_char": 0, "end_char": 1536, "text_sha256": "79d5ec9a2d5c447e349d0e00742a2f2a05a3c9f9581199c4dde1f9b7910c029c"} [metformin-p19332510] Targeted disruption of the multidrug and toxin extrusion 1 (mate1) gene in mice reduces renal secretion of metformin. (2009). https://pubmed.ncbi.nlm.nih.gov/19332510/ DOI: 10.1124/mol.109.056242
Complete structured claim and evidence
The greatest accumulation of metformin occurred in small-intestinal tissue, exceeding 1000 micromol/kg wet weight at 0.5-2 hours, and intravenous metformin was also selectively accumulated there.
Metformin → Small-intestinal tissue metformin accumulation source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/8165821.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "60471d633165552bd5a5c4e9e5ff05686d069ceedfd367ca892828c66d116bbd", "start_char": 0, "end_char": 1265, "text_sha256": "60471d633165552bd5a5c4e9e5ff05686d069ceedfd367ca892828c66d116bbd"}
experimental_model
Radiolabelled metformin tissue distribution in normal and streptozotocin-diabetic mice
exposure
Oral metformin 50 mg/kg with 14C-metformin, and a separate intravenous study
limitations
Mouse tissue concentrations at a single dose level. Metformin is not metabolised, so these are distribution rather than metabolic findings.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse
plain_language
The gut wall holds far more of the drug than blood does, even when the dose is given by vein.
primary_references
[metformin-p8165821] Accumulation of metformin by tissues of the normal and diabetic mouse. (1994). https://pubmed.ncbi.nlm.nih.gov/8165821/ DOI: 10.3109/00498259409043220
tissue_or_cell_type
Small intestine, stomach, colon, salivary gland, kidney, liver, heart and skeletal muscle
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 294–305
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radiolabelled metformin tissue distribution in normal and streptozotocin-diabetic mice · source_derived_draft · unverified_draft
### metformin-intestinal-depot The greatest accumulation of metformin occurred in small-intestinal tissue, exceeding 1000 micromol/kg wet weight at 0.5-2 hours, and intravenous metformin was also selectively accumulated there. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The gut wall holds far more of the drug than blood does, even when the dose is given by vein. organism: Mouse tissue_or_cell_type: Small intestine, stomach, colon, salivary gland, kidney, liver, heart and skeletal muscle experimental_model: Radiolabelled metformin tissue distribution in normal and streptozotocin-diabetic mice limitations: Mouse tissue concentrations at a single dose level. Metformin is not metabolised, so these are distribution rather than metabolic findings. exposure: Oral metformin 50 mg/kg with 14C-metformin, and a separate intravenous study evidence_span: {"source_cache": "artifacts/metformin-research/8165821.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "60471d633165552bd5a5c4e9e5ff05686d069ceedfd367ca892828c66d116bbd", "start_char": 0, "end_char": 1265, "text_sha256": "60471d633165552bd5a5c4e9e5ff05686d069ceedfd367ca892828c66d116bbd"} [metformin-p8165821] Accumulation of metformin by tissues of the normal and diabetic mouse. (1994). https://pubmed.ncbi.nlm.nih.gov/8165821/ DOI: 10.3109/00498259409043220
Complete structured claim and evidence
Maximum metformin concentrations in the hepatic portal vein were higher than in the inferior vena cava in both normal and diabetic mice.
Metformin → Plasma metformin exposure source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/8165821.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "60471d633165552bd5a5c4e9e5ff05686d069ceedfd367ca892828c66d116bbd", "start_char": 0, "end_char": 1265, "text_sha256": "60471d633165552bd5a5c4e9e5ff05686d069ceedfd367ca892828c66d116bbd"}
experimental_model
Radiolabelled metformin tissue distribution in normal and streptozotocin-diabetic mice
exposure
Oral metformin 50 mg/kg with 14C-metformin, and a separate intravenous study
limitations
Mouse tissue concentrations at a single dose level. Metformin is not metabolised, so these are distribution rather than metabolic findings.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse
plain_language
The liver sees a higher concentration than the rest of the body.
primary_references
[metformin-p8165821] Accumulation of metformin by tissues of the normal and diabetic mouse. (1994). https://pubmed.ncbi.nlm.nih.gov/8165821/ DOI: 10.3109/00498259409043220
tissue_or_cell_type
Small intestine, stomach, colon, salivary gland, kidney, liver, heart and skeletal muscle
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 307–318
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radiolabelled metformin tissue distribution in normal and streptozotocin-diabetic mice · source_derived_draft · unverified_draft
### metformin-portal-gradient Maximum metformin concentrations in the hepatic portal vein were higher than in the inferior vena cava in both normal and diabetic mice. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The liver sees a higher concentration than the rest of the body. organism: Mouse tissue_or_cell_type: Small intestine, stomach, colon, salivary gland, kidney, liver, heart and skeletal muscle experimental_model: Radiolabelled metformin tissue distribution in normal and streptozotocin-diabetic mice limitations: Mouse tissue concentrations at a single dose level. Metformin is not metabolised, so these are distribution rather than metabolic findings. exposure: Oral metformin 50 mg/kg with 14C-metformin, and a separate intravenous study evidence_span: {"source_cache": "artifacts/metformin-research/8165821.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "60471d633165552bd5a5c4e9e5ff05686d069ceedfd367ca892828c66d116bbd", "start_char": 0, "end_char": 1265, "text_sha256": "60471d633165552bd5a5c4e9e5ff05686d069ceedfd367ca892828c66d116bbd"} [metformin-p8165821] Accumulation of metformin by tissues of the normal and diabetic mouse. (1994). https://pubmed.ncbi.nlm.nih.gov/8165821/ DOI: 10.3109/00498259409043220
Complete structured claim and evidence
The affinity for metformin was 4.9-fold lower in human than in mouse OCT1, giving a 6.5-fold lower intrinsic clearance and an estimated liver-to-blood partition coefficient of 3.34 in human compared with 14.4 in mouse.
Human organic cation transporter 1 / OCT1 / SLC22A1 → Mouse organic cation transporter 1 / Oct1 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/33037045.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "861e39b20a78d5d85a01c5de0febda8bf1c400de4fa8ef1e6944707521604c67", "start_char": 0, "end_char": 2296, "text_sha256": "861e39b20a78d5d85a01c5de0febda8bf1c400de4fa8ef1e6944707521604c67"}
experimental_model
Stably transfected HEK293 cells comparing human and mouse OCT1, with human-mouse chimeras and homology modelling
exposure
Metformin and thiamine uptake kinetics; transmembrane-helix substitutions
limitations
A species comparison of transport affinity. It limits how far mouse OCT1 results can be read as human ones; it is not itself a human tissue measurement.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human and mouse orthologues side by side
plain_language
The mouse liver concentrates this drug far more than the human liver does.
primary_references
[metformin-p33037045] Differences in Metformin and Thiamine Uptake between Human and Mouse Organic Cation Transporter 1: Structural Determinants and Potential Consequences for Intrahepatic Concentrations. (2020). https://pubmed.ncbi.nlm.nih.gov/33037045/ DOI: 10.1124/dmd.120.000170
tissue_or_cell_type
Hepatic uptake
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 320–331
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Stably transfected HEK293 cells comparing human and mouse OCT1, with human-mouse chimeras and homology modelling · source_derived_draft · unverified_draft
### metformin-oct1-species-metformin The affinity for metformin was 4.9-fold lower in human than in mouse OCT1, giving a 6.5-fold lower intrinsic clearance and an estimated liver-to-blood partition coefficient of 3.34 in human compared with 14.4 in mouse. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The mouse liver concentrates this drug far more than the human liver does. organism: Human and mouse orthologues side by side tissue_or_cell_type: Hepatic uptake experimental_model: Stably transfected HEK293 cells comparing human and mouse OCT1, with human-mouse chimeras and homology modelling limitations: A species comparison of transport affinity. It limits how far mouse OCT1 results can be read as human ones; it is not itself a human tissue measurement. exposure: Metformin and thiamine uptake kinetics; transmembrane-helix substitutions evidence_span: {"source_cache": "artifacts/metformin-research/33037045.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "861e39b20a78d5d85a01c5de0febda8bf1c400de4fa8ef1e6944707521604c67", "start_char": 0, "end_char": 2296, "text_sha256": "861e39b20a78d5d85a01c5de0febda8bf1c400de4fa8ef1e6944707521604c67"} [metformin-p33037045] Differences in Metformin and Thiamine Uptake between Human and Mouse Organic Cation Transporter 1: Structural Determinants and Potential Consequences for Intrahepatic Concentrations. (2020). https://pubmed.ncbi.nlm.nih.gov/33037045/ DOI: 10.1124/dmd.120.000170
Complete structured claim and evidence
The affinity for thiamine was 9.5-fold lower in human than in mouse OCT1.
Human organic cation transporter 1 / OCT1 / SLC22A1 → Mouse organic cation transporter 1 / Oct1 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/33037045.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "861e39b20a78d5d85a01c5de0febda8bf1c400de4fa8ef1e6944707521604c67", "start_char": 0, "end_char": 2296, "text_sha256": "861e39b20a78d5d85a01c5de0febda8bf1c400de4fa8ef1e6944707521604c67"}
experimental_model
Stably transfected HEK293 cells comparing human and mouse OCT1, with human-mouse chimeras and homology modelling
exposure
Metformin and thiamine uptake kinetics; transmembrane-helix substitutions
limitations
A species comparison of transport affinity. It limits how far mouse OCT1 results can be read as human ones; it is not itself a human tissue measurement.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human and mouse orthologues side by side
plain_language
The same species gap applies to the vitamin the transporter carries.
primary_references
[metformin-p33037045] Differences in Metformin and Thiamine Uptake between Human and Mouse Organic Cation Transporter 1: Structural Determinants and Potential Consequences for Intrahepatic Concentrations. (2020). https://pubmed.ncbi.nlm.nih.gov/33037045/ DOI: 10.1124/dmd.120.000170
tissue_or_cell_type
Hepatic uptake
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 333–344
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Stably transfected HEK293 cells comparing human and mouse OCT1, with human-mouse chimeras and homology modelling · source_derived_draft · unverified_draft
### metformin-oct1-species-thiamine The affinity for thiamine was 9.5-fold lower in human than in mouse OCT1. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The same species gap applies to the vitamin the transporter carries. organism: Human and mouse orthologues side by side tissue_or_cell_type: Hepatic uptake experimental_model: Stably transfected HEK293 cells comparing human and mouse OCT1, with human-mouse chimeras and homology modelling limitations: A species comparison of transport affinity. It limits how far mouse OCT1 results can be read as human ones; it is not itself a human tissue measurement. exposure: Metformin and thiamine uptake kinetics; transmembrane-helix substitutions evidence_span: {"source_cache": "artifacts/metformin-research/33037045.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "861e39b20a78d5d85a01c5de0febda8bf1c400de4fa8ef1e6944707521604c67", "start_char": 0, "end_char": 2296, "text_sha256": "861e39b20a78d5d85a01c5de0febda8bf1c400de4fa8ef1e6944707521604c67"} [metformin-p33037045] Differences in Metformin and Thiamine Uptake between Human and Mouse Organic Cation Transporter 1: Structural Determinants and Potential Consequences for Intrahepatic Concentrations. (2020). https://pubmed.ncbi.nlm.nih.gov/33037045/ DOI: 10.1124/dmd.120.000170
Complete structured claim and evidence
Simultaneous substitution of transmembrane helices TMH2 and TMH3 reversed the affinity for metformin in human-mouse chimeric OCT1.
The human OCT1 transmembrane helix 2 and 3 pair in the 2020 chimera study → Human OCT1-mediated cellular metformin uptake source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/33037045.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "861e39b20a78d5d85a01c5de0febda8bf1c400de4fa8ef1e6944707521604c67", "start_char": 0, "end_char": 2296, "text_sha256": "861e39b20a78d5d85a01c5de0febda8bf1c400de4fa8ef1e6944707521604c67"}
experimental_model
Stably transfected HEK293 cells comparing human and mouse OCT1, with human-mouse chimeras and homology modelling
exposure
Metformin and thiamine uptake kinetics; transmembrane-helix substitutions
limitations
A species comparison of transport affinity. It limits how far mouse OCT1 results can be read as human ones; it is not itself a human tissue measurement.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human and mouse orthologues side by side
plain_language
Two helices carry the species difference in how tightly the drug binds.
primary_references
[metformin-p33037045] Differences in Metformin and Thiamine Uptake between Human and Mouse Organic Cation Transporter 1: Structural Determinants and Potential Consequences for Intrahepatic Concentrations. (2020). https://pubmed.ncbi.nlm.nih.gov/33037045/ DOI: 10.1124/dmd.120.000170
tissue_or_cell_type
Hepatic uptake
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 346–357
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Stably transfected HEK293 cells comparing human and mouse OCT1, with human-mouse chimeras and homology modelling · source_derived_draft · unverified_draft
### metformin-oct1-tmh-determinant Simultaneous substitution of transmembrane helices TMH2 and TMH3 reversed the affinity for metformin in human-mouse chimeric OCT1. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Two helices carry the species difference in how tightly the drug binds. organism: Human and mouse orthologues side by side tissue_or_cell_type: Hepatic uptake experimental_model: Stably transfected HEK293 cells comparing human and mouse OCT1, with human-mouse chimeras and homology modelling limitations: A species comparison of transport affinity. It limits how far mouse OCT1 results can be read as human ones; it is not itself a human tissue measurement. exposure: Metformin and thiamine uptake kinetics; transmembrane-helix substitutions evidence_span: {"source_cache": "artifacts/metformin-research/33037045.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "861e39b20a78d5d85a01c5de0febda8bf1c400de4fa8ef1e6944707521604c67", "start_char": 0, "end_char": 2296, "text_sha256": "861e39b20a78d5d85a01c5de0febda8bf1c400de4fa8ef1e6944707521604c67"} [metformin-p33037045] Differences in Metformin and Thiamine Uptake between Human and Mouse Organic Cation Transporter 1: Structural Determinants and Potential Consequences for Intrahepatic Concentrations. (2020). https://pubmed.ncbi.nlm.nih.gov/33037045/ DOI: 10.1124/dmd.120.000170
Complete structured claim and evidence
Carriage of two reduced-function OCT1 alleles was associated with metformin intolerance (odds ratio 2.41), rising to 4.13 in people also taking OCT1-inhibiting drugs.
Human OCT1 reduced-function coding variants in the 2007 and 2015 studies → Gastrointestinal intolerance of metformin source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/25510240.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f8eaf94237679ed7436f863e210d17b13a7219d064e46e7da915ed083c5b04c9", "start_char": 0, "end_char": 1355, "text_sha256": "f8eaf94237679ed7436f863e210d17b13a7219d064e46e7da915ed083c5b04c9"}
experimental_model
Case-control comparison of 251 metformin-intolerant and 1915 tolerant people in GoDARTS
exposure
Prescribed metformin, OCT1 genotype and co-prescribed OCT1 inhibitors
limitations
An association study. Intolerance is self-evidently multifactorial, and the proposed intestinal-concentration mechanism was not measured here.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
The transporter that controls where the drug goes is also linked to who cannot tolerate it.
primary_references
[metformin-p25510240] Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study. (2015). https://pubmed.ncbi.nlm.nih.gov/25510240/ DOI: 10.2337/db14-1388
tissue_or_cell_type
Gastrointestinal tolerance
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 359–370
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Case-control comparison of 251 metformin-intolerant and 1915 tolerant people in GoDARTS · source_derived_draft · unverified_draft
### metformin-oct1-intolerance Carriage of two reduced-function OCT1 alleles was associated with metformin intolerance (odds ratio 2.41), rising to 4.13 in people also taking OCT1-inhibiting drugs. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The transporter that controls where the drug goes is also linked to who cannot tolerate it. organism: Human tissue_or_cell_type: Gastrointestinal tolerance experimental_model: Case-control comparison of 251 metformin-intolerant and 1915 tolerant people in GoDARTS limitations: An association study. Intolerance is self-evidently multifactorial, and the proposed intestinal-concentration mechanism was not measured here. exposure: Prescribed metformin, OCT1 genotype and co-prescribed OCT1 inhibitors evidence_span: {"source_cache": "artifacts/metformin-research/25510240.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f8eaf94237679ed7436f863e210d17b13a7219d064e46e7da915ed083c5b04c9", "start_char": 0, "end_char": 1355, "text_sha256": "f8eaf94237679ed7436f863e210d17b13a7219d064e46e7da915ed083c5b04c9"} [metformin-p25510240] Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study. (2015). https://pubmed.ncbi.nlm.nih.gov/25510240/ DOI: 10.2337/db14-1388
Complete structured claim and evidence
The SLC47A1 rs2289669 A allele was associated with a 0.30% larger HbA1c reduction per allele during metformin treatment.
Human multidrug and toxin extrusion protein 1 / MATE1 / SLC47A1 → Glycated hemoglobin / HbA1c concentration source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/19228809.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e90099f316586ff994eff67af58f075f654413a68d8605e869755e9b8c68adb3", "start_char": 0, "end_char": 1383, "text_sha256": "e90099f316586ff994eff67af58f075f654413a68d8605e869755e9b8c68adb3"}
experimental_model
Pharmacogenetic analysis of 116 incident metformin users in the Rotterdam Study
exposure
Twelve tagging SNPs in SLC47A1 against change in HbA1c
limitations
A preliminary association in a small sample that the authors say requires replication; no mechanism was measured.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
How quickly the body clears the drug tracks with how much it lowers long-term glucose.
primary_references
[metformin-p19228809] Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: a preliminary study. (2009). https://pubmed.ncbi.nlm.nih.gov/19228809/ DOI: 10.2337/db08-1028
tissue_or_cell_type
Glycaemic response
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 372–383
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Pharmacogenetic analysis of 116 incident metformin users in the Rotterdam Study · source_derived_draft · unverified_draft
### metformin-mate1-variant-response The SLC47A1 rs2289669 A allele was associated with a 0.30% larger HbA1c reduction per allele during metformin treatment. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: How quickly the body clears the drug tracks with how much it lowers long-term glucose. organism: Human tissue_or_cell_type: Glycaemic response experimental_model: Pharmacogenetic analysis of 116 incident metformin users in the Rotterdam Study limitations: A preliminary association in a small sample that the authors say requires replication; no mechanism was measured. exposure: Twelve tagging SNPs in SLC47A1 against change in HbA1c evidence_span: {"source_cache": "artifacts/metformin-research/19228809.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e90099f316586ff994eff67af58f075f654413a68d8605e869755e9b8c68adb3", "start_char": 0, "end_char": 1383, "text_sha256": "e90099f316586ff994eff67af58f075f654413a68d8605e869755e9b8c68adb3"} [metformin-p19228809] Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: a preliminary study. (2009). https://pubmed.ncbi.nlm.nih.gov/19228809/ DOI: 10.2337/db08-1028
Complete structured claim and evidence
Metformin inhibited mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration in human cancer cells.
Metformin → Mitochondrial complex I (NADH dehydrogenase) activity source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/24843020.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae", "start_char": 0, "end_char": 1142, "text_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae"}
experimental_model
Human cancer cells and mouse xenografts with the metformin-resistant yeast NDI1 as a genetic rescue
exposure
Metformin in the presence and absence of glucose; NDI1 overexpression
limitations
Cancer-cell concentrations are far above therapeutic plasma levels. The NDI1 rescue is strong evidence that the effects run through complex I in this model, not evidence of an antitumour indication.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human cells; mouse in vivo
plain_language
The drug slows the first station of the mitochondrial energy chain.
primary_references
[metformin-p24843020] Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. (2014). https://pubmed.ncbi.nlm.nih.gov/24843020/ DOI: 10.7554/elife.02242
tissue_or_cell_type
Cancer cells and tumours
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 385–396
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cancer cells and mouse xenografts with the metformin-resistant yeast NDI1 as a genetic rescue · source_derived_draft · unverified_draft
### metformin-complex-i-inhibition Metformin inhibited mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration in human cancer cells. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug slows the first station of the mitochondrial energy chain. organism: Human cells; mouse in vivo tissue_or_cell_type: Cancer cells and tumours experimental_model: Human cancer cells and mouse xenografts with the metformin-resistant yeast NDI1 as a genetic rescue limitations: Cancer-cell concentrations are far above therapeutic plasma levels. The NDI1 rescue is strong evidence that the effects run through complex I in this model, not evidence of an antitumour indication. exposure: Metformin in the presence and absence of glucose; NDI1 overexpression evidence_span: {"source_cache": "artifacts/metformin-research/24843020.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae", "start_char": 0, "end_char": 1142, "text_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae"} [metformin-p24843020] Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. (2014). https://pubmed.ncbi.nlm.nih.gov/24843020/ DOI: 10.7554/elife.02242
Complete structured claim and evidence
Cellular respiration fell with metformin, and cells relied exclusively on glycolysis for survival in its presence.
Metformin → Cellular mitochondrial respiration source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/24843020.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae", "start_char": 0, "end_char": 1142, "text_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae"}
experimental_model
Human cancer cells and mouse xenografts with the metformin-resistant yeast NDI1 as a genetic rescue
exposure
Metformin in the presence and absence of glucose; NDI1 overexpression
limitations
Cancer-cell concentrations are far above therapeutic plasma levels. The NDI1 rescue is strong evidence that the effects run through complex I in this model, not evidence of an antitumour indication.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human cells; mouse in vivo
plain_language
With the chain slowed, the cell falls back on the oxygen-free route.
primary_references
[metformin-p24843020] Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. (2014). https://pubmed.ncbi.nlm.nih.gov/24843020/ DOI: 10.7554/elife.02242
tissue_or_cell_type
Cancer cells and tumours
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 398–409
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cancer cells and mouse xenografts with the metformin-resistant yeast NDI1 as a genetic rescue · source_derived_draft · unverified_draft
### metformin-complex-i-respiration Cellular respiration fell with metformin, and cells relied exclusively on glycolysis for survival in its presence. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: With the chain slowed, the cell falls back on the oxygen-free route. organism: Human cells; mouse in vivo tissue_or_cell_type: Cancer cells and tumours experimental_model: Human cancer cells and mouse xenografts with the metformin-resistant yeast NDI1 as a genetic rescue limitations: Cancer-cell concentrations are far above therapeutic plasma levels. The NDI1 rescue is strong evidence that the effects run through complex I in this model, not evidence of an antitumour indication. exposure: Metformin in the presence and absence of glucose; NDI1 overexpression evidence_span: {"source_cache": "artifacts/metformin-research/24843020.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae", "start_char": 0, "end_char": 1142, "text_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae"} [metformin-p24843020] Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. (2014). https://pubmed.ncbi.nlm.nih.gov/24843020/ DOI: 10.7554/elife.02242
Complete structured claim and evidence
All of the effects of metformin were reversed when the metformin-resistant yeast NADH dehydrogenase NDI1 was expressed, in cells and in mouse tumours.
Human cancer cells expressing the metformin-resistant yeast NDI1 → Cancer-cell proliferation in the cited models source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/24843020.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae", "start_char": 0, "end_char": 1142, "text_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae"}
experimental_model
Human cancer cells and mouse xenografts with the metformin-resistant yeast NDI1 as a genetic rescue
exposure
Metformin in the presence and absence of glucose; NDI1 overexpression
limitations
Cancer-cell concentrations are far above therapeutic plasma levels. The NDI1 rescue is strong evidence that the effects run through complex I in this model, not evidence of an antitumour indication.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human cells; mouse in vivo
plain_language
Putting in a replacement for the blocked step removed the drug effect, which is what pins the effect to that step.
primary_references
[metformin-p24843020] Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. (2014). https://pubmed.ncbi.nlm.nih.gov/24843020/ DOI: 10.7554/elife.02242
tissue_or_cell_type
Cancer cells and tumours
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 411–422
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cancer cells and mouse xenografts with the metformin-resistant yeast NDI1 as a genetic rescue · source_derived_draft · unverified_draft
### metformin-ndi1-rescue All of the effects of metformin were reversed when the metformin-resistant yeast NADH dehydrogenase NDI1 was expressed, in cells and in mouse tumours. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Putting in a replacement for the blocked step removed the drug effect, which is what pins the effect to that step. organism: Human cells; mouse in vivo tissue_or_cell_type: Cancer cells and tumours experimental_model: Human cancer cells and mouse xenografts with the metformin-resistant yeast NDI1 as a genetic rescue limitations: Cancer-cell concentrations are far above therapeutic plasma levels. The NDI1 rescue is strong evidence that the effects run through complex I in this model, not evidence of an antitumour indication. exposure: Metformin in the presence and absence of glucose; NDI1 overexpression evidence_span: {"source_cache": "artifacts/metformin-research/24843020.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae", "start_char": 0, "end_char": 1142, "text_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae"} [metformin-p24843020] Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. (2014). https://pubmed.ncbi.nlm.nih.gov/24843020/ DOI: 10.7554/elife.02242
Complete structured claim and evidence
Metformin reduced hypoxic activation of hypoxia-inducible factor 1 in these cells.
Metformin → Hypoxic activation of hypoxia-inducible factor 1 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/24843020.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae", "start_char": 0, "end_char": 1142, "text_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae"}
experimental_model
Human cancer cells and mouse xenografts with the metformin-resistant yeast NDI1 as a genetic rescue
exposure
Metformin in the presence and absence of glucose; NDI1 overexpression
limitations
Cancer-cell concentrations are far above therapeutic plasma levels. The NDI1 rescue is strong evidence that the effects run through complex I in this model, not evidence of an antitumour indication.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human cells; mouse in vivo
plain_language
Slowing the chain also changed how the cell reads low oxygen.
primary_references
[metformin-p24843020] Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. (2014). https://pubmed.ncbi.nlm.nih.gov/24843020/ DOI: 10.7554/elife.02242
tissue_or_cell_type
Cancer cells and tumours
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 424–435
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cancer cells and mouse xenografts with the metformin-resistant yeast NDI1 as a genetic rescue · source_derived_draft · unverified_draft
### metformin-hif1-reduction Metformin reduced hypoxic activation of hypoxia-inducible factor 1 in these cells. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Slowing the chain also changed how the cell reads low oxygen. organism: Human cells; mouse in vivo tissue_or_cell_type: Cancer cells and tumours experimental_model: Human cancer cells and mouse xenografts with the metformin-resistant yeast NDI1 as a genetic rescue limitations: Cancer-cell concentrations are far above therapeutic plasma levels. The NDI1 rescue is strong evidence that the effects run through complex I in this model, not evidence of an antitumour indication. exposure: Metformin in the presence and absence of glucose; NDI1 overexpression evidence_span: {"source_cache": "artifacts/metformin-research/24843020.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae", "start_char": 0, "end_char": 1142, "text_sha256": "21403805272b0d702f0f60887d805b1e52b4ce87a9335fcde1d34cefda8b16ae"} [metformin-p24843020] Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. (2014). https://pubmed.ncbi.nlm.nih.gov/24843020/ DOI: 10.7554/elife.02242
Complete structured claim and evidence
Metformin reduced complex I activity in skeletal-muscle homogenates and reduced state 3 respiration of isolated mitochondria consuming glutamate and malate, while respiration on succinate through complex II was unaffected.
Metformin → Mitochondrial complex I (NADH dehydrogenase) activity source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/15047621.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c4c648ab82a982482ec339309f3cc1c84ffe457073f010b546f7a47ffa2fbdf6", "start_char": 0, "end_char": 1613, "text_sha256": "c4c648ab82a982482ec339309f3cc1c84ffe457073f010b546f7a47ffa2fbdf6"}
experimental_model
Tissue homogenates, isolated mitochondria and intact rat soleus muscle
exposure
Metformin 30 mmol/l in homogenates and 270 micromol/l for 24 h in intact muscle, compared with thiazolidinediones
limitations
Millimolar concentrations in homogenates are far above therapeutic exposure. The comparison drugs are included because the paper measured them together, not as a metformin claim.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat tissue and isolated mitochondria
plain_language
The block is specific to the first complex; feeding the chain past it restores respiration.
primary_references
[metformin-p15047621] Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? (2004). https://pubmed.ncbi.nlm.nih.gov/15047621/ DOI: 10.2337/diabetes.53.4.1052
tissue_or_cell_type
Skeletal muscle
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 437–448
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Tissue homogenates, isolated mitochondria and intact rat soleus muscle · source_derived_draft · unverified_draft
### metformin-complex-i-muscle Metformin reduced complex I activity in skeletal-muscle homogenates and reduced state 3 respiration of isolated mitochondria consuming glutamate and malate, while respiration on succinate through complex II was unaffected. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The block is specific to the first complex; feeding the chain past it restores respiration. organism: Rat tissue and isolated mitochondria tissue_or_cell_type: Skeletal muscle experimental_model: Tissue homogenates, isolated mitochondria and intact rat soleus muscle limitations: Millimolar concentrations in homogenates are far above therapeutic exposure. The comparison drugs are included because the paper measured them together, not as a metformin claim. exposure: Metformin 30 mmol/l in homogenates and 270 micromol/l for 24 h in intact muscle, compared with thiazolidinediones evidence_span: {"source_cache": "artifacts/metformin-research/15047621.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c4c648ab82a982482ec339309f3cc1c84ffe457073f010b546f7a47ffa2fbdf6", "start_char": 0, "end_char": 1613, "text_sha256": "c4c648ab82a982482ec339309f3cc1c84ffe457073f010b546f7a47ffa2fbdf6"} [metformin-p15047621] Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? (2004). https://pubmed.ncbi.nlm.nih.gov/15047621/ DOI: 10.2337/diabetes.53.4.1052
Complete structured claim and evidence
Twenty-four-hour exposure of isolated rat soleus muscle to metformin reduced glucose oxidation by about 30% and increased lactate release by about 84%.
Metformin → L-Lactate source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/15047621.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c4c648ab82a982482ec339309f3cc1c84ffe457073f010b546f7a47ffa2fbdf6", "start_char": 0, "end_char": 1613, "text_sha256": "c4c648ab82a982482ec339309f3cc1c84ffe457073f010b546f7a47ffa2fbdf6"}
experimental_model
Tissue homogenates, isolated mitochondria and intact rat soleus muscle
exposure
Metformin 30 mmol/l in homogenates and 270 micromol/l for 24 h in intact muscle, compared with thiazolidinediones
limitations
Millimolar concentrations in homogenates are far above therapeutic exposure. The comparison drugs are included because the paper measured them together, not as a metformin claim.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat tissue and isolated mitochondria
plain_language
When the chain is slowed, the cell disposes of pyruvate as lactate instead.
primary_references
[metformin-p15047621] Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? (2004). https://pubmed.ncbi.nlm.nih.gov/15047621/ DOI: 10.2337/diabetes.53.4.1052
tissue_or_cell_type
Skeletal muscle
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 450–461
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Tissue homogenates, isolated mitochondria and intact rat soleus muscle · source_derived_draft · unverified_draft
### metformin-muscle-lactate-release Twenty-four-hour exposure of isolated rat soleus muscle to metformin reduced glucose oxidation by about 30% and increased lactate release by about 84%. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: When the chain is slowed, the cell disposes of pyruvate as lactate instead. organism: Rat tissue and isolated mitochondria tissue_or_cell_type: Skeletal muscle experimental_model: Tissue homogenates, isolated mitochondria and intact rat soleus muscle limitations: Millimolar concentrations in homogenates are far above therapeutic exposure. The comparison drugs are included because the paper measured them together, not as a metformin claim. exposure: Metformin 30 mmol/l in homogenates and 270 micromol/l for 24 h in intact muscle, compared with thiazolidinediones evidence_span: {"source_cache": "artifacts/metformin-research/15047621.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c4c648ab82a982482ec339309f3cc1c84ffe457073f010b546f7a47ffa2fbdf6", "start_char": 0, "end_char": 1613, "text_sha256": "c4c648ab82a982482ec339309f3cc1c84ffe457073f010b546f7a47ffa2fbdf6"} [metformin-p15047621] Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? (2004). https://pubmed.ncbi.nlm.nih.gov/15047621/ DOI: 10.2337/diabetes.53.4.1052
Complete structured claim and evidence
Metformin non-competitively inhibited the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase.
Metformin → Human mitochondrial glycerol-3-phosphate dehydrogenase / GPD2 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/24847880.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b", "start_char": 0, "end_char": 1499, "text_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b"}
experimental_model
Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements
exposure
Acute and chronic low-dose metformin; mGPD knockdown and knockout
limitations
A redox-shuttle mechanism established in rodents at low doses; it does not by itself exclude complex I or AMPK contributions in other tissues.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat and mouse
plain_language
A second, separate enzyme target sits on the shuttle that moves reducing power into the mitochondrion.
primary_references
[metformin-p24847880] Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. (2014). https://pubmed.ncbi.nlm.nih.gov/24847880/ DOI: 10.1038/nature13270
tissue_or_cell_type
Liver
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 463–474
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements · source_derived_draft · unverified_draft
### metformin-mgpd-inhibition Metformin non-competitively inhibited the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: A second, separate enzyme target sits on the shuttle that moves reducing power into the mitochondrion. organism: Rat and mouse tissue_or_cell_type: Liver experimental_model: Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements limitations: A redox-shuttle mechanism established in rodents at low doses; it does not by itself exclude complex I or AMPK contributions in other tissues. exposure: Acute and chronic low-dose metformin; mGPD knockdown and knockout evidence_span: {"source_cache": "artifacts/metformin-research/24847880.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b", "start_char": 0, "end_char": 1499, "text_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b"} [metformin-p24847880] Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. (2014). https://pubmed.ncbi.nlm.nih.gov/24847880/ DOI: 10.1038/nature13270
Complete structured claim and evidence
Low-dose metformin increased the cytosolic redox state and decreased the mitochondrial redox state in the liver.
Metformin → Cytosolic NAD+/NADH redox state source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/24847880.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b", "start_char": 0, "end_char": 1499, "text_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b"}
experimental_model
Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements
exposure
Acute and chronic low-dose metformin; mGPD knockdown and knockout
limitations
A redox-shuttle mechanism established in rodents at low doses; it does not by itself exclude complex I or AMPK contributions in other tissues.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat and mouse
plain_language
Blocking the shuttle leaves reducing power stranded in the cell fluid.
primary_references
[metformin-p24847880] Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. (2014). https://pubmed.ncbi.nlm.nih.gov/24847880/ DOI: 10.1038/nature13270
tissue_or_cell_type
Liver
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 476–487
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements · source_derived_draft · unverified_draft
### metformin-mgpd-redox Low-dose metformin increased the cytosolic redox state and decreased the mitochondrial redox state in the liver. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Blocking the shuttle leaves reducing power stranded in the cell fluid. organism: Rat and mouse tissue_or_cell_type: Liver experimental_model: Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements limitations: A redox-shuttle mechanism established in rodents at low doses; it does not by itself exclude complex I or AMPK contributions in other tissues. exposure: Acute and chronic low-dose metformin; mGPD knockdown and knockout evidence_span: {"source_cache": "artifacts/metformin-research/24847880.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b", "start_char": 0, "end_char": 1499, "text_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b"} [metformin-p24847880] Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. (2014). https://pubmed.ncbi.nlm.nih.gov/24847880/ DOI: 10.1038/nature13270
Complete structured claim and evidence
The altered hepatocellular redox state reduced the conversion of lactate and glycerol to glucose and decreased hepatic gluconeogenesis.
Metformin → Gluconeogenesis from lactate and glycerol source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/24847880.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b", "start_char": 0, "end_char": 1499, "text_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b"}
experimental_model
Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements
exposure
Acute and chronic low-dose metformin; mGPD knockdown and knockout
limitations
A redox-shuttle mechanism established in rodents at low doses; it does not by itself exclude complex I or AMPK contributions in other tissues.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat and mouse
plain_language
Two of the raw materials for making new glucose can no longer be used.
primary_references
[metformin-p24847880] Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. (2014). https://pubmed.ncbi.nlm.nih.gov/24847880/ DOI: 10.1038/nature13270
tissue_or_cell_type
Liver
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 489–500
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements · source_derived_draft · unverified_draft
### metformin-mgpd-gluconeogenesis The altered hepatocellular redox state reduced the conversion of lactate and glycerol to glucose and decreased hepatic gluconeogenesis. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Two of the raw materials for making new glucose can no longer be used. organism: Rat and mouse tissue_or_cell_type: Liver experimental_model: Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements limitations: A redox-shuttle mechanism established in rodents at low doses; it does not by itself exclude complex I or AMPK contributions in other tissues. exposure: Acute and chronic low-dose metformin; mGPD knockdown and knockout evidence_span: {"source_cache": "artifacts/metformin-research/24847880.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b", "start_char": 0, "end_char": 1499, "text_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b"} [metformin-p24847880] Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. (2014). https://pubmed.ncbi.nlm.nih.gov/24847880/ DOI: 10.1038/nature13270
Complete structured claim and evidence
Knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats produced a phenotype akin to chronic metformin treatment and abrogated metformin-mediated increases in cytosolic redox state and inhibition of endogenous glucose production.
Antisense-oligonucleotide knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats → Hepatic glucose production / endogenous glucose production source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/24847880.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b", "start_char": 0, "end_char": 1499, "text_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b"}
experimental_model
Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements
exposure
Acute and chronic low-dose metformin; mGPD knockdown and knockout
limitations
A redox-shuttle mechanism established in rodents at low doses; it does not by itself exclude complex I or AMPK contributions in other tissues.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat and mouse
plain_language
Removing the enzyme both copied the drug and left it nothing further to do.
primary_references
[metformin-p24847880] Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. (2014). https://pubmed.ncbi.nlm.nih.gov/24847880/ DOI: 10.1038/nature13270
tissue_or_cell_type
Liver
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 502–513
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements · source_derived_draft · unverified_draft
### metformin-mgpd-knockdown-phenocopy Knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats produced a phenotype akin to chronic metformin treatment and abrogated metformin-mediated increases in cytosolic redox state and inhibition of endogenous glucose production. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Removing the enzyme both copied the drug and left it nothing further to do. organism: Rat and mouse tissue_or_cell_type: Liver experimental_model: Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements limitations: A redox-shuttle mechanism established in rodents at low doses; it does not by itself exclude complex I or AMPK contributions in other tissues. exposure: Acute and chronic low-dose metformin; mGPD knockdown and knockout evidence_span: {"source_cache": "artifacts/metformin-research/24847880.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b", "start_char": 0, "end_char": 1499, "text_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b"} [metformin-p24847880] Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. (2014). https://pubmed.ncbi.nlm.nih.gov/24847880/ DOI: 10.1038/nature13270
Complete structured claim and evidence
These findings were replicated in whole-body mitochondrial glycerophosphate dehydrogenase knockout mice.
Whole-body mitochondrial glycerophosphate dehydrogenase knockout mice → Hepatic glucose production / endogenous glucose production source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/24847880.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b", "start_char": 0, "end_char": 1499, "text_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b"}
experimental_model
Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements
exposure
Acute and chronic low-dose metformin; mGPD knockdown and knockout
limitations
A redox-shuttle mechanism established in rodents at low doses; it does not by itself exclude complex I or AMPK contributions in other tissues.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat and mouse
plain_language
A second genetic model gave the same answer.
primary_references
[metformin-p24847880] Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. (2014). https://pubmed.ncbi.nlm.nih.gov/24847880/ DOI: 10.1038/nature13270
tissue_or_cell_type
Liver
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 515–526
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements · source_derived_draft · unverified_draft
### metformin-mgpd-knockout-replication These findings were replicated in whole-body mitochondrial glycerophosphate dehydrogenase knockout mice. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: A second genetic model gave the same answer. organism: Rat and mouse tissue_or_cell_type: Liver experimental_model: Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements limitations: A redox-shuttle mechanism established in rodents at low doses; it does not by itself exclude complex I or AMPK contributions in other tissues. exposure: Acute and chronic low-dose metformin; mGPD knockdown and knockout evidence_span: {"source_cache": "artifacts/metformin-research/24847880.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b", "start_char": 0, "end_char": 1499, "text_sha256": "8378baac19afd12fd3ca66206d079db20e7229a9295414e9678979352e10d92b"} [metformin-p24847880] Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. (2014). https://pubmed.ncbi.nlm.nih.gov/24847880/ DOI: 10.1038/nature13270
Complete structured claim and evidence
Metformin activated AMPK in hepatocytes, reducing acetyl-CoA carboxylase activity, inducing fatty acid oxidation and suppressing expression of lipogenic enzymes.
Metformin → AMP-activated protein kinase complexes source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/11602624.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "86e283289def8a6e3e3098d49f321dbcca9a6cd4677ba84f26daf17467179237", "start_char": 0, "end_char": 1390, "text_sha256": "86e283289def8a6e3e3098d49f321dbcca9a6cd4677ba84f26daf17467179237"}
experimental_model
Rat hepatocytes, isolated rat skeletal muscle and metformin-treated rats with an AMPK inhibitor
exposure
Metformin in hepatocytes and in vivo; compound C AMPK inhibition
limitations
The inhibitor experiment supports a requirement for AMPK in these hepatocytes; later work in AMPK-deficient mice reached a different conclusion, recorded separately.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat
plain_language
The cell reads the drug as an energy shortage and switches to burning rather than storing.
primary_references
[metformin-p11602624] Role of AMP-activated protein kinase in mechanism of metformin action. (2001). https://pubmed.ncbi.nlm.nih.gov/11602624/ DOI: 10.1172/jci13505
tissue_or_cell_type
Liver and skeletal muscle
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 528–539
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat hepatocytes, isolated rat skeletal muscle and metformin-treated rats with an AMPK inhibitor · source_derived_draft · unverified_draft
### metformin-ampk-activation Metformin activated AMPK in hepatocytes, reducing acetyl-CoA carboxylase activity, inducing fatty acid oxidation and suppressing expression of lipogenic enzymes. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The cell reads the drug as an energy shortage and switches to burning rather than storing. organism: Rat tissue_or_cell_type: Liver and skeletal muscle experimental_model: Rat hepatocytes, isolated rat skeletal muscle and metformin-treated rats with an AMPK inhibitor limitations: The inhibitor experiment supports a requirement for AMPK in these hepatocytes; later work in AMPK-deficient mice reached a different conclusion, recorded separately. exposure: Metformin in hepatocytes and in vivo; compound C AMPK inhibition evidence_span: {"source_cache": "artifacts/metformin-research/11602624.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "86e283289def8a6e3e3098d49f321dbcca9a6cd4677ba84f26daf17467179237", "start_char": 0, "end_char": 1390, "text_sha256": "86e283289def8a6e3e3098d49f321dbcca9a6cd4677ba84f26daf17467179237"} [metformin-p11602624] Role of AMP-activated protein kinase in mechanism of metformin action. (2001). https://pubmed.ncbi.nlm.nih.gov/11602624/ DOI: 10.1172/jci13505
Complete structured claim and evidence
Activation of AMPK by metformin suppressed expression of SREBP-1, and hepatic lipogenic mRNA and protein were reduced in metformin-treated rats.
AMP-activated protein kinase complexes → Sterol regulatory element-binding protein 1 / SREBP-1 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/11602624.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "86e283289def8a6e3e3098d49f321dbcca9a6cd4677ba84f26daf17467179237", "start_char": 0, "end_char": 1390, "text_sha256": "86e283289def8a6e3e3098d49f321dbcca9a6cd4677ba84f26daf17467179237"}
experimental_model
Rat hepatocytes, isolated rat skeletal muscle and metformin-treated rats with an AMPK inhibitor
exposure
Metformin in hepatocytes and in vivo; compound C AMPK inhibition
limitations
The inhibitor experiment supports a requirement for AMPK in these hepatocytes; later work in AMPK-deficient mice reached a different conclusion, recorded separately.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat
plain_language
The switch reaches the transcription factor that drives fat synthesis.
primary_references
[metformin-p11602624] Role of AMP-activated protein kinase in mechanism of metformin action. (2001). https://pubmed.ncbi.nlm.nih.gov/11602624/ DOI: 10.1172/jci13505
tissue_or_cell_type
Liver and skeletal muscle
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 541–552
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat hepatocytes, isolated rat skeletal muscle and metformin-treated rats with an AMPK inhibitor · source_derived_draft · unverified_draft
### metformin-ampk-srebp1 Activation of AMPK by metformin suppressed expression of SREBP-1, and hepatic lipogenic mRNA and protein were reduced in metformin-treated rats. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The switch reaches the transcription factor that drives fat synthesis. organism: Rat tissue_or_cell_type: Liver and skeletal muscle experimental_model: Rat hepatocytes, isolated rat skeletal muscle and metformin-treated rats with an AMPK inhibitor limitations: The inhibitor experiment supports a requirement for AMPK in these hepatocytes; later work in AMPK-deficient mice reached a different conclusion, recorded separately. exposure: Metformin in hepatocytes and in vivo; compound C AMPK inhibition evidence_span: {"source_cache": "artifacts/metformin-research/11602624.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "86e283289def8a6e3e3098d49f321dbcca9a6cd4677ba84f26daf17467179237", "start_char": 0, "end_char": 1390, "text_sha256": "86e283289def8a6e3e3098d49f321dbcca9a6cd4677ba84f26daf17467179237"} [metformin-p11602624] Role of AMP-activated protein kinase in mechanism of metformin action. (2001). https://pubmed.ncbi.nlm.nih.gov/11602624/ DOI: 10.1172/jci13505
Complete structured claim and evidence
Using an AMPK inhibitor, AMPK activation was found to be required for the inhibitory effect of metformin on glucose production by hepatocytes.
AMP-activated protein kinase complexes → Hepatic glucose production / endogenous glucose production source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/11602624.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "86e283289def8a6e3e3098d49f321dbcca9a6cd4677ba84f26daf17467179237", "start_char": 0, "end_char": 1390, "text_sha256": "86e283289def8a6e3e3098d49f321dbcca9a6cd4677ba84f26daf17467179237"}
experimental_model
Rat hepatocytes, isolated rat skeletal muscle and metformin-treated rats with an AMPK inhibitor
exposure
Metformin in hepatocytes and in vivo; compound C AMPK inhibition
limitations
The inhibitor experiment supports a requirement for AMPK in these hepatocytes; later work in AMPK-deficient mice reached a different conclusion, recorded separately.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat
plain_language
In this experiment, blocking the sensor removed the drug effect on glucose output.
primary_references
[metformin-p11602624] Role of AMP-activated protein kinase in mechanism of metformin action. (2001). https://pubmed.ncbi.nlm.nih.gov/11602624/ DOI: 10.1172/jci13505
tissue_or_cell_type
Liver and skeletal muscle
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 554–565
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat hepatocytes, isolated rat skeletal muscle and metformin-treated rats with an AMPK inhibitor · source_derived_draft · unverified_draft
### metformin-ampk-required-hepatocyte Using an AMPK inhibitor, AMPK activation was found to be required for the inhibitory effect of metformin on glucose production by hepatocytes. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: In this experiment, blocking the sensor removed the drug effect on glucose output. organism: Rat tissue_or_cell_type: Liver and skeletal muscle experimental_model: Rat hepatocytes, isolated rat skeletal muscle and metformin-treated rats with an AMPK inhibitor limitations: The inhibitor experiment supports a requirement for AMPK in these hepatocytes; later work in AMPK-deficient mice reached a different conclusion, recorded separately. exposure: Metformin in hepatocytes and in vivo; compound C AMPK inhibition evidence_span: {"source_cache": "artifacts/metformin-research/11602624.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "86e283289def8a6e3e3098d49f321dbcca9a6cd4677ba84f26daf17467179237", "start_char": 0, "end_char": 1390, "text_sha256": "86e283289def8a6e3e3098d49f321dbcca9a6cd4677ba84f26daf17467179237"} [metformin-p11602624] Role of AMP-activated protein kinase in mechanism of metformin action. (2001). https://pubmed.ncbi.nlm.nih.gov/11602624/ DOI: 10.1172/jci13505
Complete structured claim and evidence
Deletion of LKB1 in adult mouse liver resulted in a nearly complete loss of AMPK activity, with hyperglycaemia and increased gluconeogenic and lipogenic gene expression.
Human liver kinase B1 / STK11 → AMP-activated protein kinase complexes source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/16308421.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e4762199db357f0f8002a9da8ff2ecad8e9bfcb48c963eb4b2cde7ffa363eec4", "start_char": 0, "end_char": 1103, "text_sha256": "e4762199db357f0f8002a9da8ff2ecad8e9bfcb48c963eb4b2cde7ffa363eec4"}
experimental_model
Liver-specific LKB1 deletion in adult mice with adenoviral TORC2 knockdown
exposure
Metformin in LKB1-deficient livers
limitations
A genetic requirement in this model. The same year’s consensus was later challenged by AMPK-independent findings recorded in this collection.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse
plain_language
The upstream kinase is what turns the energy sensor on in the liver.
primary_references
[metformin-p16308421] The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. (2005). https://pubmed.ncbi.nlm.nih.gov/16308421/ DOI: 10.1126/science.1120781
tissue_or_cell_type
Liver
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 567–578
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Liver-specific LKB1 deletion in adult mice with adenoviral TORC2 knockdown · source_derived_draft · unverified_draft
### metformin-lkb1-ampk-axis Deletion of LKB1 in adult mouse liver resulted in a nearly complete loss of AMPK activity, with hyperglycaemia and increased gluconeogenic and lipogenic gene expression. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The upstream kinase is what turns the energy sensor on in the liver. organism: Mouse tissue_or_cell_type: Liver experimental_model: Liver-specific LKB1 deletion in adult mice with adenoviral TORC2 knockdown limitations: A genetic requirement in this model. The same year’s consensus was later challenged by AMPK-independent findings recorded in this collection. exposure: Metformin in LKB1-deficient livers evidence_span: {"source_cache": "artifacts/metformin-research/16308421.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e4762199db357f0f8002a9da8ff2ecad8e9bfcb48c963eb4b2cde7ffa363eec4", "start_char": 0, "end_char": 1103, "text_sha256": "e4762199db357f0f8002a9da8ff2ecad8e9bfcb48c963eb4b2cde7ffa363eec4"} [metformin-p16308421] The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. (2005). https://pubmed.ncbi.nlm.nih.gov/16308421/ DOI: 10.1126/science.1120781
Complete structured claim and evidence
Metformin required LKB1 in the liver to lower blood glucose levels in these mice.
Liver-specific LKB1-deficient mouse hepatocytes in the 2010 and 2005 studies → Serum glucose concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/16308421.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e4762199db357f0f8002a9da8ff2ecad8e9bfcb48c963eb4b2cde7ffa363eec4", "start_char": 0, "end_char": 1103, "text_sha256": "e4762199db357f0f8002a9da8ff2ecad8e9bfcb48c963eb4b2cde7ffa363eec4"}
experimental_model
Liver-specific LKB1 deletion in adult mice with adenoviral TORC2 knockdown
exposure
Metformin in LKB1-deficient livers
limitations
A genetic requirement in this model. The same year’s consensus was later challenged by AMPK-independent findings recorded in this collection.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse
plain_language
Without the upstream kinase, the drug did not lower glucose in this model.
primary_references
[metformin-p16308421] The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. (2005). https://pubmed.ncbi.nlm.nih.gov/16308421/ DOI: 10.1126/science.1120781
tissue_or_cell_type
Liver
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 580–591
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Liver-specific LKB1 deletion in adult mice with adenoviral TORC2 knockdown · source_derived_draft · unverified_draft
### metformin-lkb1-required-metformin Metformin required LKB1 in the liver to lower blood glucose levels in these mice. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Without the upstream kinase, the drug did not lower glucose in this model. organism: Mouse tissue_or_cell_type: Liver experimental_model: Liver-specific LKB1 deletion in adult mice with adenoviral TORC2 knockdown limitations: A genetic requirement in this model. The same year’s consensus was later challenged by AMPK-independent findings recorded in this collection. exposure: Metformin in LKB1-deficient livers evidence_span: {"source_cache": "artifacts/metformin-research/16308421.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e4762199db357f0f8002a9da8ff2ecad8e9bfcb48c963eb4b2cde7ffa363eec4", "start_char": 0, "end_char": 1103, "text_sha256": "e4762199db357f0f8002a9da8ff2ecad8e9bfcb48c963eb4b2cde7ffa363eec4"} [metformin-p16308421] The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. (2005). https://pubmed.ncbi.nlm.nih.gov/16308421/ DOI: 10.1126/science.1120781
Complete structured claim and evidence
In mice lacking AMPK in the liver, blood glucose was comparable to wild type and the hypoglycaemic effect of metformin was maintained; metformin-induced inhibition of glucose production was amplified in both AMPK- and LKB1-deficient hepatocytes.
Liver-specific AMPK-deficient mouse hepatocytes in the 2010 study → Hepatic glucose production / endogenous glucose production source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/20577053.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f6019de6b5a35f860f55b39d91656e5fd1077d34e301d244a1ea498b96faac14", "start_char": 0, "end_char": 1707, "text_sha256": "f6019de6b5a35f860f55b39d91656e5fd1077d34e301d244a1ea498b96faac14"}
experimental_model
Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression
exposure
Metformin dose-response in hepatocytes lacking AMPK or LKB1
limitations
A direct challenge to the AMPK requirement. The measured correlate is intracellular ATP, so this is an energy-state mechanism rather than a signalling one.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse
plain_language
Removing the sensor did not remove the drug effect, and in these cells it made it larger.
primary_references
[metformin-p20577053] Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. (2010). https://pubmed.ncbi.nlm.nih.gov/20577053/ DOI: 10.1172/jci40671
tissue_or_cell_type
Liver
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 593–604
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression · source_derived_draft · unverified_draft
### metformin-ampk-independent-glucose In mice lacking AMPK in the liver, blood glucose was comparable to wild type and the hypoglycaemic effect of metformin was maintained; metformin-induced inhibition of glucose production was amplified in both AMPK- and LKB1-deficient hepatocytes. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Removing the sensor did not remove the drug effect, and in these cells it made it larger. organism: Mouse tissue_or_cell_type: Liver experimental_model: Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression limitations: A direct challenge to the AMPK requirement. The measured correlate is intracellular ATP, so this is an energy-state mechanism rather than a signalling one. exposure: Metformin dose-response in hepatocytes lacking AMPK or LKB1 evidence_span: {"source_cache": "artifacts/metformin-research/20577053.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f6019de6b5a35f860f55b39d91656e5fd1077d34e301d244a1ea498b96faac14", "start_char": 0, "end_char": 1707, "text_sha256": "f6019de6b5a35f860f55b39d91656e5fd1077d34e301d244a1ea498b96faac14"} [metformin-p20577053] Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. (2010). https://pubmed.ncbi.nlm.nih.gov/20577053/ DOI: 10.1172/jci40671
Complete structured claim and evidence
Inhibition of glucose production correlated in a dose-dependent manner with a reduction in intracellular ATP content, and was preserved when gluconeogenic genes were force-expressed through PGC-1alpha.
Metformin → Hepatocyte ATP content / cellular energy state source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/20577053.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f6019de6b5a35f860f55b39d91656e5fd1077d34e301d244a1ea498b96faac14", "start_char": 0, "end_char": 1707, "text_sha256": "f6019de6b5a35f860f55b39d91656e5fd1077d34e301d244a1ea498b96faac14"}
experimental_model
Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression
exposure
Metformin dose-response in hepatocytes lacking AMPK or LKB1
limitations
A direct challenge to the AMPK requirement. The measured correlate is intracellular ATP, so this is an energy-state mechanism rather than a signalling one.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse
plain_language
The drug lowered the cell’s energy currency, and that alone tracked the effect.
primary_references
[metformin-p20577053] Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. (2010). https://pubmed.ncbi.nlm.nih.gov/20577053/ DOI: 10.1172/jci40671
tissue_or_cell_type
Liver
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 606–617
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression · source_derived_draft · unverified_draft
### metformin-energy-state-mechanism Inhibition of glucose production correlated in a dose-dependent manner with a reduction in intracellular ATP content, and was preserved when gluconeogenic genes were force-expressed through PGC-1alpha. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug lowered the cell’s energy currency, and that alone tracked the effect. organism: Mouse tissue_or_cell_type: Liver experimental_model: Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression limitations: A direct challenge to the AMPK requirement. The measured correlate is intracellular ATP, so this is an energy-state mechanism rather than a signalling one. exposure: Metformin dose-response in hepatocytes lacking AMPK or LKB1 evidence_span: {"source_cache": "artifacts/metformin-research/20577053.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f6019de6b5a35f860f55b39d91656e5fd1077d34e301d244a1ea498b96faac14", "start_char": 0, "end_char": 1707, "text_sha256": "f6019de6b5a35f860f55b39d91656e5fd1077d34e301d244a1ea498b96faac14"} [metformin-p20577053] Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. (2010). https://pubmed.ncbi.nlm.nih.gov/20577053/ DOI: 10.1172/jci40671
Complete structured claim and evidence
Metformin stimulated phosphorylation of Thr-172 on the AMPK alpha subunit in intact cells without affecting phosphorylation by upstream kinases in cell-free assays, and the authors presented evidence that activation was not a consequence of energy-charge depletion via complex I in the two cell types tested.
Metformin → AMP-activated protein kinase complexes source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/12145153.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3ff2e09e56437d39718ec15046803356b0ab0d6e23c971cf21f4e2f865e263a2", "start_char": 0, "end_char": 1279, "text_sha256": "3ff2e09e56437d39718ec15046803356b0ab0d6e23c971cf21f4e2f865e263a2"}
experimental_model
Intact cells and cell-free upstream-kinase assays
exposure
Metformin compared with AICA riboside
limitations
A negative mechanistic result: the authors state they did not establish the definitive mechanism, only that it differs from AMP mimicry.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat hepatocytes and cell lines
plain_language
The sensor came on by a route other than a simple fall in the cell’s energy charge.
primary_references
[metformin-p12145153] The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. (2002). https://pubmed.ncbi.nlm.nih.gov/12145153/ DOI: 10.2337/diabetes.51.8.2420
tissue_or_cell_type
Hepatocytes and cultured cells
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 619–630
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Intact cells and cell-free upstream-kinase assays · source_derived_draft · unverified_draft
### metformin-nucleotide-independent Metformin stimulated phosphorylation of Thr-172 on the AMPK alpha subunit in intact cells without affecting phosphorylation by upstream kinases in cell-free assays, and the authors presented evidence that activation was not a consequence of energy-charge depletion via complex I in the two cell types tested. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The sensor came on by a route other than a simple fall in the cell’s energy charge. organism: Rat hepatocytes and cell lines tissue_or_cell_type: Hepatocytes and cultured cells experimental_model: Intact cells and cell-free upstream-kinase assays limitations: A negative mechanistic result: the authors state they did not establish the definitive mechanism, only that it differs from AMP mimicry. exposure: Metformin compared with AICA riboside evidence_span: {"source_cache": "artifacts/metformin-research/12145153.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3ff2e09e56437d39718ec15046803356b0ab0d6e23c971cf21f4e2f865e263a2", "start_char": 0, "end_char": 1279, "text_sha256": "3ff2e09e56437d39718ec15046803356b0ab0d6e23c971cf21f4e2f865e263a2"} [metformin-p12145153] The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. (2002). https://pubmed.ncbi.nlm.nih.gov/12145153/ DOI: 10.2337/diabetes.51.8.2420
Complete structured claim and evidence
A photoactive metformin probe identified PEN2, a subunit of gamma-secretase, as a binding partner of metformin with a dissociation constant at micromolar levels.
Metformin → Human presenilin enhancer gamma-secretase subunit / PEN2 / PSENEN source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/35197629.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983", "start_char": 0, "end_char": 1549, "text_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983"}
experimental_model
Photoactive metformin probe, binding studies, knockouts in mice and C. elegans
exposure
Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants
limitations
A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human cells, mouse and C. elegans
plain_language
At doses people actually take, the drug sticks to a specific protein.
primary_references
[metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8
tissue_or_cell_type
Lysosome, liver and intestine
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 632–643
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Photoactive metformin probe, binding studies, knockouts in mice and C. elegans · source_derived_draft · unverified_draft
### metformin-pen2-binding A photoactive metformin probe identified PEN2, a subunit of gamma-secretase, as a binding partner of metformin with a dissociation constant at micromolar levels. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: At doses people actually take, the drug sticks to a specific protein. organism: Human cells, mouse and C. elegans tissue_or_cell_type: Lysosome, liver and intestine experimental_model: Photoactive metformin probe, binding studies, knockouts in mice and C. elegans limitations: A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes. exposure: Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants evidence_span: {"source_cache": "artifacts/metformin-research/35197629.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983", "start_char": 0, "end_char": 1549, "text_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983"} [metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8
Complete structured claim and evidence
Metformin-bound PEN2 formed a complex with ATP6AP1, a subunit of the v-ATPase.
Human presenilin enhancer gamma-secretase subunit / PEN2 / PSENEN → Human v-ATPase accessory subunit ATP6AP1 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/35197629.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983", "start_char": 0, "end_char": 1549, "text_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983"}
experimental_model
Photoactive metformin probe, binding studies, knockouts in mice and C. elegans
exposure
Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants
limitations
A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human cells, mouse and C. elegans
plain_language
The bound protein then grabs part of the lysosome’s proton pump.
primary_references
[metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8
tissue_or_cell_type
Lysosome, liver and intestine
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 645–656
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Photoactive metformin probe, binding studies, knockouts in mice and C. elegans · source_derived_draft · unverified_draft
### metformin-pen2-atp6ap1 Metformin-bound PEN2 formed a complex with ATP6AP1, a subunit of the v-ATPase. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The bound protein then grabs part of the lysosome’s proton pump. organism: Human cells, mouse and C. elegans tissue_or_cell_type: Lysosome, liver and intestine experimental_model: Photoactive metformin probe, binding studies, knockouts in mice and C. elegans limitations: A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes. exposure: Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants evidence_span: {"source_cache": "artifacts/metformin-research/35197629.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983", "start_char": 0, "end_char": 1549, "text_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983"} [metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8
Complete structured claim and evidence
Clinically relevant concentrations of metformin inhibited the lysosomal proton pump v-ATPase, leading to AMPK activation without effects on cellular AMP levels.
Metformin → Lysosomal vacuolar H+-ATPase (v-ATPase) source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/35197629.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983", "start_char": 0, "end_char": 1549, "text_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983"}
experimental_model
Photoactive metformin probe, binding studies, knockouts in mice and C. elegans
exposure
Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants
limitations
A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human cells, mouse and C. elegans
plain_language
The energy sensor is switched on at the lysosome rather than by a fall in cellular AMP.
primary_references
[metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8
tissue_or_cell_type
Lysosome, liver and intestine
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 658–669
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Photoactive metformin probe, binding studies, knockouts in mice and C. elegans · source_derived_draft · unverified_draft
### metformin-vatpase-inhibition Clinically relevant concentrations of metformin inhibited the lysosomal proton pump v-ATPase, leading to AMPK activation without effects on cellular AMP levels. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The energy sensor is switched on at the lysosome rather than by a fall in cellular AMP. organism: Human cells, mouse and C. elegans tissue_or_cell_type: Lysosome, liver and intestine experimental_model: Photoactive metformin probe, binding studies, knockouts in mice and C. elegans limitations: A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes. exposure: Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants evidence_span: {"source_cache": "artifacts/metformin-research/35197629.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983", "start_char": 0, "end_char": 1549, "text_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983"} [metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8
Complete structured claim and evidence
Knockout of PEN2, or re-introduction of a PEN2 mutant that does not bind ATP6AP1, blunted AMPK activation.
Liver-specific Pen2 knockout mice in the 2022 study → Lysosome-associated AMPK activation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/35197629.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983", "start_char": 0, "end_char": 1549, "text_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983"}
experimental_model
Photoactive metformin probe, binding studies, knockouts in mice and C. elegans
exposure
Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants
limitations
A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human cells, mouse and C. elegans
plain_language
Without that protein the switch is not thrown.
primary_references
[metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8
tissue_or_cell_type
Lysosome, liver and intestine
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 671–682
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Photoactive metformin probe, binding studies, knockouts in mice and C. elegans · source_derived_draft · unverified_draft
### metformin-pen2-null-ampk Knockout of PEN2, or re-introduction of a PEN2 mutant that does not bind ATP6AP1, blunted AMPK activation. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Without that protein the switch is not thrown. organism: Human cells, mouse and C. elegans tissue_or_cell_type: Lysosome, liver and intestine experimental_model: Photoactive metformin probe, binding studies, knockouts in mice and C. elegans limitations: A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes. exposure: Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants evidence_span: {"source_cache": "artifacts/metformin-research/35197629.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983", "start_char": 0, "end_char": 1549, "text_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983"} [metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8
Complete structured claim and evidence
Liver-specific knockout of Pen2 abolished the metformin-mediated reduction of hepatic fat content.
Liver-specific Pen2 knockout mice in the 2022 study → Hepatic fat content source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/35197629.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983", "start_char": 0, "end_char": 1549, "text_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983"}
experimental_model
Photoactive metformin probe, binding studies, knockouts in mice and C. elegans
exposure
Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants
limitations
A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human cells, mouse and C. elegans
plain_language
The liver effect needed the binding partner in the liver.
primary_references
[metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8
tissue_or_cell_type
Lysosome, liver and intestine
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 684–695
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Photoactive metformin probe, binding studies, knockouts in mice and C. elegans · source_derived_draft · unverified_draft
### metformin-pen2-null-liver-fat Liver-specific knockout of Pen2 abolished the metformin-mediated reduction of hepatic fat content. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The liver effect needed the binding partner in the liver. organism: Human cells, mouse and C. elegans tissue_or_cell_type: Lysosome, liver and intestine experimental_model: Photoactive metformin probe, binding studies, knockouts in mice and C. elegans limitations: A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes. exposure: Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants evidence_span: {"source_cache": "artifacts/metformin-research/35197629.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983", "start_char": 0, "end_char": 1549, "text_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983"} [metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8
Complete structured claim and evidence
Intestine-specific knockout of Pen2 impaired the glucose-lowering effects of metformin.
Intestine-specific Pen2 knockout mice in the 2022 study → Serum glucose concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/35197629.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983", "start_char": 0, "end_char": 1549, "text_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983"}
experimental_model
Photoactive metformin probe, binding studies, knockouts in mice and C. elegans
exposure
Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants
limitations
A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human cells, mouse and C. elegans
plain_language
Part of the glucose effect is produced in the gut, not the liver.
primary_references
[metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8
tissue_or_cell_type
Lysosome, liver and intestine
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 697–708
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Photoactive metformin probe, binding studies, knockouts in mice and C. elegans · source_derived_draft · unverified_draft
### metformin-pen2-null-intestine-glucose Intestine-specific knockout of Pen2 impaired the glucose-lowering effects of metformin. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Part of the glucose effect is produced in the gut, not the liver. organism: Human cells, mouse and C. elegans tissue_or_cell_type: Lysosome, liver and intestine experimental_model: Photoactive metformin probe, binding studies, knockouts in mice and C. elegans limitations: A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes. exposure: Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants evidence_span: {"source_cache": "artifacts/metformin-research/35197629.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983", "start_char": 0, "end_char": 1549, "text_sha256": "587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983"} [metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8
Complete structured claim and evidence
The anti-proliferative effect of metformin was due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis, because complex I supports proliferation by regenerating NAD+.
Metformin → Cellular aspartate biosynthesis source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/27746050.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3", "start_char": 0, "end_char": 1079, "text_sha256": "661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3"}
experimental_model
Cancer cells in varied culture environments with complex I inhibitors
exposure
Metformin and other complex I inhibitors across environments differing in NAD+ regeneration and aspartate supply
limitations
Establishes that sensitivity is environment-dependent; it argues against reading a culture concentration as a fixed drug property.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human and mouse cancer cells
plain_language
The real shortage is the carrier the chain recycles and the amino acid that depends on it.
primary_references
[metformin-p27746050] Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. (2016). https://pubmed.ncbi.nlm.nih.gov/27746050/ DOI: 10.1016/j.cmet.2016.09.006
tissue_or_cell_type
Cancer cells in culture and in vivo
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 710–721
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cancer cells in varied culture environments with complex I inhibitors · source_derived_draft · unverified_draft
### metformin-nad-aspartate The anti-proliferative effect of metformin was due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis, because complex I supports proliferation by regenerating NAD+. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The real shortage is the carrier the chain recycles and the amino acid that depends on it. organism: Human and mouse cancer cells tissue_or_cell_type: Cancer cells in culture and in vivo experimental_model: Cancer cells in varied culture environments with complex I inhibitors limitations: Establishes that sensitivity is environment-dependent; it argues against reading a culture concentration as a fixed drug property. exposure: Metformin and other complex I inhibitors across environments differing in NAD+ regeneration and aspartate supply evidence_span: {"source_cache": "artifacts/metformin-research/27746050.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3", "start_char": 0, "end_char": 1079, "text_sha256": "661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3"} [metformin-p27746050] Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. (2016). https://pubmed.ncbi.nlm.nih.gov/27746050/ DOI: 10.1016/j.cmet.2016.09.006
Complete structured claim and evidence
Dependency on complex I, and therefore sensitivity to metformin, was dictated by other pathways affecting NAD+ regeneration and aspartate levels, so sensitivity was not an intrinsic property of the cells.
Metformin → Cellular NAD+/NADH ratio source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/27746050.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3", "start_char": 0, "end_char": 1079, "text_sha256": "661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3"}
experimental_model
Cancer cells in varied culture environments with complex I inhibitors
exposure
Metformin and other complex I inhibitors across environments differing in NAD+ regeneration and aspartate supply
limitations
Establishes that sensitivity is environment-dependent; it argues against reading a culture concentration as a fixed drug property.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human and mouse cancer cells
plain_language
The same drug dose does different things depending on what else the cell can use.
primary_references
[metformin-p27746050] Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. (2016). https://pubmed.ncbi.nlm.nih.gov/27746050/ DOI: 10.1016/j.cmet.2016.09.006
tissue_or_cell_type
Cancer cells in culture and in vivo
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 723–734
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cancer cells in varied culture environments with complex I inhibitors · source_derived_draft · unverified_draft
### metformin-environment-sensitivity Dependency on complex I, and therefore sensitivity to metformin, was dictated by other pathways affecting NAD+ regeneration and aspartate levels, so sensitivity was not an intrinsic property of the cells. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The same drug dose does different things depending on what else the cell can use. organism: Human and mouse cancer cells tissue_or_cell_type: Cancer cells in culture and in vivo experimental_model: Cancer cells in varied culture environments with complex I inhibitors limitations: Establishes that sensitivity is environment-dependent; it argues against reading a culture concentration as a fixed drug property. exposure: Metformin and other complex I inhibitors across environments differing in NAD+ regeneration and aspartate supply evidence_span: {"source_cache": "artifacts/metformin-research/27746050.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3", "start_char": 0, "end_char": 1079, "text_sha256": "661b69cac488b8ac530cc9385bff10b367b48327d01fe1c29c75bee56ee4f6b3"} [metformin-p27746050] Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. (2016). https://pubmed.ncbi.nlm.nih.gov/27746050/ DOI: 10.1016/j.cmet.2016.09.006
Complete structured claim and evidence
Ten weeks of metformin significantly increased skeletal-muscle AMPK alpha2 activity with increased Thr172 phosphorylation and decreased acetyl-CoA carboxylase-2 activity in people with type 2 diabetes.
Metformin → Skeletal-muscle AMPK activity source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/12086935.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680", "start_char": 0, "end_char": 1474, "text_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680"}
experimental_model
Ten weeks of metformin in people with type 2 diabetes with muscle biopsies
exposure
Therapeutic metformin doses for 10 weeks
limitations
A human tissue measurement at therapeutic dose. It is an association within a treatment study, not a demonstration that AMPK causes the glucose disposal change.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
At the dose people take, the energy sensor is measurably more active in human muscle.
primary_references
[metformin-p12086935] Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. (2002). https://pubmed.ncbi.nlm.nih.gov/12086935/ DOI: 10.2337/diabetes.51.7.2074
tissue_or_cell_type
Skeletal muscle
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 736–747
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ten weeks of metformin in people with type 2 diabetes with muscle biopsies · source_derived_draft · unverified_draft
### metformin-human-muscle-ampk Ten weeks of metformin significantly increased skeletal-muscle AMPK alpha2 activity with increased Thr172 phosphorylation and decreased acetyl-CoA carboxylase-2 activity in people with type 2 diabetes. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: At the dose people take, the energy sensor is measurably more active in human muscle. organism: Human tissue_or_cell_type: Skeletal muscle experimental_model: Ten weeks of metformin in people with type 2 diabetes with muscle biopsies limitations: A human tissue measurement at therapeutic dose. It is an association within a treatment study, not a demonstration that AMPK causes the glucose disposal change. exposure: Therapeutic metformin doses for 10 weeks evidence_span: {"source_cache": "artifacts/metformin-research/12086935.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680", "start_char": 0, "end_char": 1474, "text_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680"} [metformin-p12086935] Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. (2002). https://pubmed.ncbi.nlm.nih.gov/12086935/ DOI: 10.2337/diabetes.51.7.2074
Complete structured claim and evidence
The increase in AMPK alpha2 activity was accompanied by lower muscle ATP and phosphocreatine concentrations after treatment.
Metformin → Skeletal-muscle ATP and phosphocreatine content source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/12086935.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680", "start_char": 0, "end_char": 1474, "text_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680"}
experimental_model
Ten weeks of metformin in people with type 2 diabetes with muscle biopsies
exposure
Therapeutic metformin doses for 10 weeks
limitations
A human tissue measurement at therapeutic dose. It is an association within a treatment study, not a demonstration that AMPK causes the glucose disposal change.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
Human muscle showed the fall in energy stores that the sensor responds to.
primary_references
[metformin-p12086935] Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. (2002). https://pubmed.ncbi.nlm.nih.gov/12086935/ DOI: 10.2337/diabetes.51.7.2074
tissue_or_cell_type
Skeletal muscle
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 749–760
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ten weeks of metformin in people with type 2 diabetes with muscle biopsies · source_derived_draft · unverified_draft
### metformin-human-muscle-energy The increase in AMPK alpha2 activity was accompanied by lower muscle ATP and phosphocreatine concentrations after treatment. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Human muscle showed the fall in energy stores that the sensor responds to. organism: Human tissue_or_cell_type: Skeletal muscle experimental_model: Ten weeks of metformin in people with type 2 diabetes with muscle biopsies limitations: A human tissue measurement at therapeutic dose. It is an association within a treatment study, not a demonstration that AMPK causes the glucose disposal change. exposure: Therapeutic metformin doses for 10 weeks evidence_span: {"source_cache": "artifacts/metformin-research/12086935.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680", "start_char": 0, "end_char": 1474, "text_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680"} [metformin-p12086935] Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. (2002). https://pubmed.ncbi.nlm.nih.gov/12086935/ DOI: 10.2337/diabetes.51.7.2074
Complete structured claim and evidence
Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and higher muscle glycogen concentrations.
Metformin → Skeletal-muscle glucose uptake source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/12086935.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680", "start_char": 0, "end_char": 1474, "text_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680"}
experimental_model
Ten weeks of metformin in people with type 2 diabetes with muscle biopsies
exposure
Therapeutic metformin doses for 10 weeks
limitations
A human tissue measurement at therapeutic dose. It is an association within a treatment study, not a demonstration that AMPK causes the glucose disposal change.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
More sensor activity went together with more glucose taken up, though the study does not prove one caused the other.
primary_references
[metformin-p12086935] Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. (2002). https://pubmed.ncbi.nlm.nih.gov/12086935/ DOI: 10.2337/diabetes.51.7.2074
tissue_or_cell_type
Skeletal muscle
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 762–773
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ten weeks of metformin in people with type 2 diabetes with muscle biopsies · source_derived_draft · unverified_draft
### metformin-human-muscle-disposal Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and higher muscle glycogen concentrations. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: More sensor activity went together with more glucose taken up, though the study does not prove one caused the other. organism: Human tissue_or_cell_type: Skeletal muscle experimental_model: Ten weeks of metformin in people with type 2 diabetes with muscle biopsies limitations: A human tissue measurement at therapeutic dose. It is an association within a treatment study, not a demonstration that AMPK causes the glucose disposal change. exposure: Therapeutic metformin doses for 10 weeks evidence_span: {"source_cache": "artifacts/metformin-research/12086935.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680", "start_char": 0, "end_char": 1474, "text_sha256": "a7807ae8af1c0f438eeff1dd4106d0198681e72f0333f0556786b9151b0df680"} [metformin-p12086935] Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. (2002). https://pubmed.ncbi.nlm.nih.gov/12086935/ DOI: 10.2337/diabetes.51.7.2074
Complete structured claim and evidence
In two independent randomised controlled trials metformin increased circulating GDF15, and in wild-type mice oral metformin increased circulating GDF15 with expression rising predominantly in the distal intestine and the kidney.
Metformin → Circulating GDF15 concentration source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/31875646.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a", "start_char": 0, "end_char": 1454, "text_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a"}
experimental_model
Two randomised controlled trials in people plus wild-type, Gdf15-null and Gfral-null mice
exposure
Oral metformin; high-fat diet in mice; GFRAL-antagonist antibody
limitations
The weight mechanism is separable from the glucose mechanism in this work; the mouse knockouts carry the causal claim, the human trials the GDF15 rise. A publisher correction was issued for this paper (Nature 2020;578:E24, PMID 32051582); its notice body was not available, so its impact on these records has not been assessed.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human and mouse
plain_language
The drug raises a hormone that is made mostly in the gut and kidney.
primary_references
[metformin-p31875646] GDF15 mediates the effects of metformin on body weight and energy balance. (2020). https://pubmed.ncbi.nlm.nih.gov/31875646/ DOI: 10.1038/s41586-019-1911-y
tissue_or_cell_type
Distal intestine, kidney and brainstem receptor
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 775–786
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two randomised controlled trials in people plus wild-type, Gdf15-null and Gfral-null mice · source_derived_draft · unverified_draft
### metformin-gdf15-rise In two independent randomised controlled trials metformin increased circulating GDF15, and in wild-type mice oral metformin increased circulating GDF15 with expression rising predominantly in the distal intestine and the kidney. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug raises a hormone that is made mostly in the gut and kidney. organism: Human and mouse tissue_or_cell_type: Distal intestine, kidney and brainstem receptor experimental_model: Two randomised controlled trials in people plus wild-type, Gdf15-null and Gfral-null mice limitations: The weight mechanism is separable from the glucose mechanism in this work; the mouse knockouts carry the causal claim, the human trials the GDF15 rise. A publisher correction was issued for this paper (Nature 2020;578:E24, PMID 32051582); its notice body was not available, so its impact on these records has not been assessed. exposure: Oral metformin; high-fat diet in mice; GFRAL-antagonist antibody evidence_span: {"source_cache": "artifacts/metformin-research/31875646.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a", "start_char": 0, "end_char": 1454, "text_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a"} [metformin-p31875646] GDF15 mediates the effects of metformin on body weight and energy balance. (2020). https://pubmed.ncbi.nlm.nih.gov/31875646/ DOI: 10.1038/s41586-019-1911-y
Complete structured claim and evidence
Metformin prevented high-fat-diet weight gain in wild-type mice but not in mice lacking GDF15 or its receptor GFRAL, and a GFRAL-antagonist antibody reversed the weight effect in obese mice.
Circulating GDF15 concentration → Body weight source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/31875646.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a", "start_char": 0, "end_char": 1454, "text_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a"}
experimental_model
Two randomised controlled trials in people plus wild-type, Gdf15-null and Gfral-null mice
exposure
Oral metformin; high-fat diet in mice; GFRAL-antagonist antibody
limitations
The weight mechanism is separable from the glucose mechanism in this work; the mouse knockouts carry the causal claim, the human trials the GDF15 rise. A publisher correction was issued for this paper (Nature 2020;578:E24, PMID 32051582); its notice body was not available, so its impact on these records has not been assessed.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human and mouse
plain_language
The weight effect travelled through that hormone and its brainstem receptor.
primary_references
[metformin-p31875646] GDF15 mediates the effects of metformin on body weight and energy balance. (2020). https://pubmed.ncbi.nlm.nih.gov/31875646/ DOI: 10.1038/s41586-019-1911-y
tissue_or_cell_type
Distal intestine, kidney and brainstem receptor
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 788–799
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two randomised controlled trials in people plus wild-type, Gdf15-null and Gfral-null mice · source_derived_draft · unverified_draft
### metformin-gdf15-weight Metformin prevented high-fat-diet weight gain in wild-type mice but not in mice lacking GDF15 or its receptor GFRAL, and a GFRAL-antagonist antibody reversed the weight effect in obese mice. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The weight effect travelled through that hormone and its brainstem receptor. organism: Human and mouse tissue_or_cell_type: Distal intestine, kidney and brainstem receptor experimental_model: Two randomised controlled trials in people plus wild-type, Gdf15-null and Gfral-null mice limitations: The weight mechanism is separable from the glucose mechanism in this work; the mouse knockouts carry the causal claim, the human trials the GDF15 rise. A publisher correction was issued for this paper (Nature 2020;578:E24, PMID 32051582); its notice body was not available, so its impact on these records has not been assessed. exposure: Oral metformin; high-fat diet in mice; GFRAL-antagonist antibody evidence_span: {"source_cache": "artifacts/metformin-research/31875646.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a", "start_char": 0, "end_char": 1454, "text_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a"} [metformin-p31875646] GDF15 mediates the effects of metformin on body weight and energy balance. (2020). https://pubmed.ncbi.nlm.nih.gov/31875646/ DOI: 10.1038/s41586-019-1911-y
Complete structured claim and evidence
Metformin retained its ability to lower circulating glucose in the absence of GDF15 activity.
Metformin → Serum glucose concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/31875646.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a", "start_char": 0, "end_char": 1454, "text_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a"}
experimental_model
Two randomised controlled trials in people plus wild-type, Gdf15-null and Gfral-null mice
exposure
Oral metformin; high-fat diet in mice; GFRAL-antagonist antibody
limitations
The weight mechanism is separable from the glucose mechanism in this work; the mouse knockouts carry the causal claim, the human trials the GDF15 rise. A publisher correction was issued for this paper (Nature 2020;578:E24, PMID 32051582); its notice body was not available, so its impact on these records has not been assessed.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human and mouse
plain_language
Weight and glucose are two different effects with different routes.
primary_references
[metformin-p31875646] GDF15 mediates the effects of metformin on body weight and energy balance. (2020). https://pubmed.ncbi.nlm.nih.gov/31875646/ DOI: 10.1038/s41586-019-1911-y
tissue_or_cell_type
Distal intestine, kidney and brainstem receptor
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 801–812
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two randomised controlled trials in people plus wild-type, Gdf15-null and Gfral-null mice · source_derived_draft · unverified_draft
### metformin-gdf15-glucose-separable Metformin retained its ability to lower circulating glucose in the absence of GDF15 activity. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Weight and glucose are two different effects with different routes. organism: Human and mouse tissue_or_cell_type: Distal intestine, kidney and brainstem receptor experimental_model: Two randomised controlled trials in people plus wild-type, Gdf15-null and Gfral-null mice limitations: The weight mechanism is separable from the glucose mechanism in this work; the mouse knockouts carry the causal claim, the human trials the GDF15 rise. A publisher correction was issued for this paper (Nature 2020;578:E24, PMID 32051582); its notice body was not available, so its impact on these records has not been assessed. exposure: Oral metformin; high-fat diet in mice; GFRAL-antagonist antibody evidence_span: {"source_cache": "artifacts/metformin-research/31875646.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a", "start_char": 0, "end_char": 1454, "text_sha256": "a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a"} [metformin-p31875646] GDF15 mediates the effects of metformin on body weight and energy balance. (2020). https://pubmed.ncbi.nlm.nih.gov/31875646/ DOI: 10.1038/s41586-019-1911-y
Complete structured claim and evidence
Metformin increased circulating GDF15 in mice and humans, but studies in wild-type, GDF15-knockout and GFRAL-knockout mice suggested that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance.
Experimental Gdf15-null mouse genotype → Body weight source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/36001956.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b326862a8ba767ce4e5c0a8cf5d480951464e1f95bf493ff226094b7ae29d457", "start_char": 0, "end_char": 979, "text_sha256": "b326862a8ba767ce4e5c0a8cf5d480951464e1f95bf493ff226094b7ae29d457"}
experimental_model
Wild-type, GDF15-knockout and GFRAL-knockout mice with human measurements
exposure
Metformin in knockout and wild-type mice
limitations
A direct replication attempt reaching the opposite conclusion on necessity, while confirming the GDF15 rise itself.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse and human
plain_language
A second group removed the same hormone and still saw the weight effect.
primary_references
[metformin-p36001956] The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. (2022). https://pubmed.ncbi.nlm.nih.gov/36001956/ DOI: 10.1016/j.celrep.2022.111258
tissue_or_cell_type
Whole-body energy balance
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 814–825
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Wild-type, GDF15-knockout and GFRAL-knockout mice with human measurements · source_derived_draft · unverified_draft
### metformin-gdf15-dispensable Metformin increased circulating GDF15 in mice and humans, but studies in wild-type, GDF15-knockout and GFRAL-knockout mice suggested that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: A second group removed the same hormone and still saw the weight effect. organism: Mouse and human tissue_or_cell_type: Whole-body energy balance experimental_model: Wild-type, GDF15-knockout and GFRAL-knockout mice with human measurements limitations: A direct replication attempt reaching the opposite conclusion on necessity, while confirming the GDF15 rise itself. exposure: Metformin in knockout and wild-type mice evidence_span: {"source_cache": "artifacts/metformin-research/36001956.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b326862a8ba767ce4e5c0a8cf5d480951464e1f95bf493ff226094b7ae29d457", "start_char": 0, "end_char": 979, "text_sha256": "b326862a8ba767ce4e5c0a8cf5d480951464e1f95bf493ff226094b7ae29d457"} [metformin-p36001956] The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. (2022). https://pubmed.ncbi.nlm.nih.gov/36001956/ DOI: 10.1016/j.celrep.2022.111258
Complete structured claim and evidence
Delayed-release metformin targeted to the ileum produced similar reductions in fasting and postprandial glucose despite an almost 60% reduction in systemic metformin exposure compared with immediate-release metformin.
Metformin → Serum glucose concentration source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/27216492.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d", "start_char": 0, "end_char": 3863, "text_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d"}
experimental_model
Two randomised crossover trials of delayed-release metformin targeted to the ileum
exposure
Delayed-release versus immediate-release metformin over 5 to 7 day periods
limitations
The dissociation of effect from plasma exposure is the key observation. Funded by the manufacturer of the delayed-release formulation, which the record retains.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
The drug can work from inside the gut without much of it entering the blood.
primary_references
[metformin-p27216492] Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. (2016). https://pubmed.ncbi.nlm.nih.gov/27216492/ DOI: 10.1007/s00125-016-3992-6
tissue_or_cell_type
Distal small intestine
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 827–838
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two randomised crossover trials of delayed-release metformin targeted to the ileum · source_derived_draft · unverified_draft
### metformin-gut-restricted-effect Delayed-release metformin targeted to the ileum produced similar reductions in fasting and postprandial glucose despite an almost 60% reduction in systemic metformin exposure compared with immediate-release metformin. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug can work from inside the gut without much of it entering the blood. organism: Human tissue_or_cell_type: Distal small intestine experimental_model: Two randomised crossover trials of delayed-release metformin targeted to the ileum limitations: The dissociation of effect from plasma exposure is the key observation. Funded by the manufacturer of the delayed-release formulation, which the record retains. exposure: Delayed-release versus immediate-release metformin over 5 to 7 day periods evidence_span: {"source_cache": "artifacts/metformin-research/27216492.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d", "start_char": 0, "end_char": 3863, "text_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d"} [metformin-p27216492] Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. (2016). https://pubmed.ncbi.nlm.nih.gov/27216492/ DOI: 10.1007/s00125-016-3992-6
Complete structured claim and evidence
Fasting and postprandial GLP-1 rose with all metformin treatments, with day-5 to baseline AUC ratios of 1.6-1.9.
Metformin → Glucagon-like peptide 1 / GLP-1 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/27216492.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d", "start_char": 0, "end_char": 3863, "text_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d"}
experimental_model
Two randomised crossover trials of delayed-release metformin targeted to the ileum
exposure
Delayed-release versus immediate-release metformin over 5 to 7 day periods
limitations
The dissociation of effect from plasma exposure is the key observation. Funded by the manufacturer of the delayed-release formulation, which the record retains.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
Gut hormones rose alongside the glucose effect.
primary_references
[metformin-p27216492] Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. (2016). https://pubmed.ncbi.nlm.nih.gov/27216492/ DOI: 10.1007/s00125-016-3992-6
tissue_or_cell_type
Distal small intestine
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 840–851
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two randomised crossover trials of delayed-release metformin targeted to the ileum · source_derived_draft · unverified_draft
### metformin-ileal-glp1 Fasting and postprandial GLP-1 rose with all metformin treatments, with day-5 to baseline AUC ratios of 1.6-1.9. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Gut hormones rose alongside the glucose effect. organism: Human tissue_or_cell_type: Distal small intestine experimental_model: Two randomised crossover trials of delayed-release metformin targeted to the ileum limitations: The dissociation of effect from plasma exposure is the key observation. Funded by the manufacturer of the delayed-release formulation, which the record retains. exposure: Delayed-release versus immediate-release metformin over 5 to 7 day periods evidence_span: {"source_cache": "artifacts/metformin-research/27216492.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d", "start_char": 0, "end_char": 3863, "text_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d"} [metformin-p27216492] Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. (2016). https://pubmed.ncbi.nlm.nih.gov/27216492/ DOI: 10.1007/s00125-016-3992-6
Complete structured claim and evidence
Fasting and postprandial PYY rose with all metformin treatments, with day-5 to baseline AUC ratios of 1.4-1.5.
Metformin → Peptide YY / PYY source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/27216492.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d", "start_char": 0, "end_char": 3863, "text_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d"}
experimental_model
Two randomised crossover trials of delayed-release metformin targeted to the ileum
exposure
Delayed-release versus immediate-release metformin over 5 to 7 day periods
limitations
The dissociation of effect from plasma exposure is the key observation. Funded by the manufacturer of the delayed-release formulation, which the record retains.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
Gut hormones rose alongside the glucose effect.
primary_references
[metformin-p27216492] Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. (2016). https://pubmed.ncbi.nlm.nih.gov/27216492/ DOI: 10.1007/s00125-016-3992-6
tissue_or_cell_type
Distal small intestine
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 853–864
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two randomised crossover trials of delayed-release metformin targeted to the ileum · source_derived_draft · unverified_draft
### metformin-ileal-pyy Fasting and postprandial PYY rose with all metformin treatments, with day-5 to baseline AUC ratios of 1.4-1.5. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Gut hormones rose alongside the glucose effect. organism: Human tissue_or_cell_type: Distal small intestine experimental_model: Two randomised crossover trials of delayed-release metformin targeted to the ileum limitations: The dissociation of effect from plasma exposure is the key observation. Funded by the manufacturer of the delayed-release formulation, which the record retains. exposure: Delayed-release versus immediate-release metformin over 5 to 7 day periods evidence_span: {"source_cache": "artifacts/metformin-research/27216492.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d", "start_char": 0, "end_char": 3863, "text_sha256": "c874a5c13e2e709b4b36040f281e2b187e7956b4610decddc35403170c0ed45d"} [metformin-p27216492] Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. (2016). https://pubmed.ncbi.nlm.nih.gov/27216492/ DOI: 10.1007/s00125-016-3992-6
Complete structured claim and evidence
Three days of metformin in newly diagnosed type 2 diabetes decreased Bacteroides fragilis and increased the bile acid glycoursodeoxycholic acid in the gut.
Metformin → Bacteroides fragilis source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/30397356.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf", "start_char": 0, "end_char": 1433, "text_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf"}
experimental_model
Metagenomic and metabolomic analysis in newly diagnosed type 2 diabetes with mouse colonisation experiments
exposure
Three days of metformin in treatment-naive people; B. fragilis colonisation in high-fat-diet mice
limitations
A three-day human exposure with a mouse causal test. GUDCA is identified as an intestinal FXR antagonist; whole-body FXR biology is not claimed.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human and mouse
plain_language
The drug changed which bacteria were present and which bile acid built up.
primary_references
[metformin-p30397356] Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. (2018). https://pubmed.ncbi.nlm.nih.gov/30397356/ DOI: 10.1038/s41591-018-0222-4
tissue_or_cell_type
Gut lumen and intestinal epithelium
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 866–877
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metagenomic and metabolomic analysis in newly diagnosed type 2 diabetes with mouse colonisation experiments · source_derived_draft · unverified_draft
### metformin-bfragilis-decrease Three days of metformin in newly diagnosed type 2 diabetes decreased Bacteroides fragilis and increased the bile acid glycoursodeoxycholic acid in the gut. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug changed which bacteria were present and which bile acid built up. organism: Human and mouse tissue_or_cell_type: Gut lumen and intestinal epithelium experimental_model: Metagenomic and metabolomic analysis in newly diagnosed type 2 diabetes with mouse colonisation experiments limitations: A three-day human exposure with a mouse causal test. GUDCA is identified as an intestinal FXR antagonist; whole-body FXR biology is not claimed. exposure: Three days of metformin in treatment-naive people; B. fragilis colonisation in high-fat-diet mice evidence_span: {"source_cache": "artifacts/metformin-research/30397356.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf", "start_char": 0, "end_char": 1433, "text_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf"} [metformin-p30397356] Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. (2018). https://pubmed.ncbi.nlm.nih.gov/30397356/ DOI: 10.1038/s41591-018-0222-4
Complete structured claim and evidence
GUDCA was identified as an intestinal FXR antagonist, and these changes were accompanied by inhibition of intestinal FXR signalling.
Glycoursodeoxycholic acid / GUDCA → Intestinal farnesoid X receptor signalling source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/30397356.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf", "start_char": 0, "end_char": 1433, "text_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf"}
experimental_model
Metagenomic and metabolomic analysis in newly diagnosed type 2 diabetes with mouse colonisation experiments
exposure
Three days of metformin in treatment-naive people; B. fragilis colonisation in high-fat-diet mice
limitations
A three-day human exposure with a mouse causal test. GUDCA is identified as an intestinal FXR antagonist; whole-body FXR biology is not claimed.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human and mouse
plain_language
That bile acid switches off a gut receptor that controls metabolism.
primary_references
[metformin-p30397356] Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. (2018). https://pubmed.ncbi.nlm.nih.gov/30397356/ DOI: 10.1038/s41591-018-0222-4
tissue_or_cell_type
Gut lumen and intestinal epithelium
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 879–890
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metagenomic and metabolomic analysis in newly diagnosed type 2 diabetes with mouse colonisation experiments · source_derived_draft · unverified_draft
### metformin-gudca-fxr GUDCA was identified as an intestinal FXR antagonist, and these changes were accompanied by inhibition of intestinal FXR signalling. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: That bile acid switches off a gut receptor that controls metabolism. organism: Human and mouse tissue_or_cell_type: Gut lumen and intestinal epithelium experimental_model: Metagenomic and metabolomic analysis in newly diagnosed type 2 diabetes with mouse colonisation experiments limitations: A three-day human exposure with a mouse causal test. GUDCA is identified as an intestinal FXR antagonist; whole-body FXR biology is not claimed. exposure: Three days of metformin in treatment-naive people; B. fragilis colonisation in high-fat-diet mice evidence_span: {"source_cache": "artifacts/metformin-research/30397356.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf", "start_char": 0, "end_char": 1433, "text_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf"} [metformin-p30397356] Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. (2018). https://pubmed.ncbi.nlm.nih.gov/30397356/ DOI: 10.1038/s41591-018-0222-4
Complete structured claim and evidence
High-fat-diet mice colonised with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin were abrogated.
Bacteroides fragilis → Glucose tolerance source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/30397356.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf", "start_char": 0, "end_char": 1433, "text_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf"}
experimental_model
Metagenomic and metabolomic analysis in newly diagnosed type 2 diabetes with mouse colonisation experiments
exposure
Three days of metformin in treatment-naive people; B. fragilis colonisation in high-fat-diet mice
limitations
A three-day human exposure with a mouse causal test. GUDCA is identified as an intestinal FXR antagonist; whole-body FXR biology is not claimed.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human and mouse
plain_language
Putting the bacterium back removed the benefit, which is what makes this more than a correlation.
primary_references
[metformin-p30397356] Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. (2018). https://pubmed.ncbi.nlm.nih.gov/30397356/ DOI: 10.1038/s41591-018-0222-4
tissue_or_cell_type
Gut lumen and intestinal epithelium
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 892–903
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metagenomic and metabolomic analysis in newly diagnosed type 2 diabetes with mouse colonisation experiments · source_derived_draft · unverified_draft
### metformin-bfragilis-colonisation High-fat-diet mice colonised with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin were abrogated. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Putting the bacterium back removed the benefit, which is what makes this more than a correlation. organism: Human and mouse tissue_or_cell_type: Gut lumen and intestinal epithelium experimental_model: Metagenomic and metabolomic analysis in newly diagnosed type 2 diabetes with mouse colonisation experiments limitations: A three-day human exposure with a mouse causal test. GUDCA is identified as an intestinal FXR antagonist; whole-body FXR biology is not claimed. exposure: Three days of metformin in treatment-naive people; B. fragilis colonisation in high-fat-diet mice evidence_span: {"source_cache": "artifacts/metformin-research/30397356.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf", "start_char": 0, "end_char": 1433, "text_sha256": "0dbf1f5a262207595ede745deeb9fc79ba7732dc4d6af6b5c9d654712d79c1cf"} [metformin-p30397356] Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. (2018). https://pubmed.ncbi.nlm.nih.gov/30397356/ DOI: 10.1038/s41591-018-0222-4
Complete structured claim and evidence
Metformin had strong effects on the gut microbiome in a four-month double-blind randomised trial, verified in a placebo subgroup that later switched to metformin.
Metformin → Gut microbiota composition source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/28530702.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "885eedb24772fbd218ff6497da6c39f486d0e0b0293ddd97e8fd7b3f23330b11", "start_char": 0, "end_char": 1137, "text_sha256": "885eedb24772fbd218ff6497da6c39f486d0e0b0293ddd97e8fd7b3f23330b11"}
experimental_model
Four-month double-blind randomised trial with faecal transfer to germ-free mice and a gut simulator
exposure
Metformin or placebo for 4 months in treatment-naive type 2 diabetes
limitations
The faecal transfer carries the causal claim. The metalloprotein observation is a genomic annotation, not a measured metal interaction.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human and mouse
plain_language
The drug reshapes the gut community within months.
primary_references
[metformin-p28530702] Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. (2017). https://pubmed.ncbi.nlm.nih.gov/28530702/ DOI: 10.1038/nm.4345
tissue_or_cell_type
Gut microbiome
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 905–916
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Four-month double-blind randomised trial with faecal transfer to germ-free mice and a gut simulator · source_derived_draft · unverified_draft
### metformin-microbiome-shift Metformin had strong effects on the gut microbiome in a four-month double-blind randomised trial, verified in a placebo subgroup that later switched to metformin. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug reshapes the gut community within months. organism: Human and mouse tissue_or_cell_type: Gut microbiome experimental_model: Four-month double-blind randomised trial with faecal transfer to germ-free mice and a gut simulator limitations: The faecal transfer carries the causal claim. The metalloprotein observation is a genomic annotation, not a measured metal interaction. exposure: Metformin or placebo for 4 months in treatment-naive type 2 diabetes evidence_span: {"source_cache": "artifacts/metformin-research/28530702.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "885eedb24772fbd218ff6497da6c39f486d0e0b0293ddd97e8fd7b3f23330b11", "start_char": 0, "end_char": 1137, "text_sha256": "885eedb24772fbd218ff6497da6c39f486d0e0b0293ddd97e8fd7b3f23330b11"} [metformin-p28530702] Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. (2017). https://pubmed.ncbi.nlm.nih.gov/28530702/ DOI: 10.1038/nm.4345
Complete structured claim and evidence
Transfer of faecal samples from metformin-treated donors to germ-free mice improved glucose tolerance in the recipients.
Gut microbiota composition → Glucose tolerance source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/28530702.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "885eedb24772fbd218ff6497da6c39f486d0e0b0293ddd97e8fd7b3f23330b11", "start_char": 0, "end_char": 1137, "text_sha256": "885eedb24772fbd218ff6497da6c39f486d0e0b0293ddd97e8fd7b3f23330b11"}
experimental_model
Four-month double-blind randomised trial with faecal transfer to germ-free mice and a gut simulator
exposure
Metformin or placebo for 4 months in treatment-naive type 2 diabetes
limitations
The faecal transfer carries the causal claim. The metalloprotein observation is a genomic annotation, not a measured metal interaction.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human and mouse
plain_language
Moving only the bacteria moved part of the benefit with them.
primary_references
[metformin-p28530702] Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. (2017). https://pubmed.ncbi.nlm.nih.gov/28530702/ DOI: 10.1038/nm.4345
tissue_or_cell_type
Gut microbiome
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 918–929
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Four-month double-blind randomised trial with faecal transfer to germ-free mice and a gut simulator · source_derived_draft · unverified_draft
### metformin-microbiome-transfer Transfer of faecal samples from metformin-treated donors to germ-free mice improved glucose tolerance in the recipients. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Moving only the bacteria moved part of the benefit with them. organism: Human and mouse tissue_or_cell_type: Gut microbiome experimental_model: Four-month double-blind randomised trial with faecal transfer to germ-free mice and a gut simulator limitations: The faecal transfer carries the causal claim. The metalloprotein observation is a genomic annotation, not a measured metal interaction. exposure: Metformin or placebo for 4 months in treatment-naive type 2 diabetes evidence_span: {"source_cache": "artifacts/metformin-research/28530702.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "885eedb24772fbd218ff6497da6c39f486d0e0b0293ddd97e8fd7b3f23330b11", "start_char": 0, "end_char": 1137, "text_sha256": "885eedb24772fbd218ff6497da6c39f486d0e0b0293ddd97e8fd7b3f23330b11"} [metformin-p28530702] Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. (2017). https://pubmed.ncbi.nlm.nih.gov/28530702/ DOI: 10.1038/nm.4345
Complete structured claim and evidence
In a gut simulator, many of the metformin-regulated genes in species from two different phyla encoded metalloproteins or metal transporters.
Metformin → Gut microbiota composition source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/28530702.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "885eedb24772fbd218ff6497da6c39f486d0e0b0293ddd97e8fd7b3f23330b11", "start_char": 0, "end_char": 1137, "text_sha256": "885eedb24772fbd218ff6497da6c39f486d0e0b0293ddd97e8fd7b3f23330b11"}
experimental_model
Four-month double-blind randomised trial with faecal transfer to germ-free mice and a gut simulator
exposure
Metformin or placebo for 4 months in treatment-naive type 2 diabetes
limitations
The faecal transfer carries the causal claim. The metalloprotein observation is a genomic annotation, not a measured metal interaction.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human and mouse
plain_language
The genes the drug touched in bacteria were unusually often metal-handling genes.
primary_references
[metformin-p28530702] Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. (2017). https://pubmed.ncbi.nlm.nih.gov/28530702/ DOI: 10.1038/nm.4345
tissue_or_cell_type
Gut microbiome
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 931–942
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Four-month double-blind randomised trial with faecal transfer to germ-free mice and a gut simulator · source_derived_draft · unverified_draft
### metformin-microbial-metalloproteins In a gut simulator, many of the metformin-regulated genes in species from two different phyla encoded metalloproteins or metal transporters. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The genes the drug touched in bacteria were unusually often metal-handling genes. organism: Human and mouse tissue_or_cell_type: Gut microbiome experimental_model: Four-month double-blind randomised trial with faecal transfer to germ-free mice and a gut simulator limitations: The faecal transfer carries the causal claim. The metalloprotein observation is a genomic annotation, not a measured metal interaction. exposure: Metformin or placebo for 4 months in treatment-naive type 2 diabetes evidence_span: {"source_cache": "artifacts/metformin-research/28530702.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "885eedb24772fbd218ff6497da6c39f486d0e0b0293ddd97e8fd7b3f23330b11", "start_char": 0, "end_char": 1137, "text_sha256": "885eedb24772fbd218ff6497da6c39f486d0e0b0293ddd97e8fd7b3f23330b11"} [metformin-p28530702] Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. (2017). https://pubmed.ncbi.nlm.nih.gov/28530702/ DOI: 10.1038/nm.4345
Complete structured claim and evidence
The reanalysis supported microbial mediation of metformin’s therapeutic effects through short-chain fatty acid production, while type 2 diabetes itself showed depletion of butyrate-producing taxa.
Metformin → Microbial short-chain fatty acid production source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/26633628.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f83ac1daddf6372ef8d16d3944ed9b6d62f0d1c12fb5815fb7c27cda2244f984", "start_char": 0, "end_char": 1570, "text_sha256": "f83ac1daddf6372ef8d16d3944ed9b6d62f0d1c12fb5815fb7c27cda2244f984"}
experimental_model
Reanalysis of 784 human gut metagenomes stratified by treatment
exposure
Metformin treatment as a confounder in type 2 diabetes metagenomes
limitations
An observational reanalysis. It separates disease signature from drug signature; it does not measure a clinical outcome. A corrigendum was issued for this paper (Nature 2017;545:116, PMID 28470190); its notice body was not available, so its impact on these records has not been assessed.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
Part of the benefit may run through the fatty acids gut bacteria make.
primary_references
[metformin-p26633628] Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. (2015). https://pubmed.ncbi.nlm.nih.gov/26633628/ DOI: 10.1038/nature15766
tissue_or_cell_type
Gut microbiome
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 944–955
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reanalysis of 784 human gut metagenomes stratified by treatment · source_derived_draft · unverified_draft
### metformin-scfa-mediation The reanalysis supported microbial mediation of metformin’s therapeutic effects through short-chain fatty acid production, while type 2 diabetes itself showed depletion of butyrate-producing taxa. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Part of the benefit may run through the fatty acids gut bacteria make. organism: Human tissue_or_cell_type: Gut microbiome experimental_model: Reanalysis of 784 human gut metagenomes stratified by treatment limitations: An observational reanalysis. It separates disease signature from drug signature; it does not measure a clinical outcome. A corrigendum was issued for this paper (Nature 2017;545:116, PMID 28470190); its notice body was not available, so its impact on these records has not been assessed. exposure: Metformin treatment as a confounder in type 2 diabetes metagenomes evidence_span: {"source_cache": "artifacts/metformin-research/26633628.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f83ac1daddf6372ef8d16d3944ed9b6d62f0d1c12fb5815fb7c27cda2244f984", "start_char": 0, "end_char": 1570, "text_sha256": "f83ac1daddf6372ef8d16d3944ed9b6d62f0d1c12fb5815fb7c27cda2244f984"} [metformin-p26633628] Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. (2015). https://pubmed.ncbi.nlm.nih.gov/26633628/ DOI: 10.1038/nature15766
Complete structured claim and evidence
A relative increase in the abundance of Escherichia species was proposed as a microbiota-mediated mechanism behind the known intestinal adverse effects of metformin.
Metformin → Escherichia species in the gut metagenome source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/26633628.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f83ac1daddf6372ef8d16d3944ed9b6d62f0d1c12fb5815fb7c27cda2244f984", "start_char": 0, "end_char": 1570, "text_sha256": "f83ac1daddf6372ef8d16d3944ed9b6d62f0d1c12fb5815fb7c27cda2244f984"}
experimental_model
Reanalysis of 784 human gut metagenomes stratified by treatment
exposure
Metformin treatment as a confounder in type 2 diabetes metagenomes
limitations
An observational reanalysis. It separates disease signature from drug signature; it does not measure a clinical outcome. A corrigendum was issued for this paper (Nature 2017;545:116, PMID 28470190); its notice body was not available, so its impact on these records has not been assessed.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
The same shift may explain why the drug upsets some people’s gut.
primary_references
[metformin-p26633628] Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. (2015). https://pubmed.ncbi.nlm.nih.gov/26633628/ DOI: 10.1038/nature15766
tissue_or_cell_type
Gut microbiome
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 957–968
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reanalysis of 784 human gut metagenomes stratified by treatment · source_derived_draft · unverified_draft
### metformin-escherichia-increase A relative increase in the abundance of Escherichia species was proposed as a microbiota-mediated mechanism behind the known intestinal adverse effects of metformin. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The same shift may explain why the drug upsets some people’s gut. organism: Human tissue_or_cell_type: Gut microbiome experimental_model: Reanalysis of 784 human gut metagenomes stratified by treatment limitations: An observational reanalysis. It separates disease signature from drug signature; it does not measure a clinical outcome. A corrigendum was issued for this paper (Nature 2017;545:116, PMID 28470190); its notice body was not available, so its impact on these records has not been assessed. exposure: Metformin treatment as a confounder in type 2 diabetes metagenomes evidence_span: {"source_cache": "artifacts/metformin-research/26633628.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f83ac1daddf6372ef8d16d3944ed9b6d62f0d1c12fb5815fb7c27cda2244f984", "start_char": 0, "end_char": 1570, "text_sha256": "f83ac1daddf6372ef8d16d3944ed9b6d62f0d1c12fb5815fb7c27cda2244f984"} [metformin-p26633628] Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. (2015). https://pubmed.ncbi.nlm.nih.gov/26633628/ DOI: 10.1038/nature15766
Complete structured claim and evidence
Upper small-intestinal metformin restored SGLT1 expression and glucose sensing in high-fat-diet rats, triggering an SGLT1-dependent pathway that lowered glucose production.
Metformin → Upper small-intestinal glucose sensing source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/29056513.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a04767b5cd42e2e3e3eced3fc1f6bc2c20d8c71adb044483fe8443ef1c59fc97", "start_char": 0, "end_char": 1110, "text_sha256": "a04767b5cd42e2e3e3eced3fc1f6bc2c20d8c71adb044483fe8443ef1c59fc97"}
experimental_model
Rat upper small-intestinal infusion, microbiota transplantation and SGLT1 measurements
exposure
Upper small-intestinal metformin in high-fat-diet rats
limitations
A regional intestinal mechanism in rats. Transplantation between rats supports the microbial step; human relevance is not established here.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat
plain_language
A sensor in the upper gut tells the liver to make less glucose, and the drug restores it.
primary_references
[metformin-p29056513] Metformin Alters Upper Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing Glucoregulatory Pathway. (2018). https://pubmed.ncbi.nlm.nih.gov/29056513/ DOI: 10.1016/j.cmet.2017.09.019
tissue_or_cell_type
Upper small intestine
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 970–981
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat upper small-intestinal infusion, microbiota transplantation and SGLT1 measurements · source_derived_draft · unverified_draft
### metformin-sglt1-sensing Upper small-intestinal metformin restored SGLT1 expression and glucose sensing in high-fat-diet rats, triggering an SGLT1-dependent pathway that lowered glucose production. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: A sensor in the upper gut tells the liver to make less glucose, and the drug restores it. organism: Rat tissue_or_cell_type: Upper small intestine experimental_model: Rat upper small-intestinal infusion, microbiota transplantation and SGLT1 measurements limitations: A regional intestinal mechanism in rats. Transplantation between rats supports the microbial step; human relevance is not established here. exposure: Upper small-intestinal metformin in high-fat-diet rats evidence_span: {"source_cache": "artifacts/metformin-research/29056513.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a04767b5cd42e2e3e3eced3fc1f6bc2c20d8c71adb044483fe8443ef1c59fc97", "start_char": 0, "end_char": 1110, "text_sha256": "a04767b5cd42e2e3e3eced3fc1f6bc2c20d8c71adb044483fe8443ef1c59fc97"} [metformin-p29056513] Metformin Alters Upper Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing Glucoregulatory Pathway. (2018). https://pubmed.ncbi.nlm.nih.gov/29056513/ DOI: 10.1016/j.cmet.2017.09.019
Complete structured claim and evidence
Metformin shifted the upper small-intestinal microbiota partly by increasing the abundance of Lactobacillus, and transplanting that microbiota into untreated rats reproduced the increase in glucose sensing through SGLT1.
Metformin → Lactobacillus species in the upper small intestine source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/29056513.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a04767b5cd42e2e3e3eced3fc1f6bc2c20d8c71adb044483fe8443ef1c59fc97", "start_char": 0, "end_char": 1110, "text_sha256": "a04767b5cd42e2e3e3eced3fc1f6bc2c20d8c71adb044483fe8443ef1c59fc97"}
experimental_model
Rat upper small-intestinal infusion, microbiota transplantation and SGLT1 measurements
exposure
Upper small-intestinal metformin in high-fat-diet rats
limitations
A regional intestinal mechanism in rats. Transplantation between rats supports the microbial step; human relevance is not established here.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Rat
plain_language
Transferring the bacteria transferred the sensing effect.
primary_references
[metformin-p29056513] Metformin Alters Upper Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing Glucoregulatory Pathway. (2018). https://pubmed.ncbi.nlm.nih.gov/29056513/ DOI: 10.1016/j.cmet.2017.09.019
tissue_or_cell_type
Upper small intestine
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 983–994
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat upper small-intestinal infusion, microbiota transplantation and SGLT1 measurements · source_derived_draft · unverified_draft
### metformin-lactobacillus-shift Metformin shifted the upper small-intestinal microbiota partly by increasing the abundance of Lactobacillus, and transplanting that microbiota into untreated rats reproduced the increase in glucose sensing through SGLT1. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Transferring the bacteria transferred the sensing effect. organism: Rat tissue_or_cell_type: Upper small intestine experimental_model: Rat upper small-intestinal infusion, microbiota transplantation and SGLT1 measurements limitations: A regional intestinal mechanism in rats. Transplantation between rats supports the microbial step; human relevance is not established here. exposure: Upper small-intestinal metformin in high-fat-diet rats evidence_span: {"source_cache": "artifacts/metformin-research/29056513.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a04767b5cd42e2e3e3eced3fc1f6bc2c20d8c71adb044483fe8443ef1c59fc97", "start_char": 0, "end_char": 1110, "text_sha256": "a04767b5cd42e2e3e3eced3fc1f6bc2c20d8c71adb044483fe8443ef1c59fc97"} [metformin-p29056513] Metformin Alters Upper Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing Glucoregulatory Pathway. (2018). https://pubmed.ncbi.nlm.nih.gov/29056513/ DOI: 10.1016/j.cmet.2017.09.019
Complete structured claim and evidence
AMPK interacted with FXR in the cytoplasm and phosphorylated it in its hinge domain, inhibiting FXR transcriptional activity and preventing coactivator recruitment.
AMP-activated protein kinase complexes → Human farnesoid X receptor / NR1H4 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/24531544.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad", "start_char": 0, "end_char": 1358, "text_sha256": "9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad"}
experimental_model
Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model
exposure
Metformin and other AMPK activators with FXR agonists
limitations
An adverse-direction finding: in a cholestasis model metformin worsened liver injury. Recorded because a mechanism record should not be filtered for favourable outcomes.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human cells and mouse
plain_language
The energy sensor directly switches down the bile-acid receptor.
primary_references
[metformin-p24531544] Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. (2014). https://pubmed.ncbi.nlm.nih.gov/24531544/ DOI: 10.1172/jci68815
tissue_or_cell_type
Liver and intestine
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 996–1007
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model · source_derived_draft · unverified_draft
### metformin-ampk-fxr AMPK interacted with FXR in the cytoplasm and phosphorylated it in its hinge domain, inhibiting FXR transcriptional activity and preventing coactivator recruitment. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The energy sensor directly switches down the bile-acid receptor. organism: Human cells and mouse tissue_or_cell_type: Liver and intestine experimental_model: Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model limitations: An adverse-direction finding: in a cholestasis model metformin worsened liver injury. Recorded because a mechanism record should not be filtered for favourable outcomes. exposure: Metformin and other AMPK activators with FXR agonists evidence_span: {"source_cache": "artifacts/metformin-research/24531544.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad", "start_char": 0, "end_char": 1358, "text_sha256": "9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad"} [metformin-p24531544] Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. (2014). https://pubmed.ncbi.nlm.nih.gov/24531544/ DOI: 10.1172/jci68815
Complete structured claim and evidence
Metformin inhibited FXR agonist induction of FXR target genes in mouse liver and intestine.
Metformin → FXR transcriptional activity source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/24531544.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad", "start_char": 0, "end_char": 1358, "text_sha256": "9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad"}
experimental_model
Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model
exposure
Metformin and other AMPK activators with FXR agonists
limitations
An adverse-direction finding: in a cholestasis model metformin worsened liver injury. Recorded because a mechanism record should not be filtered for favourable outcomes.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human cells and mouse
plain_language
The drug reaches that receptor’s gene programme in both organs.
primary_references
[metformin-p24531544] Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. (2014). https://pubmed.ncbi.nlm.nih.gov/24531544/ DOI: 10.1172/jci68815
tissue_or_cell_type
Liver and intestine
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1009–1020
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model · source_derived_draft · unverified_draft
### metformin-metformin-fxr-target-genes Metformin inhibited FXR agonist induction of FXR target genes in mouse liver and intestine. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug reaches that receptor’s gene programme in both organs. organism: Human cells and mouse tissue_or_cell_type: Liver and intestine experimental_model: Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model limitations: An adverse-direction finding: in a cholestasis model metformin worsened liver injury. Recorded because a mechanism record should not be filtered for favourable outcomes. exposure: Metformin and other AMPK activators with FXR agonists evidence_span: {"source_cache": "artifacts/metformin-research/24531544.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad", "start_char": 0, "end_char": 1358, "text_sha256": "9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad"} [metformin-p24531544] Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. (2014). https://pubmed.ncbi.nlm.nih.gov/24531544/ DOI: 10.1172/jci68815
Complete structured claim and evidence
In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis and worsened liver injury.
Metformin → Cholestatic liver injury in the 2014 mouse model source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/24531544.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad", "start_char": 0, "end_char": 1358, "text_sha256": "9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad"}
experimental_model
Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model
exposure
Metformin and other AMPK activators with FXR agonists
limitations
An adverse-direction finding: in a cholestasis model metformin worsened liver injury. Recorded because a mechanism record should not be filtered for favourable outcomes.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human cells and mouse
plain_language
In an already cholestatic liver the same mechanism made things worse.
primary_references
[metformin-p24531544] Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. (2014). https://pubmed.ncbi.nlm.nih.gov/24531544/ DOI: 10.1172/jci68815
tissue_or_cell_type
Liver and intestine
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1022–1033
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model · source_derived_draft · unverified_draft
### metformin-metformin-cholestasis In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis and worsened liver injury. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: In an already cholestatic liver the same mechanism made things worse. organism: Human cells and mouse tissue_or_cell_type: Liver and intestine experimental_model: Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model limitations: An adverse-direction finding: in a cholestasis model metformin worsened liver injury. Recorded because a mechanism record should not be filtered for favourable outcomes. exposure: Metformin and other AMPK activators with FXR agonists evidence_span: {"source_cache": "artifacts/metformin-research/24531544.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad", "start_char": 0, "end_char": 1358, "text_sha256": "9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad"} [metformin-p24531544] Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. (2014). https://pubmed.ncbi.nlm.nih.gov/24531544/ DOI: 10.1172/jci68815
Complete structured claim and evidence
Compared with placebo, metformin treatment was associated with a mean decrease in vitamin B-12 concentration of 19% over 4.3 years.
Metformin → Serum cobalamin concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/20488910.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922", "start_char": 0, "end_char": 2518, "text_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922"}
experimental_model
Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin
exposure
850 mg metformin three times daily for 4.3 years versus placebo
limitations
The strongest available human causal evidence for the B12 effect. It measured concentrations and deficiency incidence, not clinical deficiency syndromes.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
Years of the drug lower the vitamin in blood.
primary_references
[metformin-p20488910] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181
tissue_or_cell_type
Whole body
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1035–1046
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin · source_derived_draft · unverified_draft
### metformin-b12-decrease Compared with placebo, metformin treatment was associated with a mean decrease in vitamin B-12 concentration of 19% over 4.3 years. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Years of the drug lower the vitamin in blood. organism: Human tissue_or_cell_type: Whole body experimental_model: Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin limitations: The strongest available human causal evidence for the B12 effect. It measured concentrations and deficiency incidence, not clinical deficiency syndromes. exposure: 850 mg metformin three times daily for 4.3 years versus placebo evidence_span: {"source_cache": "artifacts/metformin-research/20488910.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922", "start_char": 0, "end_char": 2518, "text_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922"} [metformin-p20488910] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181
Complete structured claim and evidence
The absolute risk of vitamin B-12 deficiency below 150 pmol/l was 7.2 percentage points higher in the metformin group, with a number needed to harm of 13.8 per 4.3 years.
Metformin → Risk of biochemical vitamin B12 deficiency during metformin treatment source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/20488910.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922", "start_char": 0, "end_char": 2518, "text_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922"}
experimental_model
Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin
exposure
850 mg metformin three times daily for 4.3 years versus placebo
limitations
The strongest available human causal evidence for the B12 effect. It measured concentrations and deficiency incidence, not clinical deficiency syndromes.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
Roughly one in fourteen people treated for four years crossed into deficiency.
primary_references
[metformin-p20488910] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181
tissue_or_cell_type
Whole body
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1048–1059
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin · source_derived_draft · unverified_draft
### metformin-b12-deficiency-risk The absolute risk of vitamin B-12 deficiency below 150 pmol/l was 7.2 percentage points higher in the metformin group, with a number needed to harm of 13.8 per 4.3 years. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Roughly one in fourteen people treated for four years crossed into deficiency. organism: Human tissue_or_cell_type: Whole body experimental_model: Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin limitations: The strongest available human causal evidence for the B12 effect. It measured concentrations and deficiency incidence, not clinical deficiency syndromes. exposure: 850 mg metformin three times daily for 4.3 years versus placebo evidence_span: {"source_cache": "artifacts/metformin-research/20488910.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922", "start_char": 0, "end_char": 2518, "text_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922"} [metformin-p20488910] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181
Complete structured claim and evidence
Metformin was associated with a mean decrease in folate concentration of 5%, although after adjustment for body mass index and smoking no significant effect on folate remained.
Metformin → Serum folate concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/20488910.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922", "start_char": 0, "end_char": 2518, "text_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922"}
experimental_model
Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin
exposure
850 mg metformin three times daily for 4.3 years versus placebo
limitations
The strongest available human causal evidence for the B12 effect. It measured concentrations and deficiency incidence, not clinical deficiency syndromes.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
A small folate fall was seen but did not survive adjustment.
primary_references
[metformin-p20488910] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181
tissue_or_cell_type
Whole body
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1061–1072
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin · source_derived_draft · unverified_draft
### metformin-b12-folate-decrease Metformin was associated with a mean decrease in folate concentration of 5%, although after adjustment for body mass index and smoking no significant effect on folate remained. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: A small folate fall was seen but did not survive adjustment. organism: Human tissue_or_cell_type: Whole body experimental_model: Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin limitations: The strongest available human causal evidence for the B12 effect. It measured concentrations and deficiency incidence, not clinical deficiency syndromes. exposure: 850 mg metformin three times daily for 4.3 years versus placebo evidence_span: {"source_cache": "artifacts/metformin-research/20488910.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922", "start_char": 0, "end_char": 2518, "text_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922"} [metformin-p20488910] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181
Complete structured claim and evidence
Patients with vitamin B-12 deficiency at study end had a mean homocysteine of 23.7 micromol/l, compared with 18.1 in those with low B-12 and 14.9 in those with normal B-12.
Serum cobalamin concentration → Human fasting plasma total homocysteine concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/20488910.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922", "start_char": 0, "end_char": 2518, "text_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922"}
experimental_model
Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin
exposure
850 mg metformin three times daily for 4.3 years versus placebo
limitations
The strongest available human causal evidence for the B12 effect. It measured concentrations and deficiency incidence, not clinical deficiency syndromes.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
The lower the vitamin, the higher this metabolite climbed.
primary_references
[metformin-p20488910] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181
tissue_or_cell_type
Whole body
trigger_kind
biomarker_context Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1074–1085
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin · source_derived_draft · unverified_draft
### metformin-b12-homocysteine Patients with vitamin B-12 deficiency at study end had a mean homocysteine of 23.7 micromol/l, compared with 18.1 in those with low B-12 and 14.9 in those with normal B-12. Condition category: biomarker_context nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The lower the vitamin, the higher this metabolite climbed. organism: Human tissue_or_cell_type: Whole body experimental_model: Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin limitations: The strongest available human causal evidence for the B12 effect. It measured concentrations and deficiency incidence, not clinical deficiency syndromes. exposure: 850 mg metformin three times daily for 4.3 years versus placebo evidence_span: {"source_cache": "artifacts/metformin-research/20488910.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922", "start_char": 0, "end_char": 2518, "text_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922"} [metformin-p20488910] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181
Complete structured claim and evidence
Years of metformin use were associated with increased risk of B12 deficiency, with an odds ratio of 1.13 per year of use, and combined low and borderline-low B12 was more common in the metformin group at both 5 and 13 years.
Metformin → Risk of biochemical vitamin B12 deficiency during metformin treatment source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/26900641.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09cb74c29fe2d647d668d912a9a01962384e38bcc309a29c429d2caaed3048f1", "start_char": 0, "end_char": 1842, "text_sha256": "09cb74c29fe2d647d668d912a9a01962384e38bcc309a29c429d2caaed3048f1"}
experimental_model
Secondary analysis of the Diabetes Prevention Program Outcomes Study over 13 years
exposure
Metformin 850 mg twice daily versus placebo, then open-label metformin
limitations
Long-duration data. Neuropathy and anaemia were measured as prevalence, and the design cannot separate duration from cumulative dose.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
The risk keeps accumulating the longer the drug is taken.
primary_references
[metformin-p26900641] Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. (2016). https://pubmed.ncbi.nlm.nih.gov/26900641/ DOI: 10.1210/jc.2015-3754
tissue_or_cell_type
Whole body
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1087–1098
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Secondary analysis of the Diabetes Prevention Program Outcomes Study over 13 years · source_derived_draft · unverified_draft
### metformin-b12-duration Years of metformin use were associated with increased risk of B12 deficiency, with an odds ratio of 1.13 per year of use, and combined low and borderline-low B12 was more common in the metformin group at both 5 and 13 years. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The risk keeps accumulating the longer the drug is taken. organism: Human tissue_or_cell_type: Whole body experimental_model: Secondary analysis of the Diabetes Prevention Program Outcomes Study over 13 years limitations: Long-duration data. Neuropathy and anaemia were measured as prevalence, and the design cannot separate duration from cumulative dose. exposure: Metformin 850 mg twice daily versus placebo, then open-label metformin evidence_span: {"source_cache": "artifacts/metformin-research/26900641.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09cb74c29fe2d647d668d912a9a01962384e38bcc309a29c429d2caaed3048f1", "start_char": 0, "end_char": 1842, "text_sha256": "09cb74c29fe2d647d668d912a9a01962384e38bcc309a29c429d2caaed3048f1"} [metformin-p26900641] Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. (2016). https://pubmed.ncbi.nlm.nih.gov/26900641/ DOI: 10.1210/jc.2015-3754
Complete structured claim and evidence
Neuropathy prevalence was higher in the metformin group among those with low B12 levels, and anaemia prevalence was higher in the metformin group though it did not differ by B12 status.
Metformin → Clinical and electrophysiological severity of diabetic peripheral neuropathy source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/26900641.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09cb74c29fe2d647d668d912a9a01962384e38bcc309a29c429d2caaed3048f1", "start_char": 0, "end_char": 1842, "text_sha256": "09cb74c29fe2d647d668d912a9a01962384e38bcc309a29c429d2caaed3048f1"}
experimental_model
Secondary analysis of the Diabetes Prevention Program Outcomes Study over 13 years
exposure
Metformin 850 mg twice daily versus placebo, then open-label metformin
limitations
Long-duration data. Neuropathy and anaemia were measured as prevalence, and the design cannot separate duration from cumulative dose.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
The people with both the drug and a low vitamin had more nerve disease.
primary_references
[metformin-p26900641] Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. (2016). https://pubmed.ncbi.nlm.nih.gov/26900641/ DOI: 10.1210/jc.2015-3754
tissue_or_cell_type
Whole body
trigger_kind
biomarker_context Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1100–1111
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Secondary analysis of the Diabetes Prevention Program Outcomes Study over 13 years · source_derived_draft · unverified_draft
### metformin-b12-neuropathy-prevalence Neuropathy prevalence was higher in the metformin group among those with low B12 levels, and anaemia prevalence was higher in the metformin group though it did not differ by B12 status. Condition category: biomarker_context nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The people with both the drug and a low vitamin had more nerve disease. organism: Human tissue_or_cell_type: Whole body experimental_model: Secondary analysis of the Diabetes Prevention Program Outcomes Study over 13 years limitations: Long-duration data. Neuropathy and anaemia were measured as prevalence, and the design cannot separate duration from cumulative dose. exposure: Metformin 850 mg twice daily versus placebo, then open-label metformin evidence_span: {"source_cache": "artifacts/metformin-research/26900641.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09cb74c29fe2d647d668d912a9a01962384e38bcc309a29c429d2caaed3048f1", "start_char": 0, "end_char": 1842, "text_sha256": "09cb74c29fe2d647d668d912a9a01962384e38bcc309a29c429d2caaed3048f1"} [metformin-p26900641] Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. (2016). https://pubmed.ncbi.nlm.nih.gov/26900641/ DOI: 10.1210/jc.2015-3754
Complete structured claim and evidence
Each 1 g/day increment in metformin dose conferred an odds ratio of 2.88 for vitamin B12 deficiency, and use for three years or more carried an adjusted odds ratio of 2.39 compared with shorter use.
Metformin → Risk of biochemical vitamin B12 deficiency during metformin treatment source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/17030830.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0f8bbf977dd72887b2d251d3b66ab3ed60bd1917792ebef25f68bf9a8541951f", "start_char": 0, "end_char": 1862, "text_sha256": "0f8bbf977dd72887b2d251d3b66ab3ed60bd1917792ebef25f68bf9a8541951f"}
experimental_model
Nested case-control study of 155 cases and 310 matched controls
exposure
Current metformin dose and duration
limitations
Observational dose-response. Confounding by indication and by diet was adjusted for but cannot be excluded.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
Both a higher dose and a longer time raise the risk, each on its own.
primary_references
[metformin-p17030830] Risk factors of vitamin B(12) deficiency in patients receiving metformin. (2006). https://pubmed.ncbi.nlm.nih.gov/17030830/ DOI: 10.1001/archinte.166.18.1975
tissue_or_cell_type
Whole body
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1113–1124
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nested case-control study of 155 cases and 310 matched controls · source_derived_draft · unverified_draft
### metformin-b12-dose-response Each 1 g/day increment in metformin dose conferred an odds ratio of 2.88 for vitamin B12 deficiency, and use for three years or more carried an adjusted odds ratio of 2.39 compared with shorter use. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Both a higher dose and a longer time raise the risk, each on its own. organism: Human tissue_or_cell_type: Whole body experimental_model: Nested case-control study of 155 cases and 310 matched controls limitations: Observational dose-response. Confounding by indication and by diet was adjusted for but cannot be excluded. exposure: Current metformin dose and duration evidence_span: {"source_cache": "artifacts/metformin-research/17030830.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0f8bbf977dd72887b2d251d3b66ab3ed60bd1917792ebef25f68bf9a8541951f", "start_char": 0, "end_char": 1862, "text_sha256": "0f8bbf977dd72887b2d251d3b66ab3ed60bd1917792ebef25f68bf9a8541951f"} [metformin-p17030830] Risk factors of vitamin B(12) deficiency in patients receiving metformin. (2006). https://pubmed.ncbi.nlm.nih.gov/17030830/ DOI: 10.1001/archinte.166.18.1975
Complete structured claim and evidence
Serial measurements showed a similar decline in serum total vitamin B12 and in holotranscobalamin during metformin therapy.
Metformin → Circulating holotranscobalamin concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/10977010.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b", "start_char": 0, "end_char": 1267, "text_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b"}
experimental_model
Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation
exposure
Metformin for three months, then oral calcium supplementation
limitations
A small, non-randomised comparative study. The calcium-dependent ileal mechanism is the authors’ interpretation of the reversal, not a direct measurement of receptor binding.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
The carrier-bound fraction that reaches cells fell alongside the total.
primary_references
[metformin-p10977010] Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. (2000). https://pubmed.ncbi.nlm.nih.gov/10977010/ DOI: 10.2337/diacare.23.9.1227
tissue_or_cell_type
Ileal absorption
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1126–1137
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation · source_derived_draft · unverified_draft
### metformin-b12-holotc-decline Serial measurements showed a similar decline in serum total vitamin B12 and in holotranscobalamin during metformin therapy. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The carrier-bound fraction that reaches cells fell alongside the total. organism: Human tissue_or_cell_type: Ileal absorption experimental_model: Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation limitations: A small, non-randomised comparative study. The calcium-dependent ileal mechanism is the authors’ interpretation of the reversal, not a direct measurement of receptor binding. exposure: Metformin for three months, then oral calcium supplementation evidence_span: {"source_cache": "artifacts/metformin-research/10977010.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b", "start_char": 0, "end_char": 1267, "text_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b"} [metformin-p10977010] Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. (2000). https://pubmed.ncbi.nlm.nih.gov/10977010/ DOI: 10.2337/diacare.23.9.1227
Complete structured claim and evidence
Oral calcium supplementation reversed the metformin-induced depression of serum holotranscobalamin.
Oral calcium supplementation in the 2000 study → Circulating holotranscobalamin concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/10977010.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b", "start_char": 0, "end_char": 1267, "text_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b"}
experimental_model
Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation
exposure
Metformin for three months, then oral calcium supplementation
limitations
A small, non-randomised comparative study. The calcium-dependent ileal mechanism is the authors’ interpretation of the reversal, not a direct measurement of receptor binding.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
Adding calcium undid the drug’s effect on the vitamin.
primary_references
[metformin-p10977010] Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. (2000). https://pubmed.ncbi.nlm.nih.gov/10977010/ DOI: 10.2337/diacare.23.9.1227
tissue_or_cell_type
Ileal absorption
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1139–1150
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation · source_derived_draft · unverified_draft
### metformin-b12-calcium-reversal Oral calcium supplementation reversed the metformin-induced depression of serum holotranscobalamin. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Adding calcium undid the drug’s effect on the vitamin. organism: Human tissue_or_cell_type: Ileal absorption experimental_model: Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation limitations: A small, non-randomised comparative study. The calcium-dependent ileal mechanism is the authors’ interpretation of the reversal, not a direct measurement of receptor binding. exposure: Metformin for three months, then oral calcium supplementation evidence_span: {"source_cache": "artifacts/metformin-research/10977010.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b", "start_char": 0, "end_char": 1267, "text_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b"} [metformin-p10977010] Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. (2000). https://pubmed.ncbi.nlm.nih.gov/10977010/ DOI: 10.2337/diacare.23.9.1227
Complete structured claim and evidence
The authors attributed diminished B12 absorption and low serum B12 and transcobalamin-bound B12 during metformin to a calcium-dependent ileal membrane antagonism, since uptake of the B12-intrinsic factor complex by ileal cell surface receptors is calcium-dependent.
Metformin → Intestinal cobalamin absorption source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/10977010.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b", "start_char": 0, "end_char": 1267, "text_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b"}
experimental_model
Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation
exposure
Metformin for three months, then oral calcium supplementation
limitations
A small, non-randomised comparative study. The calcium-dependent ileal mechanism is the authors’ interpretation of the reversal, not a direct measurement of receptor binding.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
The proposed step is the calcium-dependent grab of the vitamin at the ileal cell surface.
primary_references
[metformin-p10977010] Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. (2000). https://pubmed.ncbi.nlm.nih.gov/10977010/ DOI: 10.2337/diacare.23.9.1227
tissue_or_cell_type
Ileal absorption
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1152–1163
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation · source_derived_draft · unverified_draft
### metformin-b12-calcium-mechanism The authors attributed diminished B12 absorption and low serum B12 and transcobalamin-bound B12 during metformin to a calcium-dependent ileal membrane antagonism, since uptake of the B12-intrinsic factor complex by ileal cell surface receptors is calcium-dependent. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The proposed step is the calcium-dependent grab of the vitamin at the ileal cell surface. organism: Human tissue_or_cell_type: Ileal absorption experimental_model: Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation limitations: A small, non-randomised comparative study. The calcium-dependent ileal mechanism is the authors’ interpretation of the reversal, not a direct measurement of receptor binding. exposure: Metformin for three months, then oral calcium supplementation evidence_span: {"source_cache": "artifacts/metformin-research/10977010.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b", "start_char": 0, "end_char": 1267, "text_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b"} [metformin-p10977010] Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. (2000). https://pubmed.ncbi.nlm.nih.gov/10977010/ DOI: 10.2337/diacare.23.9.1227
Complete structured claim and evidence
Vitamin B12 malabsorption was most prominent in patients on metformin, and pathological Schilling tests, increased glycocholic acid deconjugation and decreased faecal bile acid excretion normalised or improved after stopping the biguanide or giving antibiotics, suggesting small-intestinal bacterial overgrowth binding the intrinsic-factor-B12 complex.
Metformin → Intestinal cobalamin absorption source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/873086.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1889488dcc83ec22842eccf766b842761a6c10643dbf7d8e6f8308331dfdf01c", "start_char": 0, "end_char": 1442, "text_sha256": "1889488dcc83ec22842eccf766b842761a6c10643dbf7d8e6f8308331dfdf01c"}
experimental_model
Breath test, faecal bile acid measurement and Schilling tests in maturity-onset diabetics on biguanides
exposure
Phenformin, buformin or metformin, with antibiotic treatment as a test
limitations
A 1977 study using the Schilling test. It proposes bacterial overgrowth as the mechanism; the antibiotic reversal is suggestive rather than definitive, and it competes with the calcium-dependent explanation.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
A second explanation: bacteria in the small bowel take up the vitamin before the body can.
primary_references
[metformin-p873086] Alteration of bile acid metabolism and vitamin-B12-absorption in diabetics on biguanides. (1977). https://pubmed.ncbi.nlm.nih.gov/873086/ DOI: 10.1007/bf01219698
tissue_or_cell_type
Small intestine
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1165–1176
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Breath test, faecal bile acid measurement and Schilling tests in maturity-onset diabetics on biguanides · source_derived_draft · unverified_draft
### metformin-b12-bacterial-overgrowth Vitamin B12 malabsorption was most prominent in patients on metformin, and pathological Schilling tests, increased glycocholic acid deconjugation and decreased faecal bile acid excretion normalised or improved after stopping the biguanide or giving antibiotics, suggesting small-intestinal bacterial overgrowth binding the intrinsic-factor-B12 complex. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: A second explanation: bacteria in the small bowel take up the vitamin before the body can. organism: Human tissue_or_cell_type: Small intestine experimental_model: Breath test, faecal bile acid measurement and Schilling tests in maturity-onset diabetics on biguanides limitations: A 1977 study using the Schilling test. It proposes bacterial overgrowth as the mechanism; the antibiotic reversal is suggestive rather than definitive, and it competes with the calcium-dependent explanation. exposure: Phenformin, buformin or metformin, with antibiotic treatment as a test evidence_span: {"source_cache": "artifacts/metformin-research/873086.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1889488dcc83ec22842eccf766b842761a6c10643dbf7d8e6f8308331dfdf01c", "start_char": 0, "end_char": 1442, "text_sha256": "1889488dcc83ec22842eccf766b842761a6c10643dbf7d8e6f8308331dfdf01c"} [metformin-p873086] Alteration of bile acid metabolism and vitamin-B12-absorption in diabetics on biguanides. (1977). https://pubmed.ncbi.nlm.nih.gov/873086/ DOI: 10.1007/bf01219698
Complete structured claim and evidence
Sixteen weeks of metformin reduced folate by 7% and vitamin B12 by 14% compared with placebo.
Metformin → Serum folate concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/14535967.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a", "start_char": 0, "end_char": 1640, "text_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a"}
experimental_model
Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks
exposure
Metformin added to insulin for 16 weeks versus placebo
limitations
Short-duration randomised evidence that the folate and B12 changes precede a measurable homocysteine change.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
Both vitamins fall within months, not only after years.
primary_references
[metformin-p14535967] Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. (2003). https://pubmed.ncbi.nlm.nih.gov/14535967/ DOI: 10.1046/j.1365-2796.2003.01213.x
tissue_or_cell_type
Whole body
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1178–1189
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks · source_derived_draft · unverified_draft
### metformin-short-term-b12-folate Sixteen weeks of metformin reduced folate by 7% and vitamin B12 by 14% compared with placebo. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Both vitamins fall within months, not only after years. organism: Human tissue_or_cell_type: Whole body experimental_model: Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks limitations: Short-duration randomised evidence that the folate and B12 changes precede a measurable homocysteine change. exposure: Metformin added to insulin for 16 weeks versus placebo evidence_span: {"source_cache": "artifacts/metformin-research/14535967.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a", "start_char": 0, "end_char": 1640, "text_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a"} [metformin-p14535967] Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. (2003). https://pubmed.ncbi.nlm.nih.gov/14535967/ DOI: 10.1046/j.1365-2796.2003.01213.x
Complete structured claim and evidence
Metformin use was associated with a 4% increase in homocysteine, and the increase could be explained by the decreases in folate and vitamin B12.
Metformin → Human fasting plasma total homocysteine concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/14535967.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a", "start_char": 0, "end_char": 1640, "text_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a"}
experimental_model
Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks
exposure
Metformin added to insulin for 16 weeks versus placebo
limitations
Short-duration randomised evidence that the folate and B12 changes precede a measurable homocysteine change.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
The rise in that metabolite was accounted for by the two vitamins falling.
primary_references
[metformin-p14535967] Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. (2003). https://pubmed.ncbi.nlm.nih.gov/14535967/ DOI: 10.1046/j.1365-2796.2003.01213.x
tissue_or_cell_type
Whole body
trigger_kind
biomarker_context Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1191–1202
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks · source_derived_draft · unverified_draft
### metformin-short-term-homocysteine Metformin use was associated with a 4% increase in homocysteine, and the increase could be explained by the decreases in folate and vitamin B12. Condition category: biomarker_context nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The rise in that metabolite was accounted for by the two vitamins falling. organism: Human tissue_or_cell_type: Whole body experimental_model: Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks limitations: Short-duration randomised evidence that the folate and B12 changes precede a measurable homocysteine change. exposure: Metformin added to insulin for 16 weeks versus placebo evidence_span: {"source_cache": "artifacts/metformin-research/14535967.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a", "start_char": 0, "end_char": 1640, "text_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a"} [metformin-p14535967] Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. (2003). https://pubmed.ncbi.nlm.nih.gov/14535967/ DOI: 10.1046/j.1365-2796.2003.01213.x
Complete structured claim and evidence
Metformin-treated patients had depressed cobalamin levels and elevated fasting methylmalonic acid and homocysteine levels.
Metformin → Fasting plasma methylmalonic acid concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/19846797.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "801079bb07e94e223a1d7bd7fc99c9f229320aa56b6afa11700765f481558b33", "start_char": 0, "end_char": 1789, "text_sha256": "801079bb07e94e223a1d7bd7fc99c9f229320aa56b6afa11700765f481558b33"}
experimental_model
Prospective case-control study of 122 people with type 2 diabetes and symptomatic neuropathy
exposure
More than six months of metformin versus no metformin exposure
limitations
Case-control design with nerve conduction studies. Cumulative dose correlated with severity, but the design cannot establish that the drug caused the neuropathy.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
The marker that rises specifically when B12 is short also rose.
primary_references
[metformin-p19846797] Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. (2010). https://pubmed.ncbi.nlm.nih.gov/19846797/ DOI: 10.2337/dc09-0606
tissue_or_cell_type
Peripheral nerve
trigger_kind
biomarker_context Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1204–1215
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Prospective case-control study of 122 people with type 2 diabetes and symptomatic neuropathy · source_derived_draft · unverified_draft
### metformin-mma-elevation Metformin-treated patients had depressed cobalamin levels and elevated fasting methylmalonic acid and homocysteine levels. Condition category: biomarker_context nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The marker that rises specifically when B12 is short also rose. organism: Human tissue_or_cell_type: Peripheral nerve experimental_model: Prospective case-control study of 122 people with type 2 diabetes and symptomatic neuropathy limitations: Case-control design with nerve conduction studies. Cumulative dose correlated with severity, but the design cannot establish that the drug caused the neuropathy. exposure: More than six months of metformin versus no metformin exposure evidence_span: {"source_cache": "artifacts/metformin-research/19846797.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "801079bb07e94e223a1d7bd7fc99c9f229320aa56b6afa11700765f481558b33", "start_char": 0, "end_char": 1789, "text_sha256": "801079bb07e94e223a1d7bd7fc99c9f229320aa56b6afa11700765f481558b33"} [metformin-p19846797] Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. (2010). https://pubmed.ncbi.nlm.nih.gov/19846797/ DOI: 10.2337/dc09-0606
Complete structured claim and evidence
Clinical and electrophysiological measures identified more severe peripheral neuropathy in metformin-treated patients, and the cumulative metformin dose correlated strongly with these differences.
Metformin → Clinical and electrophysiological severity of diabetic peripheral neuropathy source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/19846797.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "801079bb07e94e223a1d7bd7fc99c9f229320aa56b6afa11700765f481558b33", "start_char": 0, "end_char": 1789, "text_sha256": "801079bb07e94e223a1d7bd7fc99c9f229320aa56b6afa11700765f481558b33"}
experimental_model
Prospective case-control study of 122 people with type 2 diabetes and symptomatic neuropathy
exposure
More than six months of metformin versus no metformin exposure
limitations
Case-control design with nerve conduction studies. Cumulative dose correlated with severity, but the design cannot establish that the drug caused the neuropathy.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
More drug over time went with worse nerve findings in this comparison.
primary_references
[metformin-p19846797] Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. (2010). https://pubmed.ncbi.nlm.nih.gov/19846797/ DOI: 10.2337/dc09-0606
tissue_or_cell_type
Peripheral nerve
trigger_kind
biomarker_context Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1217–1228
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Prospective case-control study of 122 people with type 2 diabetes and symptomatic neuropathy · source_derived_draft · unverified_draft
### metformin-neuropathy-severity Clinical and electrophysiological measures identified more severe peripheral neuropathy in metformin-treated patients, and the cumulative metformin dose correlated strongly with these differences. Condition category: biomarker_context nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: More drug over time went with worse nerve findings in this comparison. organism: Human tissue_or_cell_type: Peripheral nerve experimental_model: Prospective case-control study of 122 people with type 2 diabetes and symptomatic neuropathy limitations: Case-control design with nerve conduction studies. Cumulative dose correlated with severity, but the design cannot establish that the drug caused the neuropathy. exposure: More than six months of metformin versus no metformin exposure evidence_span: {"source_cache": "artifacts/metformin-research/19846797.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "801079bb07e94e223a1d7bd7fc99c9f229320aa56b6afa11700765f481558b33", "start_char": 0, "end_char": 1789, "text_sha256": "801079bb07e94e223a1d7bd7fc99c9f229320aa56b6afa11700765f481558b33"} [metformin-p19846797] Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. (2010). https://pubmed.ncbi.nlm.nih.gov/19846797/ DOI: 10.2337/dc09-0606
Complete structured claim and evidence
Metabolomic and isotopic uptake methods identified thiamine as a principal endogenous substrate of OCT1.
Human organic cation transporter 1 / OCT1 / SLC22A1 → Thiamine (vitamin B1) source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/24961373.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70", "start_char": 0, "end_char": 1270, "text_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70"}
experimental_model
Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake
exposure
Metformin and phenformin against thiamine uptake; acute metformin in wild-type mice
limitations
Identifies thiamine as an endogenous OCT1 substrate and shows competitive inhibition by metformin. The steatosis phenotype is a mouse phenotype.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse and human transporter
plain_language
The transporter that carries the drug into the liver normally carries vitamin B1.
primary_references
[metformin-p24961373] OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. (2014). https://pubmed.ncbi.nlm.nih.gov/24961373/ DOI: 10.1073/pnas.1314939111
tissue_or_cell_type
Liver and intestine
transport_effect
raises Identified by isotopic uptake as a principal endogenous substrate.
transport_pool
the expressing cell Identified by isotopic uptake as a principal endogenous substrate.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1230–1241
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake · source_derived_draft · unverified_draft
### metformin-oct1-thiamine-substrate Metabolomic and isotopic uptake methods identified thiamine as a principal endogenous substrate of OCT1. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The transporter that carries the drug into the liver normally carries vitamin B1. organism: Mouse and human transporter tissue_or_cell_type: Liver and intestine experimental_model: Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake limitations: Identifies thiamine as an endogenous OCT1 substrate and shows competitive inhibition by metformin. The steatosis phenotype is a mouse phenotype. exposure: Metformin and phenformin against thiamine uptake; acute metformin in wild-type mice evidence_span: {"source_cache": "artifacts/metformin-research/24961373.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70", "start_char": 0, "end_char": 1270, "text_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70"} [metformin-p24961373] OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. (2014). https://pubmed.ncbi.nlm.nih.gov/24961373/ DOI: 10.1073/pnas.1314939111
Complete structured claim and evidence
Metformin and the biguanide analogue phenformin competitively inhibited OCT1-mediated thiamine uptake.
Metformin → Cellular free-thiamine uptake source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/24961373.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70", "start_char": 0, "end_char": 1270, "text_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70"}
experimental_model
Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake
exposure
Metformin and phenformin against thiamine uptake; acute metformin in wild-type mice
limitations
Identifies thiamine as an endogenous OCT1 substrate and shows competitive inhibition by metformin. The steatosis phenotype is a mouse phenotype.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse and human transporter
plain_language
The drug and the vitamin compete for the same door.
primary_references
[metformin-p24961373] OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. (2014). https://pubmed.ncbi.nlm.nih.gov/24961373/ DOI: 10.1073/pnas.1314939111
tissue_or_cell_type
Liver and intestine
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1243–1254
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake · source_derived_draft · unverified_draft
### metformin-metformin-thiamine-competition Metformin and the biguanide analogue phenformin competitively inhibited OCT1-mediated thiamine uptake. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug and the vitamin compete for the same door. organism: Mouse and human transporter tissue_or_cell_type: Liver and intestine experimental_model: Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake limitations: Identifies thiamine as an endogenous OCT1 substrate and shows competitive inhibition by metformin. The steatosis phenotype is a mouse phenotype. exposure: Metformin and phenformin against thiamine uptake; acute metformin in wild-type mice evidence_span: {"source_cache": "artifacts/metformin-research/24961373.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70", "start_char": 0, "end_char": 1270, "text_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70"} [metformin-p24961373] OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. (2014). https://pubmed.ncbi.nlm.nih.gov/24961373/ DOI: 10.1073/pnas.1314939111
Complete structured claim and evidence
Acute administration of metformin to wild-type mice reduced intestinal accumulation of thiamine.
Metformin → Mouse intestinal thiamine accumulation source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/24961373.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70", "start_char": 0, "end_char": 1270, "text_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70"}
experimental_model
Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake
exposure
Metformin and phenformin against thiamine uptake; acute metformin in wild-type mice
limitations
Identifies thiamine as an endogenous OCT1 substrate and shows competitive inhibition by metformin. The steatosis phenotype is a mouse phenotype.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse
plain_language
In a living animal, a dose of the drug lowered how much vitamin B1 the gut held.
primary_references
[metformin-p24961373] OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. (2014). https://pubmed.ncbi.nlm.nih.gov/24961373/ DOI: 10.1073/pnas.1314939111
tissue_or_cell_type
Liver and intestine
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1256–1267
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake · source_derived_draft · unverified_draft
### metformin-metformin-intestinal-thiamine Acute administration of metformin to wild-type mice reduced intestinal accumulation of thiamine. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: In a living animal, a dose of the drug lowered how much vitamin B1 the gut held. organism: Mouse tissue_or_cell_type: Liver and intestine experimental_model: Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake limitations: Identifies thiamine as an endogenous OCT1 substrate and shows competitive inhibition by metformin. The steatosis phenotype is a mouse phenotype. exposure: Metformin and phenformin against thiamine uptake; acute metformin in wild-type mice evidence_span: {"source_cache": "artifacts/metformin-research/24961373.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70", "start_char": 0, "end_char": 1270, "text_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70"} [metformin-p24961373] OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. (2014). https://pubmed.ncbi.nlm.nih.gov/24961373/ DOI: 10.1073/pnas.1314939111
Complete structured claim and evidence
Loss of Oct1 raised the AMP to ATP ratio and activated AMPK, and thiamine deficiency itself enhanced phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase.
Thiamine (vitamin B1) → AMP-activated protein kinase complexes source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/24961373.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70", "start_char": 0, "end_char": 1270, "text_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70"}
experimental_model
Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake
exposure
Metformin and phenformin against thiamine uptake; acute metformin in wild-type mice
limitations
Identifies thiamine as an endogenous OCT1 substrate and shows competitive inhibition by metformin. The steatosis phenotype is a mouse phenotype.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Mouse and human transporter
plain_language
Short vitamin B1 switches on the same energy sensor the drug does.
primary_references
[metformin-p24961373] OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. (2014). https://pubmed.ncbi.nlm.nih.gov/24961373/ DOI: 10.1073/pnas.1314939111
tissue_or_cell_type
Liver and intestine
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1269–1280
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake · source_derived_draft · unverified_draft
### metformin-oct1-loss-ampk-thiamine Loss of Oct1 raised the AMP to ATP ratio and activated AMPK, and thiamine deficiency itself enhanced phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Short vitamin B1 switches on the same energy sensor the drug does. organism: Mouse and human transporter tissue_or_cell_type: Liver and intestine experimental_model: Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake limitations: Identifies thiamine as an endogenous OCT1 substrate and shows competitive inhibition by metformin. The steatosis phenotype is a mouse phenotype. exposure: Metformin and phenformin against thiamine uptake; acute metformin in wild-type mice evidence_span: {"source_cache": "artifacts/metformin-research/24961373.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70", "start_char": 0, "end_char": 1270, "text_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70"} [metformin-p24961373] OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. (2014). https://pubmed.ncbi.nlm.nih.gov/24961373/ DOI: 10.1073/pnas.1314939111
Complete structured claim and evidence
Human THTR-2 (SLC19A3), highly expressed in the small intestine, transported metformin with a Km of 1.15 mM, whereas THTR-1 did not.
Human thiamine transporter 2 / SLC19A3 → Metformin source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/26528626.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "67707c1e73b51b8db54bf2ffdfbb07210b877ce242d62840836f3e546dd4c6a9", "start_char": 0, "end_char": 1436, "text_sha256": "67707c1e73b51b8db54bf2ffdfbb07210b877ce242d62840836f3e546dd4c6a9"}
experimental_model
Transporter uptake assays in cells expressing human THTR-1 and THTR-2
exposure
Metformin against thiamine uptake by SLC19A2 and SLC19A3
limitations
In-vitro transport with a millimolar Km. The authors propose intestinal relevance; they do not measure human thiamine status.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human transporters, with mouse orthologue comparison
plain_language
The vitamin B1 transporter in the gut also carries the drug.
primary_references
[metformin-p26528626] Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). (2015). https://pubmed.ncbi.nlm.nih.gov/26528626/ DOI: 10.1021/acs.molpharmaceut.5b00501
tissue_or_cell_type
Small-intestinal absorption
transport_effect
raises Intestinal THTR-2 transported metformin with a Km of 1.15 mM, which is absorption.
transport_pool
the enterocyte interior Intestinal THTR-2 transported metformin with a Km of 1.15 mM, which is absorption.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1282–1293
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transporter uptake assays in cells expressing human THTR-1 and THTR-2 · source_derived_draft · unverified_draft
### metformin-thtr2-transports-metformin Human THTR-2 (SLC19A3), highly expressed in the small intestine, transported metformin with a Km of 1.15 mM, whereas THTR-1 did not. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The vitamin B1 transporter in the gut also carries the drug. organism: Human transporters, with mouse orthologue comparison tissue_or_cell_type: Small-intestinal absorption experimental_model: Transporter uptake assays in cells expressing human THTR-1 and THTR-2 limitations: In-vitro transport with a millimolar Km. The authors propose intestinal relevance; they do not measure human thiamine status. exposure: Metformin against thiamine uptake by SLC19A2 and SLC19A3 evidence_span: {"source_cache": "artifacts/metformin-research/26528626.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "67707c1e73b51b8db54bf2ffdfbb07210b877ce242d62840836f3e546dd4c6a9", "start_char": 0, "end_char": 1436, "text_sha256": "67707c1e73b51b8db54bf2ffdfbb07210b877ce242d62840836f3e546dd4c6a9"} [metformin-p26528626] Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). (2015). https://pubmed.ncbi.nlm.nih.gov/26528626/ DOI: 10.1021/acs.molpharmaceut.5b00501
Complete structured claim and evidence
Metformin, along with phenformin, chloroquine, verapamil, famotidine and amprolium, inhibited hTHTR-2-mediated uptake of both thiamine and metformin.
Metformin → Intestinal free-thiamine uptake source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/26528626.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "67707c1e73b51b8db54bf2ffdfbb07210b877ce242d62840836f3e546dd4c6a9", "start_char": 0, "end_char": 1436, "text_sha256": "67707c1e73b51b8db54bf2ffdfbb07210b877ce242d62840836f3e546dd4c6a9"}
experimental_model
Transporter uptake assays in cells expressing human THTR-1 and THTR-2
exposure
Metformin against thiamine uptake by SLC19A2 and SLC19A3
limitations
In-vitro transport with a millimolar Km. The authors propose intestinal relevance; they do not measure human thiamine status.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human transporters, with mouse orthologue comparison
plain_language
Because they share the carrier, the drug gets in the vitamin’s way.
primary_references
[metformin-p26528626] Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). (2015). https://pubmed.ncbi.nlm.nih.gov/26528626/ DOI: 10.1021/acs.molpharmaceut.5b00501
tissue_or_cell_type
Small-intestinal absorption
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1295–1306
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transporter uptake assays in cells expressing human THTR-1 and THTR-2 · source_derived_draft · unverified_draft
### metformin-metformin-inhibits-thtr2 Metformin, along with phenformin, chloroquine, verapamil, famotidine and amprolium, inhibited hTHTR-2-mediated uptake of both thiamine and metformin. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Because they share the carrier, the drug gets in the vitamin’s way. organism: Human transporters, with mouse orthologue comparison tissue_or_cell_type: Small-intestinal absorption experimental_model: Transporter uptake assays in cells expressing human THTR-1 and THTR-2 limitations: In-vitro transport with a millimolar Km. The authors propose intestinal relevance; they do not measure human thiamine status. exposure: Metformin against thiamine uptake by SLC19A2 and SLC19A3 evidence_span: {"source_cache": "artifacts/metformin-research/26528626.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "67707c1e73b51b8db54bf2ffdfbb07210b877ce242d62840836f3e546dd4c6a9", "start_char": 0, "end_char": 1436, "text_sha256": "67707c1e73b51b8db54bf2ffdfbb07210b877ce242d62840836f3e546dd4c6a9"} [metformin-p26528626] Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). (2015). https://pubmed.ncbi.nlm.nih.gov/26528626/ DOI: 10.1021/acs.molpharmaceut.5b00501
Complete structured claim and evidence
Species differences in the substrate specificity of THTR-2 between the human and mouse orthologues were observed.
Human thiamine transporter 2 / SLC19A3 → Mouse thiamine transporter 2 / Slc19a3 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/26528626.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "67707c1e73b51b8db54bf2ffdfbb07210b877ce242d62840836f3e546dd4c6a9", "start_char": 0, "end_char": 1436, "text_sha256": "67707c1e73b51b8db54bf2ffdfbb07210b877ce242d62840836f3e546dd4c6a9"}
experimental_model
Transporter uptake assays in cells expressing human THTR-1 and THTR-2
exposure
Metformin against thiamine uptake by SLC19A2 and SLC19A3
limitations
In-vitro transport with a millimolar Km. The authors propose intestinal relevance; they do not measure human thiamine status.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human transporters, with mouse orthologue comparison
plain_language
The mouse version of this carrier does not behave like the human one.
primary_references
[metformin-p26528626] Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). (2015). https://pubmed.ncbi.nlm.nih.gov/26528626/ DOI: 10.1021/acs.molpharmaceut.5b00501
tissue_or_cell_type
Small-intestinal absorption
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1308–1319
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transporter uptake assays in cells expressing human THTR-1 and THTR-2 · source_derived_draft · unverified_draft
### metformin-thtr2-species-difference Species differences in the substrate specificity of THTR-2 between the human and mouse orthologues were observed. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The mouse version of this carrier does not behave like the human one. organism: Human transporters, with mouse orthologue comparison tissue_or_cell_type: Small-intestinal absorption experimental_model: Transporter uptake assays in cells expressing human THTR-1 and THTR-2 limitations: In-vitro transport with a millimolar Km. The authors propose intestinal relevance; they do not measure human thiamine status. exposure: Metformin against thiamine uptake by SLC19A2 and SLC19A3 evidence_span: {"source_cache": "artifacts/metformin-research/26528626.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "67707c1e73b51b8db54bf2ffdfbb07210b877ce242d62840836f3e546dd4c6a9", "start_char": 0, "end_char": 1436, "text_sha256": "67707c1e73b51b8db54bf2ffdfbb07210b877ce242d62840836f3e546dd4c6a9"} [metformin-p26528626] Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). (2015). https://pubmed.ncbi.nlm.nih.gov/26528626/ DOI: 10.1021/acs.molpharmaceut.5b00501
Complete structured claim and evidence
Of 1360 screened compounds, 146 inhibited ThTR-2, and several oral drugs including metformin were predicted to reach intestinal concentrations that may result in ThTR-2-mediated drug-nutrient interactions.
Metformin → Human thiamine transporter 2 / SLC19A3 source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/31764942.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "21758b02cd824f37a6e1e076657c0cf72d08cc6babcb66773613f129dc13f15b", "start_char": 0, "end_char": 1829, "text_sha256": "21758b02cd824f37a6e1e076657c0cf72d08cc6babcb66773613f129dc13f15b"}
experimental_model
High-throughput screen of 1360 compounds, in-silico modelling and electronic health record analysis
exposure
Inhibition kinetics with IC50 values and predicted intestinal concentrations
limitations
A screen plus a records analysis, not a trial. The trial termination cited as motivation involved a different, more potent inhibitor.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human transporter and human health records
plain_language
Among many drugs tested, this one is expected to reach gut levels high enough to matter.
primary_references
[metformin-p31764942] Drug-nutrient interactions: discovering prescription drug inhibitors of the thiamine transporter ThTR-2 (SLC19A3). (2020). https://pubmed.ncbi.nlm.nih.gov/31764942/ DOI: 10.1093/ajcn/nqz255
tissue_or_cell_type
Intestinal thiamine absorption
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1321–1332
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · High-throughput screen of 1360 compounds, in-silico modelling and electronic health record analysis · source_derived_draft · unverified_draft
### metformin-thtr2-drug-screen Of 1360 screened compounds, 146 inhibited ThTR-2, and several oral drugs including metformin were predicted to reach intestinal concentrations that may result in ThTR-2-mediated drug-nutrient interactions. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Among many drugs tested, this one is expected to reach gut levels high enough to matter. organism: Human transporter and human health records tissue_or_cell_type: Intestinal thiamine absorption experimental_model: High-throughput screen of 1360 compounds, in-silico modelling and electronic health record analysis limitations: A screen plus a records analysis, not a trial. The trial termination cited as motivation involved a different, more potent inhibitor. exposure: Inhibition kinetics with IC50 values and predicted intestinal concentrations evidence_span: {"source_cache": "artifacts/metformin-research/31764942.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "21758b02cd824f37a6e1e076657c0cf72d08cc6babcb66773613f129dc13f15b", "start_char": 0, "end_char": 1829, "text_sha256": "21758b02cd824f37a6e1e076657c0cf72d08cc6babcb66773613f129dc13f15b"} [metformin-p31764942] Drug-nutrient interactions: discovering prescription drug inhibitors of the thiamine transporter ThTR-2 (SLC19A3). (2020). https://pubmed.ncbi.nlm.nih.gov/31764942/ DOI: 10.1093/ajcn/nqz255
Complete structured claim and evidence
Electronic health record analysis suggested that thiamine laboratory values are reduced in individuals receiving prescription drugs that significantly inhibit ThTR-2, particularly in vulnerable populations such as individuals with alcoholism.
Human thiamine transporter 2 / SLC19A3 → Plasma thiamine concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/31764942.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "21758b02cd824f37a6e1e076657c0cf72d08cc6babcb66773613f129dc13f15b", "start_char": 0, "end_char": 1829, "text_sha256": "21758b02cd824f37a6e1e076657c0cf72d08cc6babcb66773613f129dc13f15b"}
experimental_model
High-throughput screen of 1360 compounds, in-silico modelling and electronic health record analysis
exposure
Inhibition kinetics with IC50 values and predicted intestinal concentrations
limitations
A screen plus a records analysis, not a trial. The trial termination cited as motivation involved a different, more potent inhibitor.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human transporter and human health records
plain_language
In real records, people on these drugs had lower vitamin B1, most of all those already at risk.
primary_references
[metformin-p31764942] Drug-nutrient interactions: discovering prescription drug inhibitors of the thiamine transporter ThTR-2 (SLC19A3). (2020). https://pubmed.ncbi.nlm.nih.gov/31764942/ DOI: 10.1093/ajcn/nqz255
tissue_or_cell_type
Intestinal thiamine absorption
trigger_kind
biomarker_context Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1334–1345
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · High-throughput screen of 1360 compounds, in-silico modelling and electronic health record analysis · source_derived_draft · unverified_draft
### metformin-thtr2-records-signal Electronic health record analysis suggested that thiamine laboratory values are reduced in individuals receiving prescription drugs that significantly inhibit ThTR-2, particularly in vulnerable populations such as individuals with alcoholism. Condition category: biomarker_context nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: In real records, people on these drugs had lower vitamin B1, most of all those already at risk. organism: Human transporter and human health records tissue_or_cell_type: Intestinal thiamine absorption experimental_model: High-throughput screen of 1360 compounds, in-silico modelling and electronic health record analysis limitations: A screen plus a records analysis, not a trial. The trial termination cited as motivation involved a different, more potent inhibitor. exposure: Inhibition kinetics with IC50 values and predicted intestinal concentrations evidence_span: {"source_cache": "artifacts/metformin-research/31764942.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "21758b02cd824f37a6e1e076657c0cf72d08cc6babcb66773613f129dc13f15b", "start_char": 0, "end_char": 1829, "text_sha256": "21758b02cd824f37a6e1e076657c0cf72d08cc6babcb66773613f129dc13f15b"} [metformin-p31764942] Drug-nutrient interactions: discovering prescription drug inhibitors of the thiamine transporter ThTR-2 (SLC19A3). (2020). https://pubmed.ncbi.nlm.nih.gov/31764942/ DOI: 10.1093/ajcn/nqz255
Complete structured claim and evidence
Copper sequestration opposed the known actions of metformin on AMPK-dependent signalling, and biguanide metal-binding was required for regulation of AMPK, glucose production, gluconeogenic gene expression, mitochondrial respiration and mitochondrial copper binding.
Experimental cellular copper sequestration → AMP-activated protein kinase complexes source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/22492524.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a0b1587d871d78b3bccefc5a47b277191faf6bc3b070dbe43295a0b21a633c56", "start_char": 0, "end_char": 1526, "text_sha256": "a0b1587d871d78b3bccefc5a47b277191faf6bc3b070dbe43295a0b21a633c56"}
experimental_model
Copper sequestration and biguanide analogues in cells, with mitochondrial measurements
exposure
Metformin and analogues with and without copper sequestration
limitations
A metal-dependence result using chemical sequestration and structural analogues. It does not establish that copper status in a person changes the drug’s effect.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Cultured cells
plain_language
Take copper away and the drug stops doing several of the things it normally does.
primary_references
[metformin-p22492524] Cellular responses to the metal-binding properties of metformin. (2012). https://pubmed.ncbi.nlm.nih.gov/22492524/ DOI: 10.2337/db11-0961
tissue_or_cell_type
Mitochondria and cytoplasm
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1347–1358
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Copper sequestration and biguanide analogues in cells, with mitochondrial measurements · source_derived_draft · unverified_draft
### metformin-copper-dependence-ampk Copper sequestration opposed the known actions of metformin on AMPK-dependent signalling, and biguanide metal-binding was required for regulation of AMPK, glucose production, gluconeogenic gene expression, mitochondrial respiration and mitochondrial copper binding. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Take copper away and the drug stops doing several of the things it normally does. organism: Cultured cells tissue_or_cell_type: Mitochondria and cytoplasm experimental_model: Copper sequestration and biguanide analogues in cells, with mitochondrial measurements limitations: A metal-dependence result using chemical sequestration and structural analogues. It does not establish that copper status in a person changes the drug’s effect. exposure: Metformin and analogues with and without copper sequestration evidence_span: {"source_cache": "artifacts/metformin-research/22492524.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a0b1587d871d78b3bccefc5a47b277191faf6bc3b070dbe43295a0b21a633c56", "start_char": 0, "end_char": 1526, "text_sha256": "a0b1587d871d78b3bccefc5a47b277191faf6bc3b070dbe43295a0b21a633c56"} [metformin-p22492524] Cellular responses to the metal-binding properties of metformin. (2012). https://pubmed.ncbi.nlm.nih.gov/22492524/ DOI: 10.2337/db11-0961
Complete structured claim and evidence
Regulation of S6 phosphorylation was prevented only by direct modification of the metal-liganding groups of the biguanide structure, supporting that AMPK and S6 phosphorylation are regulated independently by biguanides.
Metformin → Ribosomal protein S6 phosphorylation source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/22492524.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a0b1587d871d78b3bccefc5a47b277191faf6bc3b070dbe43295a0b21a633c56", "start_char": 0, "end_char": 1526, "text_sha256": "a0b1587d871d78b3bccefc5a47b277191faf6bc3b070dbe43295a0b21a633c56"}
experimental_model
Copper sequestration and biguanide analogues in cells, with mitochondrial measurements
exposure
Metformin and analogues with and without copper sequestration
limitations
A metal-dependence result using chemical sequestration and structural analogues. It does not establish that copper status in a person changes the drug’s effect.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Cultured cells
plain_language
Two of the drug’s effects depend on the metal in different ways, so they are separate routes.
primary_references
[metformin-p22492524] Cellular responses to the metal-binding properties of metformin. (2012). https://pubmed.ncbi.nlm.nih.gov/22492524/ DOI: 10.2337/db11-0961
tissue_or_cell_type
Mitochondria and cytoplasm
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1360–1371
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Copper sequestration and biguanide analogues in cells, with mitochondrial measurements · source_derived_draft · unverified_draft
### metformin-copper-s6-independent Regulation of S6 phosphorylation was prevented only by direct modification of the metal-liganding groups of the biguanide structure, supporting that AMPK and S6 phosphorylation are regulated independently by biguanides. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Two of the drug’s effects depend on the metal in different ways, so they are separate routes. organism: Cultured cells tissue_or_cell_type: Mitochondria and cytoplasm experimental_model: Copper sequestration and biguanide analogues in cells, with mitochondrial measurements limitations: A metal-dependence result using chemical sequestration and structural analogues. It does not establish that copper status in a person changes the drug’s effect. exposure: Metformin and analogues with and without copper sequestration evidence_span: {"source_cache": "artifacts/metformin-research/22492524.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a0b1587d871d78b3bccefc5a47b277191faf6bc3b070dbe43295a0b21a633c56", "start_char": 0, "end_char": 1526, "text_sha256": "a0b1587d871d78b3bccefc5a47b277191faf6bc3b070dbe43295a0b21a633c56"} [metformin-p22492524] Cellular responses to the metal-binding properties of metformin. (2012). https://pubmed.ncbi.nlm.nih.gov/22492524/ DOI: 10.2337/db11-0961
Complete structured claim and evidence
Metformin can occur as an anion in aqueous medium at moderate pH and forms much stronger complexes with Cu(II) ions than the comparator propanediimidamide, suggesting that biguanides may induce oxidation of Cu(I) ions extracted from proteins.
Metformin → Copper(II) ion source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/24433134.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a6dda36e30a49ba48e8200b6de36f39a8ab80a1bcbda819c03d3442bb8705963", "start_char": 0, "end_char": 1430, "text_sha256": "a6dda36e30a49ba48e8200b6de36f39a8ab80a1bcbda819c03d3442bb8705963"}
experimental_model
Computational and binding comparison of metformin and propanediimidamide with copper
exposure
Copper(I) and copper(II) binding energies, pKa and hydrophilicity
limitations
A chemistry study proposing a pro-oxidant role. It is explicitly a hypothesis about mitochondrial activity, not a cellular measurement.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Chemical and computational
plain_language
The drug grabs copper tightly enough that it could pull it off proteins and oxidise it.
primary_references
[metformin-p24433134] Biomolecular mode of action of metformin in relation to its copper binding properties. (2014). https://pubmed.ncbi.nlm.nih.gov/24433134/ DOI: 10.1021/bi401444n
tissue_or_cell_type
Molecular interaction
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1373–1384
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Computational and binding comparison of metformin and propanediimidamide with copper · source_derived_draft · unverified_draft
### metformin-copper-binding-chemistry Metformin can occur as an anion in aqueous medium at moderate pH and forms much stronger complexes with Cu(II) ions than the comparator propanediimidamide, suggesting that biguanides may induce oxidation of Cu(I) ions extracted from proteins. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug grabs copper tightly enough that it could pull it off proteins and oxidise it. organism: Chemical and computational tissue_or_cell_type: Molecular interaction experimental_model: Computational and binding comparison of metformin and propanediimidamide with copper limitations: A chemistry study proposing a pro-oxidant role. It is explicitly a hypothesis about mitochondrial activity, not a cellular measurement. exposure: Copper(I) and copper(II) binding energies, pKa and hydrophilicity evidence_span: {"source_cache": "artifacts/metformin-research/24433134.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a6dda36e30a49ba48e8200b6de36f39a8ab80a1bcbda819c03d3442bb8705963", "start_char": 0, "end_char": 1430, "text_sha256": "a6dda36e30a49ba48e8200b6de36f39a8ab80a1bcbda819c03d3442bb8705963"} [metformin-p24433134] Biomolecular mode of action of metformin in relation to its copper binding properties. (2014). https://pubmed.ncbi.nlm.nih.gov/24433134/ DOI: 10.1021/bi401444n
Complete structured claim and evidence
Metformin significantly reduced fasting hepatic glucose production from 12.9 to 11.0 micromol/kg/min but did not enhance total body glucose disposal during insulin stimulation.
Metformin → Hepatic glucose production / endogenous glucose production source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/8923861.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "164b296465a3d5730d3dba4c66062ce97c227e61b866b6a42c5beb772f51d688", "start_char": 0, "end_char": 3516, "text_sha256": "164b296465a3d5730d3dba4c66062ce97c227e61b866b6a42c5beb772f51d688"}
experimental_model
Randomised double-blind placebo-controlled trial with tracer infusions and euglycaemic clamp
exposure
15 weeks of metformin versus placebo in 20 people with type 2 diabetes
limitations
Tracer measurement of where the glucose effect comes from. Lactate turnover was measured directly and did not change, which bears on lactate safety questions.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
In people, the drug works by making the liver release less glucose, not by improving uptake.
primary_references
[metformin-p8923861] Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. (1996). https://pubmed.ncbi.nlm.nih.gov/8923861/ DOI: 10.1210/jcem.81.11.8923861
tissue_or_cell_type
Liver and whole body
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1386–1397
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomised double-blind placebo-controlled trial with tracer infusions and euglycaemic clamp · source_derived_draft · unverified_draft
### metformin-human-hgp-reduction Metformin significantly reduced fasting hepatic glucose production from 12.9 to 11.0 micromol/kg/min but did not enhance total body glucose disposal during insulin stimulation. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: In people, the drug works by making the liver release less glucose, not by improving uptake. organism: Human tissue_or_cell_type: Liver and whole body experimental_model: Randomised double-blind placebo-controlled trial with tracer infusions and euglycaemic clamp limitations: Tracer measurement of where the glucose effect comes from. Lactate turnover was measured directly and did not change, which bears on lactate safety questions. exposure: 15 weeks of metformin versus placebo in 20 people with type 2 diabetes evidence_span: {"source_cache": "artifacts/metformin-research/8923861.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "164b296465a3d5730d3dba4c66062ce97c227e61b866b6a42c5beb772f51d688", "start_char": 0, "end_char": 3516, "text_sha256": "164b296465a3d5730d3dba4c66062ce97c227e61b866b6a42c5beb772f51d688"} [metformin-p8923861] Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. (1996). https://pubmed.ncbi.nlm.nih.gov/8923861/ DOI: 10.1210/jcem.81.11.8923861
Complete structured claim and evidence
The authors concluded that suppression of accelerated basal hepatic glucose production was most likely secondary to an inhibition of hepatic glycogenolysis, since the percentage of gluconeogenesis from lactate and the rate of lactate-derived gluconeogenesis were unchanged.
Metformin → Hepatic glycogenolysis source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/8923861.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "164b296465a3d5730d3dba4c66062ce97c227e61b866b6a42c5beb772f51d688", "start_char": 0, "end_char": 3516, "text_sha256": "164b296465a3d5730d3dba4c66062ce97c227e61b866b6a42c5beb772f51d688"}
experimental_model
Randomised double-blind placebo-controlled trial with tracer infusions and euglycaemic clamp
exposure
15 weeks of metformin versus placebo in 20 people with type 2 diabetes
limitations
Tracer measurement of where the glucose effect comes from. Lactate turnover was measured directly and did not change, which bears on lactate safety questions.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
The reduction came from breaking down stored glycogen less, not from making less new glucose.
primary_references
[metformin-p8923861] Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. (1996). https://pubmed.ncbi.nlm.nih.gov/8923861/ DOI: 10.1210/jcem.81.11.8923861
tissue_or_cell_type
Liver and whole body
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1399–1410
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomised double-blind placebo-controlled trial with tracer infusions and euglycaemic clamp · source_derived_draft · unverified_draft
### metformin-human-glycogenolysis The authors concluded that suppression of accelerated basal hepatic glucose production was most likely secondary to an inhibition of hepatic glycogenolysis, since the percentage of gluconeogenesis from lactate and the rate of lactate-derived gluconeogenesis were unchanged. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The reduction came from breaking down stored glycogen less, not from making less new glucose. organism: Human tissue_or_cell_type: Liver and whole body experimental_model: Randomised double-blind placebo-controlled trial with tracer infusions and euglycaemic clamp limitations: Tracer measurement of where the glucose effect comes from. Lactate turnover was measured directly and did not change, which bears on lactate safety questions. exposure: 15 weeks of metformin versus placebo in 20 people with type 2 diabetes evidence_span: {"source_cache": "artifacts/metformin-research/8923861.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "164b296465a3d5730d3dba4c66062ce97c227e61b866b6a42c5beb772f51d688", "start_char": 0, "end_char": 3516, "text_sha256": "164b296465a3d5730d3dba4c66062ce97c227e61b866b6a42c5beb772f51d688"} [metformin-p8923861] Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. (1996). https://pubmed.ncbi.nlm.nih.gov/8923861/ DOI: 10.1210/jcem.81.11.8923861
Complete structured claim and evidence
Basal lactate turnover and lactate oxidation, and total lactate turnover during the insulin clamp, were similar before and after metformin treatment.
Metformin → Whole-body lactate turnover source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/metformin-research/8923861.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "164b296465a3d5730d3dba4c66062ce97c227e61b866b6a42c5beb772f51d688", "start_char": 0, "end_char": 3516, "text_sha256": "164b296465a3d5730d3dba4c66062ce97c227e61b866b6a42c5beb772f51d688"}
experimental_model
Randomised double-blind placebo-controlled trial with tracer infusions and euglycaemic clamp
exposure
15 weeks of metformin versus placebo in 20 people with type 2 diabetes
limitations
Tracer measurement of where the glucose effect comes from. Lactate turnover was measured directly and did not change, which bears on lactate safety questions.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
At therapeutic doses in this study, lactate handling did not change.
primary_references
[metformin-p8923861] Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. (1996). https://pubmed.ncbi.nlm.nih.gov/8923861/ DOI: 10.1210/jcem.81.11.8923861
tissue_or_cell_type
Liver and whole body
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1412–1423
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomised double-blind placebo-controlled trial with tracer infusions and euglycaemic clamp · source_derived_draft · unverified_draft
### metformin-human-lactate-turnover Basal lactate turnover and lactate oxidation, and total lactate turnover during the insulin clamp, were similar before and after metformin treatment. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: At therapeutic doses in this study, lactate handling did not change. organism: Human tissue_or_cell_type: Liver and whole body experimental_model: Randomised double-blind placebo-controlled trial with tracer infusions and euglycaemic clamp limitations: Tracer measurement of where the glucose effect comes from. Lactate turnover was measured directly and did not change, which bears on lactate safety questions. exposure: 15 weeks of metformin versus placebo in 20 people with type 2 diabetes evidence_span: {"source_cache": "artifacts/metformin-research/8923861.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "164b296465a3d5730d3dba4c66062ce97c227e61b866b6a42c5beb772f51d688", "start_char": 0, "end_char": 3516, "text_sha256": "164b296465a3d5730d3dba4c66062ce97c227e61b866b6a42c5beb772f51d688"} [metformin-p8923861] Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. (1996). https://pubmed.ncbi.nlm.nih.gov/8923861/ DOI: 10.1210/jcem.81.11.8923861
Complete structured claim and evidence
Ten of fourteen patients with lactic acidosis during metformin treatment had significant metformin accumulation, generally because metformin was not withdrawn despite conditions affecting its renal elimination, and serum creatinine correlated positively with plasma metformin.
Serum creatinine concentration → Plasma metformin exposure source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/7555503.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301", "start_char": 0, "end_char": 2221, "text_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301"}
experimental_model
Plasma metformin measurement by HPLC in 14 people with lactic acidosis during metformin treatment
exposure
Chronic metformin with intercurrent renal failure
limitations
A case series in an intensive-care setting. It argues against a simple dose-toxicity relationship; the numbers are small.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
When the kidneys fail and the drug is not stopped, it builds up.
primary_references
[metformin-p7555503] Role of metformin accumulation in metformin-associated lactic acidosis. (1995). https://pubmed.ncbi.nlm.nih.gov/7555503/ DOI: 10.2337/diacare.18.6.779
tissue_or_cell_type
Whole body
trigger_kind
machinery_impairment Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1425–1436
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Plasma metformin measurement by HPLC in 14 people with lactic acidosis during metformin treatment · source_derived_draft · unverified_draft
### metformin-accumulation-lactic-acidosis Ten of fourteen patients with lactic acidosis during metformin treatment had significant metformin accumulation, generally because metformin was not withdrawn despite conditions affecting its renal elimination, and serum creatinine correlated positively with plasma metformin. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: When the kidneys fail and the drug is not stopped, it builds up. organism: Human tissue_or_cell_type: Whole body experimental_model: Plasma metformin measurement by HPLC in 14 people with lactic acidosis during metformin treatment limitations: A case series in an intensive-care setting. It argues against a simple dose-toxicity relationship; the numbers are small. exposure: Chronic metformin with intercurrent renal failure evidence_span: {"source_cache": "artifacts/metformin-research/7555503.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301", "start_char": 0, "end_char": 2221, "text_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301"} [metformin-p7555503] Role of metformin accumulation in metformin-associated lactic acidosis. (1995). https://pubmed.ncbi.nlm.nih.gov/7555503/ DOI: 10.2337/diacare.18.6.779
Complete structured claim and evidence
Metformin-associated lactic acidosis was not necessarily due to metformin accumulation, true type B aerobic lactic acidosis seemed exceptional, and neither the severity of the clinical picture nor the degree of accumulation predicted survival.
Metformin-associated lactic acidosis → Blood lactate concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/7555503.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301", "start_char": 0, "end_char": 2221, "text_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301"}
experimental_model
Plasma metformin measurement by HPLC in 14 people with lactic acidosis during metformin treatment
exposure
Chronic metformin with intercurrent renal failure
limitations
A case series in an intensive-care setting. It argues against a simple dose-toxicity relationship; the numbers are small.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
The drug level alone did not decide who developed the acidosis or who survived it.
primary_references
[metformin-p7555503] Role of metformin accumulation in metformin-associated lactic acidosis. (1995). https://pubmed.ncbi.nlm.nih.gov/7555503/ DOI: 10.2337/diacare.18.6.779
tissue_or_cell_type
Whole body
trigger_kind
biomarker_context Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1438–1449
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Plasma metformin measurement by HPLC in 14 people with lactic acidosis during metformin treatment · source_derived_draft · unverified_draft
### metformin-acidosis-not-only-accumulation Metformin-associated lactic acidosis was not necessarily due to metformin accumulation, true type B aerobic lactic acidosis seemed exceptional, and neither the severity of the clinical picture nor the degree of accumulation predicted survival. Condition category: biomarker_context nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug level alone did not decide who developed the acidosis or who survived it. organism: Human tissue_or_cell_type: Whole body experimental_model: Plasma metformin measurement by HPLC in 14 people with lactic acidosis during metformin treatment limitations: A case series in an intensive-care setting. It argues against a simple dose-toxicity relationship; the numbers are small. exposure: Chronic metformin with intercurrent renal failure evidence_span: {"source_cache": "artifacts/metformin-research/7555503.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301", "start_char": 0, "end_char": 2221, "text_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301"} [metformin-p7555503] Role of metformin accumulation in metformin-associated lactic acidosis. (1995). https://pubmed.ncbi.nlm.nih.gov/7555503/ DOI: 10.2337/diacare.18.6.779
Complete structured claim and evidence
The crude incidence of lactic acidosis was 3.3 cases per 100,000 person-years among metformin users and 4.8 among sulfonylurea users, and relevant comorbidities known as risk factors were identifiable in all six cases.
Metformin → Incidence of lactic acidosis during oral antidiabetes-drug use source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/metformin-research/18782901.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1fb3a7b0fff3f288a6d6f3da8e2fea2746e2869eee8e4171fbf6568e48124243", "start_char": 0, "end_char": 1676, "text_sha256": "1fb3a7b0fff3f288a6d6f3da8e2fea2746e2869eee8e4171fbf6568e48124243"}
experimental_model
Nested case-control analysis in 50,048 people with type 2 diabetes in the UK General Practice Research Database
exposure
Current use of oral antidiabetes drugs
limitations
A population incidence estimate. Six cases in total is a very small numerator, and comorbidity was present in all of them.
nutrient_topic
Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin
organism
Human
plain_language
The event is very rare, and it was no more common than with the comparison drug.
primary_references
[metformin-p18782901] Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis. (2008). https://pubmed.ncbi.nlm.nih.gov/18782901/ DOI: 10.2337/dc08-1171
tissue_or_cell_type
Whole body
trigger_kind
biomarker_context Imported condition classification; unverified.
Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1451–1462
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nested case-control analysis in 50,048 people with type 2 diabetes in the UK General Practice Research Database · source_derived_draft · unverified_draft
### metformin-lactic-acidosis-incidence The crude incidence of lactic acidosis was 3.3 cases per 100,000 person-years among metformin users and 4.8 among sulfonylurea users, and relevant comorbidities known as risk factors were identifiable in all six cases. Condition category: biomarker_context nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The event is very rare, and it was no more common than with the comparison drug. organism: Human tissue_or_cell_type: Whole body experimental_model: Nested case-control analysis in 50,048 people with type 2 diabetes in the UK General Practice Research Database limitations: A population incidence estimate. Six cases in total is a very small numerator, and comorbidity was present in all of them. exposure: Current use of oral antidiabetes drugs evidence_span: {"source_cache": "artifacts/metformin-research/18782901.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1fb3a7b0fff3f288a6d6f3da8e2fea2746e2869eee8e4171fbf6568e48124243", "start_char": 0, "end_char": 1676, "text_sha256": "1fb3a7b0fff3f288a6d6f3da8e2fea2746e2869eee8e4171fbf6568e48124243"} [metformin-p18782901] Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis. (2008). https://pubmed.ncbi.nlm.nih.gov/18782901/ DOI: 10.2337/dc08-1171
Complete structured claim and evidence

Availability and dependencies

Each situation shows the normal role first, then what the sources report under a specific condition. A shortfall in the diet, a fault in the machinery, and a low blood reading are kept separate because they are not the same thing.

When the liver cannot take metformin up

Condition: machinery_impairment · Experimental Oct1 deletion in mice, and reduced-function OCT1 variants in people.

Normal role: OCT1 carries metformin from portal blood into hepatocytes.

Recorded consequence: Hepatic metformin falls to the extracellular space, and the drug’s hepatic and glucose-lowering effects fall with it.

Scope: Mouse knockout and human genetic variation

When metformin cannot be cleared into urine

Condition: machinery_impairment · Experimental Mate1 deletion in mice.

Normal role: MATE1 secretes metformin across the luminal membrane into urine.

Recorded consequence: Renal and secretory clearance fall to roughly a fifth, and blood exposure roughly doubles.

Scope: Mouse knockout pharmacokinetics

When the blocked step is bypassed

Condition: machinery_impairment · Expression of the rotenone-insensitive yeast NADH dehydrogenase NDI1.

Normal role: Metformin inhibits complex I, which the cell needs to re-oxidise NADH.

Recorded consequence: The drug loses its effect on proliferation, HIF-1 activation and tumour growth.

Scope: Human cancer cells and mouse xenografts

When the redox shuttle enzyme is removed

Condition: machinery_impairment · Antisense knockdown in rats and whole-body knockout in mice.

Normal role: Mitochondrial glycerophosphate dehydrogenase carries reducing equivalents into the mitochondrion.

Recorded consequence: The knockdown phenotype resembles chronic metformin, and metformin loses its effect on redox state and glucose production.

Scope: Rat and mouse liver

When the upstream kinase is deleted from the liver

Condition: machinery_impairment · Liver-specific LKB1 deletion in adult mice.

Normal role: LKB1 phosphorylates and activates AMPK in hepatocytes.

Recorded consequence: AMPK activity is nearly lost, gluconeogenic gene expression rises, and metformin does not lower blood glucose.

Scope: Mouse liver

When the energy sensor is deleted from the liver

Condition: machinery_impairment · Liver-specific AMPK deletion, and separately LKB1 deletion, in mice.

Normal role: AMPK is the proposed mediator of metformin’s effect on hepatic glucose production.

Recorded consequence: Glucose production and gluconeogenic gene expression were normal, and metformin still inhibited glucose production.

Scope: Mouse liver and isolated hepatocytes

When the low-dose binding partner is missing

Condition: machinery_impairment · Knockout of PEN2, or a PEN2 mutant that cannot bind ATP6AP1.

Normal role: PEN2 binds metformin and, through ATP6AP1, links it to lysosomal AMPK activation.

Recorded consequence: AMPK activation is blunted, hepatic fat is no longer reduced, and the glucose-lowering effect is impaired.

Scope: Mouse liver and intestine, cultured cells and C. elegans

When the weight-signalling hormone or its receptor is missing

Condition: machinery_impairment · Gdf15-null and Gfral-null mice, and a GFRAL-antagonist antibody.

Normal role: Metformin raises GDF15, which acts on the brainstem receptor GFRAL to reduce food intake.

Recorded consequence: The weight effect is lost while the glucose-lowering effect remains.

Scope: Mouse high-fat-diet models

When the hormone is missing and the weight effect remains

Condition: machinery_impairment · GDF15 and GFRAL knockout mice in a replication study.

Normal role: GDF15 has been proposed as the mediator of metformin-induced weight loss.

Recorded consequence: Weight and energy balance responses to metformin persisted.

Scope: Mouse energy-balance studies

When the kidneys can no longer clear the drug

Condition: machinery_impairment · Intercurrent renal failure during continued metformin treatment.

Normal role: Metformin is eliminated unchanged by renal tubular secretion through OCT2 and the MATE transporters.

Recorded consequence: Plasma metformin rises, and in accumulating patients it correlates with arterial lactate.

Scope: Human intensive-care case series

Reading a lactate measurement during metformin treatment

Condition: biomarker_context · A raised lactate in a person taking metformin.

Normal role: Lactate is produced continuously and cleared largely by the liver and kidney.

Recorded consequence: Accumulation, shock and tissue hypoxia are separate contributors, and the drug level does not predict the outcome.

Scope: Human case series and a population cohort

How common lactic acidosis actually is

Condition: biomarker_context · Population-level surveillance of current oral antidiabetes drug use.

Normal role: Lactic acidosis is the feared adverse event associated with biguanides.

Recorded consequence: Incidence was very low and comparable to sulfonylureas, with comorbidity in every case.

Scope: UK primary-care database

The sources

Every document behind this chapter is preserved word for word. Open one to read it in full with its recorded conflicts marked in place.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source

Recorded disagreements

Where two sources say different things, both are kept and the difference is explained. You can discuss a disagreement or propose a mechanism that might account for it.

Does metformin need AMPK and LKB1 to lower hepatic glucose production?Two laboratories using liver-specific genetic models reported opposite answers. Compound C inhibition in rat hepatocytes and liver-specific LKB1 deletion in mice supported a requirement, while liver-specific AMPK deletion and LKB1 deletion in a later study left the effect intact and even amplified it, with the fall in hepatocyte ATP tracking the effect instead. The models differ in how AMPK was removed, in the dose of metformin used, and in whether an inhibitor or a genetic deletion was used, and the later study measured energy state directly. Which difference accounts for the disagreement is not established.Read the recorded disagreement
Is the GDF15-GFRAL pathway necessary for metformin to lower body weight?Both groups agree that metformin raises circulating GDF15 in mice and in people. They disagree on necessity: one reported that the weight effect is absent in Gdf15-null and Gfral-null mice and is reversed by a GFRAL-antagonist antibody, the other that weight and energy balance responses persist in the same knockouts. Diet composition, dose, duration and the degree of GDF15 induction differ between the studies. The reason for the difference is not established.Read the recorded disagreement
Why does metformin lower vitamin B12: calcium-dependent ileal uptake, or bacterial overgrowth?Both explanations come from human studies of the same effect. The 2000 study found that oral calcium reversed the fall in holotranscobalamin and attributed the effect to calcium-dependent antagonism at the ileal receptor. The 1977 study found deconjugation of bile acids and Schilling-test abnormalities that improved with antibiotics, and attributed the malabsorption to small-intestinal bacterial overgrowth. Neither study tested the other mechanism, the eras and methods differ, and the two are not mutually exclusive. The reason for the difference is not established.Read the recorded disagreement

Open questions in this collection

Questions the curators could not answer from the sources in front of them, kept here with the reason each one is still open. These are gaps in this collection, not findings or proof that no one has studied them.

Whether the small-intestinal metformin depot measured in mice sets the concentration that reaches human intestinal targets such as THTR-2 and the microbiota.Tissue concentrations were measured in mice; human intestinal tissue concentrations at therapeutic doses were not measured in these records.
Whether reduced-function OCT1 genotypes change the size of the vitamin B12 or thiamine effects of metformin.The transporter, intolerance and vitamin studies were performed separately; no record here links genotype to a nutrient outcome.
Whether the intestinal, microbial and hepatic routes to lower glucose are additive, redundant, or the same route measured in different places.The delayed-release, microbiota-transfer and hepatocyte records each isolate one route; no record here removes two routes at once.
Whether the transporter competition between metformin and thiamine measurably lowers thiamine status in people taking metformin.The transport and mouse records establish competition; the human record here is an electronic-health-record signal across many inhibitor drugs, not a metformin-specific measurement.
Whether correcting vitamin B12 during metformin treatment changes neuropathy outcomes.The neuropathy records are cross-sectional or prevalence-based; no record here reports a randomised correction trial with a nerve outcome.
Whether the copper dependence seen with chemical sequestration in cells has any counterpart at human copper status.The copper records are cell and chemistry studies; no record here measures copper status in treated people.
At what metformin concentration each proposed target, complex I, mitochondrial glycerophosphate dehydrogenase, and the PEN2/v-ATPase route, is actually engaged in human liver at therapeutic doses.The records here use different concentrations in different species; no single study compared all three targets across the therapeutic range in human tissue.
Whether the lysosomal PEN2 route and the mitochondrial targets act in series, in parallel, or in different tissues.Each was established in its own model, and no record here tests one route with the other removed.

Chapters are assembled from supplied drafts and curated literature summaries. Statements remain unverified against the primary studies, and the ledger is not medical advice.

Evidence, AI assistance and curation standards

Metformin

The mechanisms

Rat Oct1 expression produced time-dependent and saturable metformin uptake in CHO cells, with a Km of 377 microM.

Rat Oct1 also transported buformin with a Km of 49 microM, a higher affinity than for metformin.

Rat Oct1 also transported phenformin with a Km of 16 microM, a higher affinity than for metformin.

Liver distribution of metformin in Oct1(-/-) mice was more than 30-fold lower than in Oct1(+/+) mice and was accounted for by the extracellular space.

Distribution of metformin to the small intestine was also decreased in Oct1(-/-) mice, whereas renal distribution and urinary excretion differed only minimally.

Seven non-synonymous OCT1 polymorphisms showed reduced metformin uptake, including OCT1-420del, which has normal activity for model substrates.

In mouse hepatocytes, deletion of Oct1 reduced the effect of metformin on AMPK phosphorylation and on gluconeogenesis.

In Oct1-deficient mice the glucose-lowering effects of metformin were completely abolished.

In clinical studies the effects of metformin in glucose tolerance tests were significantly smaller in people carrying reduced-function OCT1 polymorphisms.

Human and rat OCT2 had roughly 10-fold and 100-fold greater capacity to transport metformin than OCT1 in the transfected-cell comparison.

Renal OCT2 expression was the key factor controlling concentrative accumulation of metformin in the rat kidney.

MATE1 transported metformin in a proton-gradient-dependent manner, with a Michaelis-Menten constant of 0.78 mM.

MATE2-K transported metformin in a proton-gradient-dependent manner, with a Michaelis-Menten constant of 1.98 mM.

MATE1 and MATE2-K together mediate tubular secretion of intracellular ionic compounds across the kidney brush-border membranes.

hMATE2-K is expressed predominantly in the kidney and localises to the brush-border membranes of proximal tubules, where it transports metformin with a Km of 1.05 mM.

Intracellular acidification stimulated hMATE2-K-dependent transport of organic cations including metformin and thiamine.

Renal clearance and renal secretory clearance of metformin in Mate1(-/-) mice were approximately 18% and 14% of those in wild-type mice.

Mate1(-/-) mice showed a two-fold increase in the area under the blood metformin concentration-time curve.

The greatest accumulation of metformin occurred in small-intestinal tissue, exceeding 1000 micromol/kg wet weight at 0.5-2 hours, and intravenous metformin was also selectively accumulated there.

Maximum metformin concentrations in the hepatic portal vein were higher than in the inferior vena cava in both normal and diabetic mice.

The affinity for metformin was 4.9-fold lower in human than in mouse OCT1, giving a 6.5-fold lower intrinsic clearance and an estimated liver-to-blood partition coefficient of 3.34 in human compared with 14.4 in mouse.

The affinity for thiamine was 9.5-fold lower in human than in mouse OCT1.

Simultaneous substitution of transmembrane helices TMH2 and TMH3 reversed the affinity for metformin in human-mouse chimeric OCT1.

Carriage of two reduced-function OCT1 alleles was associated with metformin intolerance (odds ratio 2.41), rising to 4.13 in people also taking OCT1-inhibiting drugs.

The SLC47A1 rs2289669 A allele was associated with a 0.30% larger HbA1c reduction per allele during metformin treatment.

Metformin inhibited mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration in human cancer cells.

Cellular respiration fell with metformin, and cells relied exclusively on glycolysis for survival in its presence.

All of the effects of metformin were reversed when the metformin-resistant yeast NADH dehydrogenase NDI1 was expressed, in cells and in mouse tumours.

Metformin reduced hypoxic activation of hypoxia-inducible factor 1 in these cells.

Metformin reduced complex I activity in skeletal-muscle homogenates and reduced state 3 respiration of isolated mitochondria consuming glutamate and malate, while respiration on succinate through complex II was unaffected.

Twenty-four-hour exposure of isolated rat soleus muscle to metformin reduced glucose oxidation by about 30% and increased lactate release by about 84%.

Metformin non-competitively inhibited the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase.

Low-dose metformin increased the cytosolic redox state and decreased the mitochondrial redox state in the liver.

The altered hepatocellular redox state reduced the conversion of lactate and glycerol to glucose and decreased hepatic gluconeogenesis.

Knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats produced a phenotype akin to chronic metformin treatment and abrogated metformin-mediated increases in cytosolic redox state and inhibition of endogenous glucose production.

These findings were replicated in whole-body mitochondrial glycerophosphate dehydrogenase knockout mice.

Metformin activated AMPK in hepatocytes, reducing acetyl-CoA carboxylase activity, inducing fatty acid oxidation and suppressing expression of lipogenic enzymes.

Activation of AMPK by metformin suppressed expression of SREBP-1, and hepatic lipogenic mRNA and protein were reduced in metformin-treated rats.

Using an AMPK inhibitor, AMPK activation was found to be required for the inhibitory effect of metformin on glucose production by hepatocytes.

Deletion of LKB1 in adult mouse liver resulted in a nearly complete loss of AMPK activity, with hyperglycaemia and increased gluconeogenic and lipogenic gene expression.

Metformin required LKB1 in the liver to lower blood glucose levels in these mice.

In mice lacking AMPK in the liver, blood glucose was comparable to wild type and the hypoglycaemic effect of metformin was maintained; metformin-induced inhibition of glucose production was amplified in both AMPK- and LKB1-deficient hepatocytes.

Inhibition of glucose production correlated in a dose-dependent manner with a reduction in intracellular ATP content, and was preserved when gluconeogenic genes were force-expressed through PGC-1alpha.

A photoactive metformin probe identified PEN2, a subunit of gamma-secretase, as a binding partner of metformin with a dissociation constant at micromolar levels.

Metformin-bound PEN2 formed a complex with ATP6AP1, a subunit of the v-ATPase.

Clinically relevant concentrations of metformin inhibited the lysosomal proton pump v-ATPase, leading to AMPK activation without effects on cellular AMP levels.

Knockout of PEN2, or re-introduction of a PEN2 mutant that does not bind ATP6AP1, blunted AMPK activation.

Liver-specific knockout of Pen2 abolished the metformin-mediated reduction of hepatic fat content.

Intestine-specific knockout of Pen2 impaired the glucose-lowering effects of metformin.

The anti-proliferative effect of metformin was due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis, because complex I supports proliferation by regenerating NAD+.

Dependency on complex I, and therefore sensitivity to metformin, was dictated by other pathways affecting NAD+ regeneration and aspartate levels, so sensitivity was not an intrinsic property of the cells.

Ten weeks of metformin significantly increased skeletal-muscle AMPK alpha2 activity with increased Thr172 phosphorylation and decreased acetyl-CoA carboxylase-2 activity in people with type 2 diabetes.

The increase in AMPK alpha2 activity was accompanied by lower muscle ATP and phosphocreatine concentrations after treatment.

Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and higher muscle glycogen concentrations.

In two independent randomised controlled trials metformin increased circulating GDF15, and in wild-type mice oral metformin increased circulating GDF15 with expression rising predominantly in the distal intestine and the kidney.

Metformin prevented high-fat-diet weight gain in wild-type mice but not in mice lacking GDF15 or its receptor GFRAL, and a GFRAL-antagonist antibody reversed the weight effect in obese mice.

Metformin retained its ability to lower circulating glucose in the absence of GDF15 activity.

Metformin increased circulating GDF15 in mice and humans, but studies in wild-type, GDF15-knockout and GFRAL-knockout mice suggested that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance.

Delayed-release metformin targeted to the ileum produced similar reductions in fasting and postprandial glucose despite an almost 60% reduction in systemic metformin exposure compared with immediate-release metformin.

Fasting and postprandial GLP-1 rose with all metformin treatments, with day-5 to baseline AUC ratios of 1.6-1.9.

Fasting and postprandial PYY rose with all metformin treatments, with day-5 to baseline AUC ratios of 1.4-1.5.

Three days of metformin in newly diagnosed type 2 diabetes decreased Bacteroides fragilis and increased the bile acid glycoursodeoxycholic acid in the gut.

GUDCA was identified as an intestinal FXR antagonist, and these changes were accompanied by inhibition of intestinal FXR signalling.

High-fat-diet mice colonised with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin were abrogated.

Metformin had strong effects on the gut microbiome in a four-month double-blind randomised trial, verified in a placebo subgroup that later switched to metformin.

Transfer of faecal samples from metformin-treated donors to germ-free mice improved glucose tolerance in the recipients.

In a gut simulator, many of the metformin-regulated genes in species from two different phyla encoded metalloproteins or metal transporters.

The reanalysis supported microbial mediation of metformin’s therapeutic effects through short-chain fatty acid production, while type 2 diabetes itself showed depletion of butyrate-producing taxa.

A relative increase in the abundance of Escherichia species was proposed as a microbiota-mediated mechanism behind the known intestinal adverse effects of metformin.

Upper small-intestinal metformin restored SGLT1 expression and glucose sensing in high-fat-diet rats, triggering an SGLT1-dependent pathway that lowered glucose production.

Metformin shifted the upper small-intestinal microbiota partly by increasing the abundance of Lactobacillus, and transplanting that microbiota into untreated rats reproduced the increase in glucose sensing through SGLT1.

AMPK interacted with FXR in the cytoplasm and phosphorylated it in its hinge domain, inhibiting FXR transcriptional activity and preventing coactivator recruitment.

Metformin inhibited FXR agonist induction of FXR target genes in mouse liver and intestine.

In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis and worsened liver injury.

Compared with placebo, metformin treatment was associated with a mean decrease in vitamin B-12 concentration of 19% over 4.3 years.

The absolute risk of vitamin B-12 deficiency below 150 pmol/l was 7.2 percentage points higher in the metformin group, with a number needed to harm of 13.8 per 4.3 years.

Metformin was associated with a mean decrease in folate concentration of 5%, although after adjustment for body mass index and smoking no significant effect on folate remained.

Patients with vitamin B-12 deficiency at study end had a mean homocysteine of 23.7 micromol/l, compared with 18.1 in those with low B-12 and 14.9 in those with normal B-12.