Metformin

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text; Figure 4I

experimental_model

Worm lifespan with defined E. coli deletion mutants.

limitations

No human lifespan extension or agmatine-sulfate/metformin combination efficacy is established.

nutrient_topic

Agmatine Sulfate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Agmatine Sulfate

plain_language

A drug response depended on the microbes in a specific experimental system.

primary_references

Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31474368/ · DOI 10.1016/j.cell.2019.08.003

trigger_kind

machinery_impairment Imported condition classification; unverified.

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 412–418

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Worm lifespan with defined E. coli deletion mutants. · source_derived_draft · unverified_draft

## agmatine-sulfate-bacterial-metformin A drug response depended on the microbes in a specific experimental system. Metformin no longer extended C. elegans lifespan when worms ate E. coli lacking both agmatine-production genes adiA and speA. Model: Worm lifespan with defined E. coli deletion mutants. Limitations: No human lifespan extension or agmatine-sulfate/metformin combination efficacy is established. Evidence access: Primary full text; Figure 4I Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31474368/ · DOI 10.1016/j.cell.2019.08.003

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary full text; Figure 5

experimental_model

Human microbiome composition and diet-constrained metabolic modeling.

limitations

Not a direct measurement of plasma agmatine or proof that agmatine causes metformin benefits in humans.

nutrient_topic

Agmatine Sulfate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Agmatine Sulfate

plain_language

The human evidence here concerns a modeled capacity rather than a measured causal mediator.

primary_references

Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31474368/ · DOI 10.1016/j.cell.2019.08.003

trigger_kind

biomarker_context Imported condition classification; unverified.

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 420–426

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human microbiome composition and diet-constrained metabolic modeling. · source_derived_draft · unverified_draft

## agmatine-sulfate-microbiome-prediction The human evidence here concerns a modeled capacity rather than a measured causal mediator. Microbial-community models predicted higher agmatine-production capacity in metformin-treated cohorts, including longitudinal treatment data. Model: Human microbiome composition and diet-constrained metabolic modeling. Limitations: Not a direct measurement of plasma agmatine or proof that agmatine causes metformin benefits in humans. Evidence access: Primary full text; Figure 5 Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31474368/ · DOI 10.1016/j.cell.2019.08.003

cross_nutrient

false

experimental_model

Seven healthy adult completers; three experimental days separated by one-month washouts

exposure

Oral carbon-13 cyanocobalamin with metformin 850 mg versus tracer alone

limitations

Small acute tracer pilot in healthy adults; cannot establish prevention of chronic deficiency or identify the exact molecular metformin target. Doses describe the experiment, not advice.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

A single metformin exposure lowered measured B12 tracer availability.

primary_references

[muralidharan-2024-calcium] Effect of calcium supplementation on reversing metformin-based inhibition of vitamin B12 bioavailability in healthy adults using a [13C] cyanocobalamin tracer - A pilot study. (2024). https://pubmed.ncbi.nlm.nih.gov/38901951/ DOI: 10.1016/j.clnesp.2024.04.024

tissue_or_cell_type

Intestinal absorption assessed from serial venous tracer measurements

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 452–463

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Seven healthy adult completers; three experimental days separated by one-month washouts · source_derived_draft · unverified_draft

### b12-abs-metformin-tracer In seven healthy completers, tracer bioavailability averaged 30.8% with metformin 850 mg versus 42.6% on the control day (paired comparison p=0.010). Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A single metformin exposure lowered measured B12 tracer availability. organism: Homo sapiens tissue_or_cell_type: Intestinal absorption assessed from serial venous tracer measurements experimental_model: Seven healthy adult completers; three experimental days separated by one-month washouts limitations: Small acute tracer pilot in healthy adults; cannot establish prevention of chronic deficiency or identify the exact molecular metformin target. Doses describe the experiment, not advice. exposure: Oral carbon-13 cyanocobalamin with metformin 850 mg versus tracer alone cross_nutrient: false [muralidharan-2024-calcium] Effect of calcium supplementation on reversing metformin-based inhibition of vitamin B12 bioavailability in healthy adults using a [13C] cyanocobalamin tracer - A pilot study. (2024). https://pubmed.ncbi.nlm.nih.gov/38901951/ DOI: 10.1016/j.clnesp.2024.04.024

experimental_model

DPP/DPPOS secondary analysis: initial randomized metformin/placebo period followed by open-label follow-up. Stored-sample analytic groups: year 5 placebo 857/metformin 858; year 13 placebo 756/metformin 764.

exposure

Metformin 850 mg twice daily initially; B12 assessed at approximately 5 and 13 years. Long-term exposure is not continuously blinded randomized treatment.

limitations

Stored-sample subsets and open-label exposure after the initial trial limit continuous randomized interpretation.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

The long-term follow-up supports a status association, with different results for different thresholds and visits.

primary_references

[b12-aroda2016] 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

Human blood or whole-person endpoints

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1649–1659

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · DPP/DPPOS secondary analysis: initial randomized metformin/placebo period followed by open-label follow-up. Stored-sample analytic groups: year 5 placebo 857/metformin 858; year 13 placebo 756/metformin 764. · source_derived_draft · unverified_draft

### b12-metformin-dppos-longitudinal Low B12 (at most 203 pg/mL) was more frequent with metformin at year 5 (4.3% versus 2.3%) but not significantly at year 13 (7.4% versus 5.4%); low-or-borderline B12 (at most 298 pg/mL) remained more frequent at both assessments. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The long-term follow-up supports a status association, with different results for different thresholds and visits. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: DPP/DPPOS secondary analysis: initial randomized metformin/placebo period followed by open-label follow-up. Stored-sample analytic groups: year 5 placebo 857/metformin 858; year 13 placebo 756/metformin 764. limitations: Stored-sample subsets and open-label exposure after the initial trial limit continuous randomized interpretation. exposure: Metformin 850 mg twice daily initially; B12 assessed at approximately 5 and 13 years. Long-term exposure is not continuously blinded randomized treatment. [b12-aroda2016] 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

cross_nutrient

Preserves the B12/folate/homocysteine measurements without a universal depletion cascade.

experimental_model

Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes.

exposure

Metformin 850 mg three times daily versus placebo for 4.3 years; historical experimental exposure.

limitations

End-study B12 strata are not randomized mediators. The folate decrease lost significance after adjustment for BMI and smoking.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

A B12 effect did not make the overall homocysteine trial result statistically significant.

primary_references

[b12-dejager2010] 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

Human blood or whole-person endpoints

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1636–1647

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes. · source_derived_draft · unverified_draft

### b12-metformin-homocysteine-boundary The overall metformin-versus-placebo homocysteine change was +5% (95% CI -1% to 11%; P=0.091), although participants with low end-study B12 had higher homocysteine. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A B12 effect did not make the overall homocysteine trial result statistically significant. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes. limitations: End-study B12 strata are not randomized mediators. The folate decrease lost significance after adjustment for BMI and smoking. exposure: Metformin 850 mg three times daily versus placebo for 4.3 years; historical experimental exposure. cross_nutrient: Preserves the B12/folate/homocysteine measurements without a universal depletion cascade. [b12-dejager2010] 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

experimental_model

Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes.

exposure

Metformin 850 mg three times daily versus placebo for 4.3 years; historical experimental exposure.

limitations

Insulin-treated type 2 diabetes; does not directly establish the absorption mechanism or a neurologic outcome.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Long-term metformin exposure increased biochemical B12 deficiency in this trial.

primary_references

[b12-dejager2010] 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

Human blood or whole-person endpoints

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1624–1634

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes. · source_derived_draft · unverified_draft

### b12-metformin-randomized-status Over 4.3 years, metformin lowered B12 concentration by 19% relative to placebo and increased the absolute risk of B12 below 150 pmol/L by 7.2 percentage points (95% CI 2.3–12.1). Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Long-term metformin exposure increased biochemical B12 deficiency in this trial. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes. limitations: Insulin-treated type 2 diabetes; does not directly establish the absorption mechanism or a neurologic outcome. exposure: Metformin 850 mg three times daily versus placebo for 4.3 years; historical experimental exposure. [b12-dejager2010] 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

evidence_span

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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

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

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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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

evidence_span

{"source_cache": "artifacts/glucan-research/25258083.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "68c4cae9a0e4477a52864e63ecaf5ec977752b5d3246a9ba54aa22d160e41872", "start_char": 0, "end_char": 1225, "text_sha256": "68c4cae9a0e4477a52864e63ecaf5ec977752b5d3246a9ba54aa22d160e41872"}

experimental_model

Histone modification profiling and genome-wide transcriptome of trained human monocytes, with pathway inhibition and a myeloid conditional knockout

exposure

Beta-glucan training with inhibition of Akt, mTOR or HIF-1 alpha, and metformin as an AMPK activator

limitations

The metformin result is an experimental inhibition of an induced response, not a clinical interaction study.

nutrient_topic

Beta-glucan research collection; topical membership is not evidence of a direct clinical effect, and each preparation is recorded as its own entity with no family link joining any pair. · Beta-glucan

organism

Human cells and mouse

plain_language

The rewiring costs energy: block the cell from burning glucose the fast way and the training does not take.

primary_references

[bg-p25258083] mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. (2014). https://pubmed.ncbi.nlm.nih.gov/25258083/ DOI: 10.1126/science.1250684

tissue_or_cell_type

Monocyte

Beta-glucan: a structural family rather than an agent, what decides whether a bound glucan actually signals, the complement route that a cereal and a yeast preparation share, and the unequal human evidence behind each (2026-09-22) · lines 437–448

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Histone modification profiling and genome-wide transcriptome of trained human monocytes, with pathway inhibition and a myeloid conditional knockout · source_derived_draft · unverified_draft

### bg-training-needs-aerobic-glycolysis Trained monocytes display high glucose consumption, high lactate production and a high ratio of NAD+ to NADH, reflecting a shift in metabolism with an increase in glycolysis dependent on the activation of mammalian target of rapamycin through a dectin-1-Akt-HIF-1 alpha pathway, inhibition of Akt, mTOR or HIF-1 alpha blocked monocyte induction of trained immunity whereas the AMP-activated protein kinase activator metformin inhibited the innate immune response to fungal infection, and mice with a myeloid cell-specific defect in HIF-1 alpha were unable to mount trained immunity against bacterial sepsis. Condition category: normal nutrient_topic: Beta-glucan research collection; topical membership is not evidence of a direct clinical effect, and each preparation is recorded as its own entity with no family link joining any pair. plain_language: The rewiring costs energy: block the cell from burning glucose the fast way and the training does not take. organism: Human cells and mouse tissue_or_cell_type: Monocyte experimental_model: Histone modification profiling and genome-wide transcriptome of trained human monocytes, with pathway inhibition and a myeloid conditional knockout limitations: The metformin result is an experimental inhibition of an induced response, not a clinical interaction study. exposure: Beta-glucan training with inhibition of Akt, mTOR or HIF-1 alpha, and metformin as an AMPK activator evidence_span: {"source_cache": "artifacts/glucan-research/25258083.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "68c4cae9a0e4477a52864e63ecaf5ec977752b5d3246a9ba54aa22d160e41872", "start_char": 0, "end_char": 1225, "text_sha256": "68c4cae9a0e4477a52864e63ecaf5ec977752b5d3246a9ba54aa22d160e41872"} [bg-p25258083] mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. (2014). https://pubmed.ncbi.nlm.nih.gov/25258083/ DOI: 10.1126/science.1250684

evidence_span

{"source_cache": "artifacts/berberine-research/33174626.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0dbd2401295c8f6e093461899378d5e9b7c2c5757be0bd12d335edf07216afa9", "start_char": 0, "end_char": 1812, "text_sha256": "0dbd2401295c8f6e093461899378d5e9b7c2c5757be0bd12d335edf07216afa9"}

experimental_model

Clinical transporter-probe cocktail with in-vitro prediction

exposure

Characterized goldenseal botanical product, not purified berberine

limitations

Goldenseal contains multiple alkaloids. This result must not be attributed exclusively to berberine; unchanged renal clearance favors an absorption-related explanation.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Sixteen healthy human volunteers

plain_language

The tested botanical mixture changed metformin exposure; purified berberine was not the clinical intervention.

primary_references

[berberine-p33174626] Assessing Transporter-Mediated Natural Product-Drug Interactions Via In vitro-In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail. (2021). https://pubmed.ncbi.nlm.nih.gov/33174626/ DOI: 10.1002/cpt.2107

tissue_or_cell_type

Oral metformin exposure

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 870–881

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Clinical transporter-probe cocktail with in-vitro prediction · source_derived_draft · unverified_draft

### berberine-goldenseal-metformin Goldenseal reduced metformin AUC by 23% without changing its half-life or renal clearance. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The tested botanical mixture changed metformin exposure; purified berberine was not the clinical intervention. organism: Sixteen healthy human volunteers tissue_or_cell_type: Oral metformin exposure experimental_model: Clinical transporter-probe cocktail with in-vitro prediction limitations: Goldenseal contains multiple alkaloids. This result must not be attributed exclusively to berberine; unchanged renal clearance favors an absorption-related explanation. exposure: Characterized goldenseal botanical product, not purified berberine evidence_span: {"source_cache": "artifacts/berberine-research/33174626.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0dbd2401295c8f6e093461899378d5e9b7c2c5757be0bd12d335edf07216afa9", "start_char": 0, "end_char": 1812, "text_sha256": "0dbd2401295c8f6e093461899378d5e9b7c2c5757be0bd12d335edf07216afa9"} [berberine-p33174626] Assessing Transporter-Mediated Natural Product-Drug Interactions Via In vitro-In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail. (2021). https://pubmed.ncbi.nlm.nih.gov/33174626/ DOI: 10.1002/cpt.2107

evidence_span

{"source_cache": "artifacts/berberine-research/37562957.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646", "start_char": 0, "end_char": 2598, "text_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646"}

experimental_model

Transporter-expressing cells and oral-versus-intravenous mouse pharmacokinetics

exposure

Goldenseal extract and isolated berberine or hydrastine were tested separately

limitations

Extract potency was normalized to berberine content but does not mean berberine alone caused the effect. Transported probe was metformin, so thiamine depletion was not measured.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Human transporters in HEK293 cells; mice

plain_language

The mixture and each transporter remain separate database entries.

primary_references

[berberine-p37562957] Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice. (2023). https://pubmed.ncbi.nlm.nih.gov/37562957/ DOI: 10.1124/dmd.123.001360

tissue_or_cell_type

Intestinal uptake

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 909–920

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transporter-expressing cells and oral-versus-intravenous mouse pharmacokinetics · source_derived_draft · unverified_draft

### berberine-goldenseal-slc19a3 Goldenseal extract inhibited THTR2-mediated metformin transport in transfected cells. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The mixture and each transporter remain separate database entries. organism: Human transporters in HEK293 cells; mice tissue_or_cell_type: Intestinal uptake experimental_model: Transporter-expressing cells and oral-versus-intravenous mouse pharmacokinetics limitations: Extract potency was normalized to berberine content but does not mean berberine alone caused the effect. Transported probe was metformin, so thiamine depletion was not measured. exposure: Goldenseal extract and isolated berberine or hydrastine were tested separately evidence_span: {"source_cache": "artifacts/berberine-research/37562957.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646", "start_char": 0, "end_char": 2598, "text_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646"} [berberine-p37562957] Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice. (2023). https://pubmed.ncbi.nlm.nih.gov/37562957/ DOI: 10.1124/dmd.123.001360

evidence_span

{"source_cache": "artifacts/berberine-research/37562957.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646", "start_char": 0, "end_char": 2598, "text_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646"}

experimental_model

Transporter-expressing cells and oral-versus-intravenous mouse pharmacokinetics

exposure

Goldenseal extract and isolated berberine or hydrastine were tested separately

limitations

Extract potency was normalized to berberine content but does not mean berberine alone caused the effect. Transported probe was metformin, so thiamine depletion was not measured.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Human transporters in HEK293 cells; mice

plain_language

The mixture and each transporter remain separate database entries.

primary_references

[berberine-p37562957] Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice. (2023). https://pubmed.ncbi.nlm.nih.gov/37562957/ DOI: 10.1124/dmd.123.001360

tissue_or_cell_type

Intestinal uptake

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 883–894

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transporter-expressing cells and oral-versus-intravenous mouse pharmacokinetics · source_derived_draft · unverified_draft

### berberine-goldenseal-slc22a3 Goldenseal extract inhibited OCT3-mediated metformin transport in transfected cells. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The mixture and each transporter remain separate database entries. organism: Human transporters in HEK293 cells; mice tissue_or_cell_type: Intestinal uptake experimental_model: Transporter-expressing cells and oral-versus-intravenous mouse pharmacokinetics limitations: Extract potency was normalized to berberine content but does not mean berberine alone caused the effect. Transported probe was metformin, so thiamine depletion was not measured. exposure: Goldenseal extract and isolated berberine or hydrastine were tested separately evidence_span: {"source_cache": "artifacts/berberine-research/37562957.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646", "start_char": 0, "end_char": 2598, "text_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646"} [berberine-p37562957] Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice. (2023). https://pubmed.ncbi.nlm.nih.gov/37562957/ DOI: 10.1124/dmd.123.001360

evidence_span

{"source_cache": "artifacts/berberine-research/37562957.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646", "start_char": 0, "end_char": 2598, "text_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646"}

experimental_model

Transporter-expressing cells and oral-versus-intravenous mouse pharmacokinetics

exposure

Goldenseal extract and isolated berberine or hydrastine were tested separately

limitations

Extract potency was normalized to berberine content but does not mean berberine alone caused the effect. Transported probe was metformin, so thiamine depletion was not measured.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Human transporters in HEK293 cells; mice

plain_language

The mixture and each transporter remain separate database entries.

primary_references

[berberine-p37562957] Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice. (2023). https://pubmed.ncbi.nlm.nih.gov/37562957/ DOI: 10.1124/dmd.123.001360

tissue_or_cell_type

Intestinal uptake

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 896–907

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transporter-expressing cells and oral-versus-intravenous mouse pharmacokinetics · source_derived_draft · unverified_draft

### berberine-goldenseal-slc29a4 Goldenseal extract inhibited PMAT-mediated metformin transport in transfected cells. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The mixture and each transporter remain separate database entries. organism: Human transporters in HEK293 cells; mice tissue_or_cell_type: Intestinal uptake experimental_model: Transporter-expressing cells and oral-versus-intravenous mouse pharmacokinetics limitations: Extract potency was normalized to berberine content but does not mean berberine alone caused the effect. Transported probe was metformin, so thiamine depletion was not measured. exposure: Goldenseal extract and isolated berberine or hydrastine were tested separately evidence_span: {"source_cache": "artifacts/berberine-research/37562957.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646", "start_char": 0, "end_char": 2598, "text_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646"} [berberine-p37562957] Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice. (2023). https://pubmed.ncbi.nlm.nih.gov/37562957/ DOI: 10.1124/dmd.123.001360

evidence_span

{"source_cache": "artifacts/berberine-research/37562957.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646", "start_char": 0, "end_char": 2598, "text_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646"}

experimental_model

Transporter-expressing cells and oral-versus-intravenous mouse pharmacokinetics

exposure

Goldenseal extract and isolated berberine or hydrastine were tested separately

limitations

Extract potency was normalized to berberine content but does not mean berberine alone caused the effect. Transported probe was metformin, so thiamine depletion was not measured.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Human transporters in HEK293 cells; mice

plain_language

The whole botanical product cannot be treated as equivalent to one ingredient.

primary_references

[berberine-p37562957] Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice. (2023). https://pubmed.ncbi.nlm.nih.gov/37562957/ DOI: 10.1124/dmd.123.001360

tissue_or_cell_type

Intestinal uptake

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 922–933

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transporter-expressing cells and oral-versus-intravenous mouse pharmacokinetics · source_derived_draft · unverified_draft

### berberine-isolated-berberine-mouse-null Isolated berberine did not alter metformin pharmacokinetics in the mouse experiment, whereas goldenseal extract reduced metformin Cmax. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The whole botanical product cannot be treated as equivalent to one ingredient. organism: Human transporters in HEK293 cells; mice tissue_or_cell_type: Intestinal uptake experimental_model: Transporter-expressing cells and oral-versus-intravenous mouse pharmacokinetics limitations: Extract potency was normalized to berberine content but does not mean berberine alone caused the effect. Transported probe was metformin, so thiamine depletion was not measured. exposure: Goldenseal extract and isolated berberine or hydrastine were tested separately evidence_span: {"source_cache": "artifacts/berberine-research/37562957.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646", "start_char": 0, "end_char": 2598, "text_sha256": "3d19a5ed2d4ef8f98675f7932f2ea70d6848fc1105362f39681e1c595e204646"} [berberine-p37562957] Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice. (2023). https://pubmed.ncbi.nlm.nih.gov/37562957/ DOI: 10.1124/dmd.123.001360

evidence_span

{"source_cache": "artifacts/berberine-research/25359200.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db", "start_char": 0, "end_char": 1353, "text_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db"}

experimental_model

Transporter-expressing cells and intravenous rat pharmacokinetics

exposure

Intravenous metformin 2 mg/kg and berberine 10 mg/kg in rats; in-vitro concentration-response

limitations

HEK293 is the host cell, not proof that the expressed transporter is human; the indexed proteins are rat Slc22a1/Slc22a2. Intravenous rat results cannot determine an oral human interaction. Assayed substrate was metformin, not thiamine.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Rat OCT1/2 in HEK293 cells and rats; rat protein identity indexed in primary-publication chemical records

plain_language

Blocking uptake or elimination can increase circulating drug after intravenous dosing.

primary_references

[berberine-p25359200] Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin. (2015). https://pubmed.ncbi.nlm.nih.gov/25359200/ DOI: 10.1007/s12272-014-0510-6

tissue_or_cell_type

Metformin uptake and disposition

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 792–803

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transporter-expressing cells and intravenous rat pharmacokinetics · source_derived_draft · unverified_draft

### berberine-metformin-iv-rat Intravenous berberine coadministration increased metformin AUC and reduced systemic clearance in rats. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Blocking uptake or elimination can increase circulating drug after intravenous dosing. organism: Rat OCT1/2 in HEK293 cells and rats; rat protein identity indexed in primary-publication chemical records tissue_or_cell_type: Metformin uptake and disposition experimental_model: Transporter-expressing cells and intravenous rat pharmacokinetics limitations: HEK293 is the host cell, not proof that the expressed transporter is human; the indexed proteins are rat Slc22a1/Slc22a2. Intravenous rat results cannot determine an oral human interaction. Assayed substrate was metformin, not thiamine. exposure: Intravenous metformin 2 mg/kg and berberine 10 mg/kg in rats; in-vitro concentration-response evidence_span: {"source_cache": "artifacts/berberine-research/25359200.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db", "start_char": 0, "end_char": 1353, "text_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db"} [berberine-p25359200] Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin. (2015). https://pubmed.ncbi.nlm.nih.gov/25359200/ DOI: 10.1007/s12272-014-0510-6

evidence_span

{"source_cache": "artifacts/berberine-research/30428337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8", "start_char": 0, "end_char": 1775, "text_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8"}

experimental_model

Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells

exposure

Oral metformin/berberine coadministration; concentration-dependent transport assays

limitations

Route differs from the intravenous rat study. Changes in plasma, kidney tissue and excretion are separate outcomes; not proof of improved human combination efficacy.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Rats and recombinant rat OCT1, OCT2 and MATE1

plain_language

Lower blood levels do not necessarily mean lower levels in every organ.

primary_references

[berberine-p30428337] Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine. (2019). https://pubmed.ncbi.nlm.nih.gov/30428337/ DOI: 10.1016/j.ejps.2018.11.010

tissue_or_cell_type

Intestinal uptake, kidney distribution and excretion

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 857–868

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells · source_derived_draft · unverified_draft

### berberine-metformin-kidney-rat Berberine increased kidney metformin concentration despite lower early plasma exposure in the oral rat study. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Lower blood levels do not necessarily mean lower levels in every organ. organism: Rats and recombinant rat OCT1, OCT2 and MATE1 tissue_or_cell_type: Intestinal uptake, kidney distribution and excretion experimental_model: Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells limitations: Route differs from the intravenous rat study. Changes in plasma, kidney tissue and excretion are separate outcomes; not proof of improved human combination efficacy. exposure: Oral metformin/berberine coadministration; concentration-dependent transport assays evidence_span: {"source_cache": "artifacts/berberine-research/30428337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8", "start_char": 0, "end_char": 1775, "text_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8"} [berberine-p30428337] Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine. (2019). https://pubmed.ncbi.nlm.nih.gov/30428337/ DOI: 10.1016/j.ejps.2018.11.010

evidence_span

{"source_cache": "artifacts/berberine-research/30428337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8", "start_char": 0, "end_char": 1775, "text_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8"}

experimental_model

Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells

exposure

Oral metformin/berberine coadministration; concentration-dependent transport assays

limitations

Route differs from the intravenous rat study. Changes in plasma, kidney tissue and excretion are separate outcomes; not proof of improved human combination efficacy.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Rats and recombinant rat OCT1, OCT2 and MATE1

plain_language

An intestinal effect can reverse the direction seen after intravenous dosing.

primary_references

[berberine-p30428337] Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine. (2019). https://pubmed.ncbi.nlm.nih.gov/30428337/ DOI: 10.1016/j.ejps.2018.11.010

tissue_or_cell_type

Intestinal uptake, kidney distribution and excretion

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 844–855

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells · source_derived_draft · unverified_draft

### berberine-metformin-oral-rat Oral berberine coadministration decreased metformin Cmax and AUC over the first four hours in rats. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: An intestinal effect can reverse the direction seen after intravenous dosing. organism: Rats and recombinant rat OCT1, OCT2 and MATE1 tissue_or_cell_type: Intestinal uptake, kidney distribution and excretion experimental_model: Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells limitations: Route differs from the intravenous rat study. Changes in plasma, kidney tissue and excretion are separate outcomes; not proof of improved human combination efficacy. exposure: Oral metformin/berberine coadministration; concentration-dependent transport assays evidence_span: {"source_cache": "artifacts/berberine-research/30428337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8", "start_char": 0, "end_char": 1775, "text_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8"} [berberine-p30428337] Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine. (2019). https://pubmed.ncbi.nlm.nih.gov/30428337/ DOI: 10.1016/j.ejps.2018.11.010

evidence_span

{"source_cache": "artifacts/berberine-research/25359200.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db", "start_char": 0, "end_char": 1353, "text_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db"}

experimental_model

Transporter-expressing cells and intravenous rat pharmacokinetics

exposure

Intravenous metformin 2 mg/kg and berberine 10 mg/kg in rats; in-vitro concentration-response

limitations

HEK293 is the host cell, not proof that the expressed transporter is human; the indexed proteins are rat Slc22a1/Slc22a2. Intravenous rat results cannot determine an oral human interaction. Assayed substrate was metformin, not thiamine.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Rat OCT1/2 in HEK293 cells and rats; rat protein identity indexed in primary-publication chemical records

plain_language

Transport inhibition is a distinct interaction mechanism from liver CYP inhibition.

primary_references

[berberine-p25359200] Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin. (2015). https://pubmed.ncbi.nlm.nih.gov/25359200/ DOI: 10.1007/s12272-014-0510-6

tissue_or_cell_type

Metformin uptake and disposition

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 766–777

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transporter-expressing cells and intravenous rat pharmacokinetics · source_derived_draft · unverified_draft

### berberine-metformin-rat-slc22a1 Berberine inhibited rat OCT1-mediated metformin uptake in transfected cells, with reported IC50 7.28 micromolar. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Transport inhibition is a distinct interaction mechanism from liver CYP inhibition. organism: Rat OCT1/2 in HEK293 cells and rats; rat protein identity indexed in primary-publication chemical records tissue_or_cell_type: Metformin uptake and disposition experimental_model: Transporter-expressing cells and intravenous rat pharmacokinetics limitations: HEK293 is the host cell, not proof that the expressed transporter is human; the indexed proteins are rat Slc22a1/Slc22a2. Intravenous rat results cannot determine an oral human interaction. Assayed substrate was metformin, not thiamine. exposure: Intravenous metformin 2 mg/kg and berberine 10 mg/kg in rats; in-vitro concentration-response evidence_span: {"source_cache": "artifacts/berberine-research/25359200.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db", "start_char": 0, "end_char": 1353, "text_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db"} [berberine-p25359200] Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin. (2015). https://pubmed.ncbi.nlm.nih.gov/25359200/ DOI: 10.1007/s12272-014-0510-6

evidence_span

{"source_cache": "artifacts/berberine-research/25359200.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db", "start_char": 0, "end_char": 1353, "text_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db"}

experimental_model

Transporter-expressing cells and intravenous rat pharmacokinetics

exposure

Intravenous metformin 2 mg/kg and berberine 10 mg/kg in rats; in-vitro concentration-response

limitations

HEK293 is the host cell, not proof that the expressed transporter is human; the indexed proteins are rat Slc22a1/Slc22a2. Intravenous rat results cannot determine an oral human interaction. Assayed substrate was metformin, not thiamine.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Rat OCT1/2 in HEK293 cells and rats; rat protein identity indexed in primary-publication chemical records

plain_language

Transport inhibition is a distinct interaction mechanism from liver CYP inhibition.

primary_references

[berberine-p25359200] Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin. (2015). https://pubmed.ncbi.nlm.nih.gov/25359200/ DOI: 10.1007/s12272-014-0510-6

tissue_or_cell_type

Metformin uptake and disposition

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 779–790

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transporter-expressing cells and intravenous rat pharmacokinetics · source_derived_draft · unverified_draft

### berberine-metformin-rat-slc22a2 Berberine inhibited rat OCT2-mediated metformin uptake in transfected cells, with reported IC50 11.3 micromolar. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Transport inhibition is a distinct interaction mechanism from liver CYP inhibition. organism: Rat OCT1/2 in HEK293 cells and rats; rat protein identity indexed in primary-publication chemical records tissue_or_cell_type: Metformin uptake and disposition experimental_model: Transporter-expressing cells and intravenous rat pharmacokinetics limitations: HEK293 is the host cell, not proof that the expressed transporter is human; the indexed proteins are rat Slc22a1/Slc22a2. Intravenous rat results cannot determine an oral human interaction. Assayed substrate was metformin, not thiamine. exposure: Intravenous metformin 2 mg/kg and berberine 10 mg/kg in rats; in-vitro concentration-response evidence_span: {"source_cache": "artifacts/berberine-research/25359200.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db", "start_char": 0, "end_char": 1353, "text_sha256": "e46385d733a3c5fc9c39b89a27ef7ca62d228258ae47bb605c6a86eca68ee8db"} [berberine-p25359200] Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin. (2015). https://pubmed.ncbi.nlm.nih.gov/25359200/ DOI: 10.1007/s12272-014-0510-6

evidence_span

{"source_cache": "artifacts/berberine-research/18442638.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0d85d3f03994b65869cd6c52fb46d679f220e4221a6764b38833468818551b66", "start_char": 0, "end_char": 1655, "text_sha256": "0d85d3f03994b65869cd6c52fb46d679f220e4221a6764b38833468818551b66"}

experimental_model

Small randomized comparison plus uncontrolled add-on cohort

exposure

Three-month berberine/metformin comparison and berberine add-on study

limitations

Small pilot, not an equivalence trial proving berberine substitutes for metformin. Add-on cohort lacks a concurrent placebo comparison.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Adults with type 2 diabetes

plain_language

A small comparison is encouraging but does not establish interchangeable clinical treatment.

primary_references

[berberine-p18442638] Efficacy of berberine in patients with type 2 diabetes mellitus. (2008). https://pubmed.ncbi.nlm.nih.gov/18442638/ DOI: 10.1016/j.metabol.2008.01.013

tissue_or_cell_type

Glycemic control and gastrointestinal effects

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 1221–1232

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Small randomized comparison plus uncontrolled add-on cohort · source_derived_draft · unverified_draft

### berberine-pilot-metformin A 36-person pilot reported similar glucose-lowering responses in berberine and metformin groups. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: A small comparison is encouraging but does not establish interchangeable clinical treatment. organism: Adults with type 2 diabetes tissue_or_cell_type: Glycemic control and gastrointestinal effects experimental_model: Small randomized comparison plus uncontrolled add-on cohort limitations: Small pilot, not an equivalence trial proving berberine substitutes for metformin. Add-on cohort lacks a concurrent placebo comparison. exposure: Three-month berberine/metformin comparison and berberine add-on study evidence_span: {"source_cache": "artifacts/berberine-research/18442638.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0d85d3f03994b65869cd6c52fb46d679f220e4221a6764b38833468818551b66", "start_char": 0, "end_char": 1655, "text_sha256": "0d85d3f03994b65869cd6c52fb46d679f220e4221a6764b38833468818551b66"} [berberine-p18442638] Efficacy of berberine in patients with type 2 diabetes mellitus. (2008). https://pubmed.ncbi.nlm.nih.gov/18442638/ DOI: 10.1016/j.metabol.2008.01.013

evidence_span

{"source_cache": "artifacts/berberine-research/30428337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8", "start_char": 0, "end_char": 1775, "text_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8"}

experimental_model

Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells

exposure

Oral metformin/berberine coadministration; concentration-dependent transport assays

limitations

Route differs from the intravenous rat study. Changes in plasma, kidney tissue and excretion are separate outcomes; not proof of improved human combination efficacy.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Rats and recombinant rat OCT1, OCT2 and MATE1

plain_language

This identifies the rat transporter independently, preserving species.

primary_references

[berberine-p30428337] Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine. (2019). https://pubmed.ncbi.nlm.nih.gov/30428337/ DOI: 10.1016/j.ejps.2018.11.010

tissue_or_cell_type

Intestinal uptake, kidney distribution and excretion

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 805–816

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells · source_derived_draft · unverified_draft

### berberine-rat-metformin-rat-slc22a1 Berberine inhibited rat OCT1-mediated metformin transport, with IC50 18.8 micromolar. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: This identifies the rat transporter independently, preserving species. organism: Rats and recombinant rat OCT1, OCT2 and MATE1 tissue_or_cell_type: Intestinal uptake, kidney distribution and excretion experimental_model: Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells limitations: Route differs from the intravenous rat study. Changes in plasma, kidney tissue and excretion are separate outcomes; not proof of improved human combination efficacy. exposure: Oral metformin/berberine coadministration; concentration-dependent transport assays evidence_span: {"source_cache": "artifacts/berberine-research/30428337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8", "start_char": 0, "end_char": 1775, "text_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8"} [berberine-p30428337] Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine. (2019). https://pubmed.ncbi.nlm.nih.gov/30428337/ DOI: 10.1016/j.ejps.2018.11.010

evidence_span

{"source_cache": "artifacts/berberine-research/30428337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8", "start_char": 0, "end_char": 1775, "text_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8"}

experimental_model

Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells

exposure

Oral metformin/berberine coadministration; concentration-dependent transport assays

limitations

Route differs from the intravenous rat study. Changes in plasma, kidney tissue and excretion are separate outcomes; not proof of improved human combination efficacy.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Rats and recombinant rat OCT1, OCT2 and MATE1

plain_language

This identifies the rat transporter independently, preserving species.

primary_references

[berberine-p30428337] Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine. (2019). https://pubmed.ncbi.nlm.nih.gov/30428337/ DOI: 10.1016/j.ejps.2018.11.010

tissue_or_cell_type

Intestinal uptake, kidney distribution and excretion

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 818–829

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells · source_derived_draft · unverified_draft

### berberine-rat-metformin-rat-slc22a2 Berberine inhibited rat OCT2-mediated metformin transport, with IC50 1.02 micromolar. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: This identifies the rat transporter independently, preserving species. organism: Rats and recombinant rat OCT1, OCT2 and MATE1 tissue_or_cell_type: Intestinal uptake, kidney distribution and excretion experimental_model: Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells limitations: Route differs from the intravenous rat study. Changes in plasma, kidney tissue and excretion are separate outcomes; not proof of improved human combination efficacy. exposure: Oral metformin/berberine coadministration; concentration-dependent transport assays evidence_span: {"source_cache": "artifacts/berberine-research/30428337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8", "start_char": 0, "end_char": 1775, "text_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8"} [berberine-p30428337] Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine. (2019). https://pubmed.ncbi.nlm.nih.gov/30428337/ DOI: 10.1016/j.ejps.2018.11.010

evidence_span

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experimental_model

Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells

exposure

Oral metformin/berberine coadministration; concentration-dependent transport assays

limitations

Route differs from the intravenous rat study. Changes in plasma, kidney tissue and excretion are separate outcomes; not proof of improved human combination efficacy.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Rats and recombinant rat OCT1, OCT2 and MATE1

plain_language

This identifies the rat transporter independently, preserving species.

primary_references

[berberine-p30428337] Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine. (2019). https://pubmed.ncbi.nlm.nih.gov/30428337/ DOI: 10.1016/j.ejps.2018.11.010

tissue_or_cell_type

Intestinal uptake, kidney distribution and excretion

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 831–842

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells · source_derived_draft · unverified_draft

### berberine-rat-metformin-rat-slc47a1 Berberine inhibited rat MATE1-mediated metformin transport, with IC50 10.7 micromolar. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: This identifies the rat transporter independently, preserving species. organism: Rats and recombinant rat OCT1, OCT2 and MATE1 tissue_or_cell_type: Intestinal uptake, kidney distribution and excretion experimental_model: Oral rat pharmacokinetics, intestinal sacs and rat-transporter-expressing cells limitations: Route differs from the intravenous rat study. Changes in plasma, kidney tissue and excretion are separate outcomes; not proof of improved human combination efficacy. exposure: Oral metformin/berberine coadministration; concentration-dependent transport assays evidence_span: {"source_cache": "artifacts/berberine-research/30428337.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8", "start_char": 0, "end_char": 1775, "text_sha256": "d35cfbe70c74323ef13e51af7affae3f13a4ff7b80a1d278620b8ced217346d8"} [berberine-p30428337] Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine. (2019). https://pubmed.ncbi.nlm.nih.gov/30428337/ DOI: 10.1016/j.ejps.2018.11.010

cross_nutrient

true

experimental_model

21 adults with type 2 diabetes; 14 switched to metformin, then received calcium

exposure

Oral calcium after three months of metformin; dose not specified in inspected abstract

limitations

Small sequential comparative intervention. Serum holo-TC is an indirect absorption readout and does not directly prove membrane calcium antagonism.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Calcium increased the circulating B12-carrier marker after metformin.

primary_references

[bauman-2000-calcium] 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

Circulating holo-transcobalamin

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 439–450

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 21 adults with type 2 diabetes; 14 switched to metformin, then received calcium · source_derived_draft · unverified_draft

### b12-abs-bauman-calcium-holotc In the comparative diabetes study, adding oral calcium after three months of metformin reversed the decline in serum holo-transcobalamin. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium increased the circulating B12-carrier marker after metformin. organism: Homo sapiens tissue_or_cell_type: Circulating holo-transcobalamin experimental_model: 21 adults with type 2 diabetes; 14 switched to metformin, then received calcium limitations: Small sequential comparative intervention. Serum holo-TC is an indirect absorption readout and does not directly prove membrane calcium antagonism. exposure: Oral calcium after three months of metformin; dose not specified in inspected abstract cross_nutrient: true [bauman-2000-calcium] 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

cross_nutrient

true

experimental_model

Seven healthy adult completers; three experimental days separated by one-month washouts

exposure

Metformin 850 mg plus calcium 500 mg and carbon-13 cyanocobalamin

limitations

Small acute tracer pilot in healthy adults; cannot establish prevention of chronic deficiency or identify the exact molecular metformin target. Doses describe the experiment, not advice.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Calcium coadministration reversed the tracer reduction in this pilot.

primary_references

[muralidharan-2024-calcium] Effect of calcium supplementation on reversing metformin-based inhibition of vitamin B12 bioavailability in healthy adults using a [13C] cyanocobalamin tracer - A pilot study. (2024). https://pubmed.ncbi.nlm.nih.gov/38901951/ DOI: 10.1016/j.clnesp.2024.04.024

tissue_or_cell_type

Intestinal absorption assessed from serial venous tracer measurements

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 465–476

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Seven healthy adult completers; three experimental days separated by one-month washouts · source_derived_draft · unverified_draft

### b12-abs-calcium-tracer-rescue Adding calcium 500 mg to metformin 850 mg raised mean tracer bioavailability from 30.8% to 46.4% in seven healthy completers (p=0.003). Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium coadministration reversed the tracer reduction in this pilot. organism: Homo sapiens tissue_or_cell_type: Intestinal absorption assessed from serial venous tracer measurements experimental_model: Seven healthy adult completers; three experimental days separated by one-month washouts limitations: Small acute tracer pilot in healthy adults; cannot establish prevention of chronic deficiency or identify the exact molecular metformin target. Doses describe the experiment, not advice. exposure: Metformin 850 mg plus calcium 500 mg and carbon-13 cyanocobalamin cross_nutrient: true [muralidharan-2024-calcium] Effect of calcium supplementation on reversing metformin-based inhibition of vitamin B12 bioavailability in healthy adults using a [13C] cyanocobalamin tracer - A pilot study. (2024). https://pubmed.ncbi.nlm.nih.gov/38901951/ DOI: 10.1016/j.clnesp.2024.04.024

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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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

evidence_span

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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

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

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

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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

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

evidence_span

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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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human cancer-cell pharmacological inhibition and proliferation assay.

limitations

Inhibitor results do not resolve individual LDH isoforms or establish a clinical combination.

nutrient_topic

NAD+ collection; molecular form, preparation, species, exposure and manipulation remain explicit. · NAD+

plain_language

Blocking the backup redox route removes its rescue effect.

primary_references

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

trigger_kind

machinery_impairment Imported condition classification; unverified.

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 356–362

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell pharmacological inhibition and proliferation assay. · source_derived_draft · unverified_draft

## nad-plus-ldh-inhibition Blocking the backup redox route removes its rescue effect. The LDH inhibitor GSK2837808A partially inhibited pyruvate-to-lactate conversion and restored metformin sensitivity in pyruvate-containing cancer-cell medium. Model: Human cancer-cell pharmacological inhibition and proliferation assay. Limitations: Inhibitor results do not resolve individual LDH isoforms or establish a clinical combination. Evidence access: Primary full text 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

evidence_access

Primary full text

experimental_model

Cancer-cell culture, complex-I-dependent respiration and nutrient manipulation.

limitations

Experimental concentrations and culture composition matter; not a medication adjustment or claim that metformin has one mechanism in all tissues.

nutrient_topic

NAD+ collection; molecular form, preparation, species, exposure and manipulation remain explicit. · NAD+

plain_language

Available nutrients can change the effect of an inhibitor on the same pathway.

primary_references

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

NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19) · lines 220–226

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cancer-cell culture, complex-I-dependent respiration and nutrient manipulation. · source_derived_draft · unverified_draft

## nad-plus-pyruvate-metformin Available nutrients can change the effect of an inhibitor on the same pathway. Pyruvate supplied an alternative electron-acceptor route for NAD+ regeneration and aspartate synthesis, reducing the antiproliferative effect of metformin in the tested cancer cells. Model: Cancer-cell culture, complex-I-dependent respiration and nutrient manipulation. Limitations: Experimental concentrations and culture composition matter; not a medication adjustment or claim that metformin has one mechanism in all tissues. Evidence access: Primary full text 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

evidence_access

Primary full text

experimental_model

HEK293 expression and phosphorylation assays; the paper labels the construct site S485.

limitations

Construct site numbering is retained without silently mapping it to a human endogenous isoform. No universal AMPK inhibition across all tissues.

nutrient_topic

L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine

plain_language

Changing the inhibitory phosphorylation site interrupted the measured drug interaction.

primary_references

Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 330–336

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · HEK293 expression and phosphorylation assays; the paper labels the construct site S485. · source_derived_draft · unverified_draft

## histidine-imp-ampk Changing the inhibitory phosphorylation site interrupted the measured drug interaction. In HEK293 cells, imidazole propionate suppressed metformin-induced AMPK activation; expression of the study-labeled AMPK S485A mutant prevented suppression of activating T172 phosphorylation. Model: HEK293 expression and phosphorylation assays; the paper labels the construct site S485. Limitations: Construct site numbering is retained without silently mapping it to a human endogenous isoform. No universal AMPK inhibition across all tissues. Evidence access: Primary full text Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012

evidence_access

Primary full text

experimental_model

Human type 2 diabetes plasma comparison.

limitations

Confounding and reverse causation remain possible; no randomized metabolite or histidine intervention.

nutrient_topic

L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine

plain_language

The human association is consistent with a hypothesis but does not test the mechanism.

primary_references

Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 354–360

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human type 2 diabetes plasma comparison. · source_derived_draft · unverified_draft

## histidine-imp-human-metformin The human association is consistent with a hypothesis but does not test the mechanism. Metformin-treated participants with high blood glucose had higher circulating imidazole propionate in the observational comparison. Model: Human type 2 diabetes plasma comparison. Limitations: Confounding and reverse causation remain possible; no randomized metabolite or histidine intervention. Evidence access: Primary full text Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012

evidence_access

Primary full text

experimental_model

Mouse pretreatment and metformin experiments; separate from observational human plasma data.

limitations

Not evidence that histidine supplementation causes metformin failure in humans.

nutrient_topic

L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine

plain_language

A microbial metabolite changed a drug response in an animal model.

primary_references

Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 346–352

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse pretreatment and metformin experiments; separate from observational human plasma data. · source_derived_draft · unverified_draft

## histidine-imp-mouse-metformin A microbial metabolite changed a drug response in an animal model. Imidazole-propionate pretreatment prevented the measured glucose-lowering response to metformin in mice. Model: Mouse pretreatment and metformin experiments; separate from observational human plasma data. Limitations: Not evidence that histidine supplementation causes metformin failure in humans. Evidence access: Primary full text Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012