L-Lactate

evidence_access

Primary abstract

experimental_model

Human-fecal isolates and defined cocultures.

limitations

Strain-specific capacity; several other butyrate-producing species did not use lactate.

nutrient_topic

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

plain_language

Cooperating bacteria turned lactate from starch fermentation into butyrate.

primary_references

Lactate-utilizing bacteria, isolated from human feces, that produce butyrate as a major fermentation product. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15466518/ · DOI 10.1128/AEM.70.10.5810-5817.2004

Butyrate: microbial production, fuel use, signaling and nutrient interactions (2026-09-19) · lines 62–68

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human-fecal isolates and defined cocultures. · source_derived_draft · unverified_draft

## butyrate-lactate-crossfeeding Cooperating bacteria turned lactate from starch fermentation into butyrate. E. hallii-related and A. caccae isolates consumed lactate and formed butyrate; coculture with starch-utilizing B. adolescentis removed detectable L-lactate and generated butyrate. Model: Human-fecal isolates and defined cocultures. Limitations: Strain-specific capacity; several other butyrate-producing species did not use lactate. Evidence access: Primary abstract Lactate-utilizing bacteria, isolated from human feces, that produce butyrate as a major fermentation product. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15466518/ · DOI 10.1128/AEM.70.10.5810-5817.2004

evidence_span

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experimental_model

Protein interaction, glial metabolism and SFO neuronal recordings

exposure

Elevated sodium; Nax knockout; lactate exposure

limitations

Brain salt-sensing pathway in experimental preparations; not a human sodium-intake threshold.

nutrient_topic

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

organism

Mouse SFO and mammalian cell preparations

plain_language

Lactate can pass information from sodium-sensing glia to nearby neurons.

primary_references

[sodium-p17408578] Glial Nax channels control lactate signaling to neurons for brain [Na+] sensing. (2007). https://pubmed.ncbi.nlm.nih.gov/17408578/ DOI: 10.1016/j.neuron.2007.03.014

tissue_or_cell_type

Glial cells and GABAergic neurons of the subfornical organ

Sodium: gradients, nutrient transport, fluid regulation and loss states (2026-09-17) · lines 473–484

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Protein interaction, glial metabolism and SFO neuronal recordings · source_derived_draft · unverified_draft

### sodium-lactate-neurons Lactate stimulated the activity of SFO GABAergic neurons. Condition category: normal nutrient_topic: Sodium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Lactate can pass information from sodium-sensing glia to nearby neurons. organism: Mouse SFO and mammalian cell preparations tissue_or_cell_type: Glial cells and GABAergic neurons of the subfornical organ experimental_model: Protein interaction, glial metabolism and SFO neuronal recordings limitations: Brain salt-sensing pathway in experimental preparations; not a human sodium-intake threshold. exposure: Elevated sodium; Nax knockout; lactate exposure evidence_span: {"source_cache": "artifacts/sodium-research/17408578.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5df7ccac391e94f2688ccacf287fda852b7a52e5279d1488ef48f0f52a3c6265", "start_char": 0, "end_char": 953, "text_sha256": "5df7ccac391e94f2688ccacf287fda852b7a52e5279d1488ef48f0f52a3c6265"} [sodium-p17408578] Glial Nax channels control lactate signaling to neurons for brain [Na+] sensing. (2007). https://pubmed.ncbi.nlm.nih.gov/17408578/ DOI: 10.1016/j.neuron.2007.03.014

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

dose

1:1 fructose/glucose gavage, typically 0.5 g/kg each; dose series 0.25-2 g/kg each

duration

Acute tracing; knockout portal AUC 0-30 min

evidence_access

Primary full-text methods/results and metadata inspected.

evidence_scope

literature_reviewed; source-specific curation

experimental_model

Male C57BL/6 mice, with Khk knockout comparisons

exposure_scope

Component mixture

limitations

Approximately 90% low-dose clearance is a mouse result, not an established human percentage. Fasting, feeding and prior exposure change clearance.

nutrient_topic

HFCS chapter: actual formulation studies, component biochemistry and interventions are explicitly distinguished. · High-Fructose Corn Syrup / HFCS

organism

Male C57BL/6 mice, with Khk knockout comparisons

plain_language

Mouse intestinal tracing detected fructose-derived lactate in portal blood.

primary_references

The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids. (2018). https://pubmed.ncbi.nlm.nih.gov/29414685/ DOI: 10.1016/j.cmet.2017.12.016

route

Oral gavage with isotope tracers

tissue

Small intestine, portal blood and liver

High-Fructose Corn Syrup: mechanism of action and metabolic impact (2026-09-20) · lines 161–171

Original AI-assisted curation of twenty primary studies and official FDA composition information, with one reused canonical glucose-transport claim. Study-specific citations, negative findings and limitations retained. Not publisher full text. · supports · Male C57BL/6 mice, with Khk knockout comparisons · source_derived_draft · unverified_draft

## hfcs-intestinal-lactate Mouse intestinal tracing detected fructose-derived lactate in portal blood. Model/species: Male C57BL/6 mice, with Khk knockout comparisons Tissue: Small intestine, portal blood and liver Exposure: 1:1 fructose/glucose gavage, typically 0.5 g/kg each; dose series 0.25-2 g/kg each Route: Oral gavage with isotope tracers Duration: Acute tracing; knockout portal AUC 0-30 min Exposure scope: Component mixture Limits: Approximately 90% low-dose clearance is a mouse result, not an established human percentage. Fasting, feeding and prior exposure change clearance. Reference: The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids. (2018). https://pubmed.ncbi.nlm.nih.gov/29414685/ DOI: 10.1016/j.cmet.2017.12.016 Access: Primary full-text methods/results and metadata inspected.

evidence_access

Primary abstract

experimental_model

Anaerobic batch cultures.

limitations

A substrate-preference experiment does not mean dietary glucose universally suppresses human butyrate production.

nutrient_topic

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

plain_language

The available carbohydrate changed which substrate microbes used first.

primary_references

Lactate-utilizing bacteria, isolated from human feces, that produce butyrate as a major fermentation product. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15466518/ · DOI 10.1128/AEM.70.10.5810-5817.2004

Butyrate: microbial production, fuel use, signaling and nutrient interactions (2026-09-19) · lines 70–76

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Anaerobic batch cultures. · source_derived_draft · unverified_draft

## butyrate-glucose-switch The available carbohydrate changed which substrate microbes used first. Adding glucose prevented lactate utilization by the tested lactate-to-butyrate isolates until glucose was exhausted. Model: Anaerobic batch cultures. Limitations: A substrate-preference experiment does not mean dietary glucose universally suppresses human butyrate production. Evidence access: Primary abstract Lactate-utilizing bacteria, isolated from human feces, that produce butyrate as a major fermentation product. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15466518/ · DOI 10.1128/AEM.70.10.5810-5817.2004

evidence_access

Primary full text

experimental_model

Purified human AARS1 binding experiments in a gastric-cancer mechanism study.

limitations

These assay affinities do not establish intracellular competition or an effect of oral alanine on lactylation.

nutrient_topic

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

plain_language

One enzyme can recognize alanine and a second metabolite.

primary_references

The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38512451/ · DOI 10.1172/JCI174587

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 64–70

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human AARS1 binding experiments in a gastric-cancer mechanism study. · source_derived_draft · unverified_draft

## alanine-aars-alanine-binding One enzyme can recognize alanine and a second metabolite. Binding assays with recombinant human AARS1 measured alanine binding with a reported dissociation constant of 0.45 micromolar, compared with 2.06 micromolar for lactate. Model: Purified human AARS1 binding experiments in a gastric-cancer mechanism study. Limitations: These assay affinities do not establish intracellular competition or an effect of oral alanine on lactylation. Evidence access: Primary full text The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38512451/ · DOI 10.1172/JCI174587

evidence_access

Primary full text

experimental_model

Recombinant enzyme and human gastric cancer cell experiments.

limitations

This is an enzyme connection, not proof that adding L-alanine promotes or inhibits lactylation. Beta-alanine inhibitor findings must not be transferred to L-alanine.

nutrient_topic

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

plain_language

The alanine-handling enzyme also has a separate lactate-driven signaling activity.

primary_references

The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38512451/ · DOI 10.1172/JCI174587

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 72–78

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant enzyme and human gastric cancer cell experiments. · source_derived_draft · unverified_draft

## alanine-aars-lactylation The alanine-handling enzyme also has a separate lactate-driven signaling activity. Human AARS1 used lactate and ATP for protein lactylation; the study identified YAP K90 and TEAD1 K108 modification and activation in gastric cancer models. Model: Recombinant enzyme and human gastric cancer cell experiments. Limitations: This is an enzyme connection, not proof that adding L-alanine promotes or inhibits lactylation. Beta-alanine inhibitor findings must not be transferred to L-alanine. Evidence access: Primary full text The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38512451/ · DOI 10.1172/JCI174587

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

8988T, Tu8902 and MiaPaCa2 cell experiments.

limitations

Culture rescue does not establish safe dietary restriction or supplementation strategies. Correction record: Publisher erratum corrects the second image label in Fig. 3a to hPSC-LC3 + 8988T, matching Fig. 3b; production labeling correction, not a retraction or independent study. https://www.nature.com/articles/nature19851.pdf

nutrient_topic

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

plain_language

Different carbon sources were not interchangeable in the nutrient-limited culture.

primary_references

Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27509858/ · DOI 10.1038/nature19084

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 168–174

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 8988T, Tu8902 and MiaPaCa2 cell experiments. · source_derived_draft · unverified_draft

## alanine-pdac-glucose-rescue Different carbon sources were not interchangeable in the nutrient-limited culture. Adding 1 mM alanine or pyruvate rescued proliferation under 0.5 mM glucose in the tested human PDAC cultures, while 1 mM lactate did not reproduce that rescue. Model: 8988T, Tu8902 and MiaPaCa2 cell experiments. Limitations: Culture rescue does not establish safe dietary restriction or supplementation strategies. Correction record: Publisher erratum corrects the second image label in Fig. 3a to hPSC-LC3 + 8988T, matching Fig. 3b; production labeling correction, not a retraction or independent study. https://www.nature.com/articles/nature19851.pdf Evidence access: Primary full text Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27509858/ · DOI 10.1038/nature19084

evidence_span

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experimental_model

Protein interaction, glial metabolism and SFO neuronal recordings

exposure

Elevated sodium; Nax knockout; lactate exposure

limitations

Brain salt-sensing pathway in experimental preparations; not a human sodium-intake threshold.

nutrient_topic

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

organism

Mouse SFO and mammalian cell preparations

plain_language

Glial cells turn a sodium signal into a metabolic signal carried by lactate.

primary_references

[sodium-p17408578] Glial Nax channels control lactate signaling to neurons for brain [Na+] sensing. (2007). https://pubmed.ncbi.nlm.nih.gov/17408578/ DOI: 10.1016/j.neuron.2007.03.014

tissue_or_cell_type

Glial cells and GABAergic neurons of the subfornical organ

Sodium: gradients, nutrient transport, fluid regulation and loss states (2026-09-17) · lines 460–471

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Protein interaction, glial metabolism and SFO neuronal recordings · source_derived_draft · unverified_draft

### sodium-nax-lactate The sodium-associated increase in SFO lactate production occurred in wild-type but not Nax-knockout mice. Condition category: normal nutrient_topic: Sodium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glial cells turn a sodium signal into a metabolic signal carried by lactate. organism: Mouse SFO and mammalian cell preparations tissue_or_cell_type: Glial cells and GABAergic neurons of the subfornical organ experimental_model: Protein interaction, glial metabolism and SFO neuronal recordings limitations: Brain salt-sensing pathway in experimental preparations; not a human sodium-intake threshold. exposure: Elevated sodium; Nax knockout; lactate exposure evidence_span: {"source_cache": "artifacts/sodium-research/17408578.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5df7ccac391e94f2688ccacf287fda852b7a52e5279d1488ef48f0f52a3c6265", "start_char": 0, "end_char": 953, "text_sha256": "5df7ccac391e94f2688ccacf287fda852b7a52e5279d1488ef48f0f52a3c6265"} [sodium-p17408578] Glial Nax channels control lactate signaling to neurons for brain [Na+] sensing. (2007). https://pubmed.ncbi.nlm.nih.gov/17408578/ DOI: 10.1016/j.neuron.2007.03.014

evidence_access

Primary abstract

experimental_model

Human prostate-cancer cell experiments; xenografts also studied.

limitations

Not evidence of effective or safe diabetes treatment.

nutrient_topic

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

plain_language

Fuel handling changed in these cancer cells.

primary_references

Cucurbitacin D Reprograms Glucose Metabolic Network in Prostate Cancer. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30875788/ · DOI 10.3390/cancers11030364

Cucurbitacins: thiol chemistry, cytoskeleton, metabolic dependencies and signaling (2026-09-20) · lines 308–314

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human prostate-cancer cell experiments; xenografts also studied. · source_derived_draft · unverified_draft

## cucurbitacin-d-glucose Fuel handling changed in these cancer cells. Cucurbitacin D at 0.1–1 micromolar reduced glucose uptake and lactate output in human PC3 and DU145 experiments. Model: Human prostate-cancer cell experiments; xenografts also studied. Limitations: Not evidence of effective or safe diabetes treatment. Evidence access: Primary abstract Cucurbitacin D Reprograms Glucose Metabolic Network in Prostate Cancer. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30875788/ · DOI 10.3390/cancers11030364

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Magnesium status -> response during thiamine-containing treatment.

experimental_model

Low-Mg thiamine-only subgroup n=22; two-hour measurement.

exposure

Thiamine 250 mg as Pabrinex, magnesium sulfate 2 g, or both; biochemical samples at two hours. Initial magnesium-only group then received thiamine. Study regimens, not recommendations.

limitations

Subgroup finding; no direct PDH flux or universal magnesium gate demonstrated. Pabrinex is multivitamins.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Homo sapiens

plain_language

Low magnesium identified a subgroup whose lactate did not normalize with the vitamin infusion alone.

primary_references

[b1-maguire2022] Randomised trial of intravenous thiamine and/or magnesium sulphate administration on erythrocyte transketolase activity, lactate concentrations and alcohol withdrawal scores (2022). https://pubmed.ncbi.nlm.nih.gov/35484175/ DOI: 10.1038/s41598-022-10970-x

tissue_or_cell_type

Plasma

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1611–1622

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Low-Mg thiamine-only subgroup n=22; two-hour measurement. · source_derived_draft · unverified_draft

### b1-aws-low-mg-lactate-response Median lactate normalized across overall treatment groups, but not in the low-magnesium subgroup receiving the thiamine-containing preparation alone. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Low magnesium identified a subgroup whose lactate did not normalize with the vitamin infusion alone. organism: Homo sapiens tissue_or_cell_type: Plasma experimental_model: Low-Mg thiamine-only subgroup n=22; two-hour measurement. limitations: Subgroup finding; no direct PDH flux or universal magnesium gate demonstrated. Pabrinex is multivitamins. cross_nutrient: Magnesium status -> response during thiamine-containing treatment. exposure: Thiamine 250 mg as Pabrinex, magnesium sulfate 2 g, or both; biochemical samples at two hours. Initial magnesium-only group then received thiamine. Study regimens, not recommendations. [b1-maguire2022] Randomised trial of intravenous thiamine and/or magnesium sulphate administration on erythrocyte transketolase activity, lactate concentrations and alcohol withdrawal scores (2022). https://pubmed.ncbi.nlm.nih.gov/35484175/ DOI: 10.1038/s41598-022-10970-x

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Prespecified subgroup within pilot trial.

exposure

Intravenous thiamine 200 mg twice daily versus placebo for up to seven days or hospital discharge; trial exposure only.

limitations

Small subgroup; treatment did not improve overall-cohort outcomes and the exact mediator was not measured.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Homo sapiens

plain_language

Baseline status may help explain why some patients responded differently.

primary_references

[b1-donnino2016] Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study (2016). https://pubmed.ncbi.nlm.nih.gov/26771781/ DOI: 10.1097/ccm.0000000000001572

tissue_or_cell_type

Plasma

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1648–1658

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Prespecified subgroup within pilot trial. · source_derived_draft · unverified_draft

### b1-sepsis-deficient-subgroup Among the 35% classified deficient at baseline, the prespecified subgroup had lower 24-hour lactate with thiamine than placebo. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Baseline status may help explain why some patients responded differently. organism: Homo sapiens tissue_or_cell_type: Plasma experimental_model: Prespecified subgroup within pilot trial. limitations: Small subgroup; treatment did not improve overall-cohort outcomes and the exact mediator was not measured. exposure: Intravenous thiamine 200 mg twice daily versus placebo for up to seven days or hospital discharge; trial exposure only. [b1-donnino2016] Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study (2016). https://pubmed.ncbi.nlm.nih.gov/26771781/ DOI: 10.1097/ccm.0000000000001572

experimental_model

88 patients; placebo comparison.

exposure

Intravenous thiamine 200 mg twice daily versus placebo for up to seven days or hospital discharge; trial exposure only.

limitations

The study was small; overall null results do not rule out deficiency-specific effects.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Homo sapiens

plain_language

An essential metabolic cofactor did not improve this endpoint for the whole trial population.

primary_references

[b1-donnino2016] Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study (2016). https://pubmed.ncbi.nlm.nih.gov/26771781/ DOI: 10.1097/ccm.0000000000001572

tissue_or_cell_type

Plasma

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1636–1646

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 88 patients; placebo comparison. · source_derived_draft · unverified_draft

### b1-sepsis-overall-lactate-null Thiamine did not significantly lower the 24-hour lactate primary outcome in the overall septic-shock pilot cohort. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: An essential metabolic cofactor did not improve this endpoint for the whole trial population. organism: Homo sapiens tissue_or_cell_type: Plasma experimental_model: 88 patients; placebo comparison. limitations: The study was small; overall null results do not rule out deficiency-specific effects. exposure: Intravenous thiamine 200 mg twice daily versus placebo for up to seven days or hospital discharge; trial exposure only. [b1-donnino2016] Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study (2016). https://pubmed.ncbi.nlm.nih.gov/26771781/ DOI: 10.1097/ccm.0000000000001572

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Six postoperative cases with severely limited oral intake.

exposure

Study-specific exposure described in the model; no regimen inferred beyond the accessed evidence.

limitations

Clinical observations; no isolated test of PDH activity or tissue-specific thiamine threshold.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Homo sapiens

plain_language

Calories alone did not supply the cofactors needed to use them normally.

primary_references

[b1-nakasaki1997] Clinical and biochemical aspects of thiamine treatment for metabolic acidosis during total parenteral nutrition (1997). https://pubmed.ncbi.nlm.nih.gov/9106788/ DOI: 10.1016/s0899-9007(96)00384-x

tissue_or_cell_type

Blood/systemic metabolism

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1783–1793

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Six postoperative cases with severely limited oral intake. · source_derived_draft · unverified_draft

### b1-tpn-lactate-pyruvate Six patients developed severe lactic acidosis within four weeks of vitamin-unsupplemented parenteral nutrition; lactate and pyruvate were elevated. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calories alone did not supply the cofactors needed to use them normally. organism: Homo sapiens tissue_or_cell_type: Blood/systemic metabolism experimental_model: Six postoperative cases with severely limited oral intake. limitations: Clinical observations; no isolated test of PDH activity or tissue-specific thiamine threshold. exposure: Study-specific exposure described in the model; no regimen inferred beyond the accessed evidence. [b1-nakasaki1997] Clinical and biochemical aspects of thiamine treatment for metabolic acidosis during total parenteral nutrition (1997). https://pubmed.ncbi.nlm.nih.gov/9106788/ DOI: 10.1016/s0899-9007(96)00384-x

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Case-series treatment response after conventional measures had failed.

exposure

Study-specific exposure described in the model; no regimen inferred beyond the accessed evidence.

limitations

Not every patient responded or survived; no universal rescue claim.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Homo sapiens

plain_language

A treatment response supported a role for the missing vitamin.

primary_references

[b1-nakasaki1997] Clinical and biochemical aspects of thiamine treatment for metabolic acidosis during total parenteral nutrition (1997). https://pubmed.ncbi.nlm.nih.gov/9106788/ DOI: 10.1016/s0899-9007(96)00384-x

tissue_or_cell_type

Blood/clinical course

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1795–1805

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Case-series treatment response after conventional measures had failed. · source_derived_draft · unverified_draft

### b1-tpn-thiamine-response Thiamine replenishment resolved lactic acidosis and improved clinical status in three patients in the reported series. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: A treatment response supported a role for the missing vitamin. organism: Homo sapiens tissue_or_cell_type: Blood/clinical course experimental_model: Case-series treatment response after conventional measures had failed. limitations: Not every patient responded or survived; no universal rescue claim. exposure: Study-specific exposure described in the model; no regimen inferred beyond the accessed evidence. [b1-nakasaki1997] Clinical and biochemical aspects of thiamine treatment for metabolic acidosis during total parenteral nutrition (1997). https://pubmed.ncbi.nlm.nih.gov/9106788/ DOI: 10.1016/s0899-9007(96)00384-x

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_location

Results: three neurologically affected infants

evidence_span

All 3 had blood lactic acidosis

experimental_model

Nine Israeli infants aged 2-12 months exposed to a defective soy-based formula in the 2003 outbreak; clinical examination, erythrocyte transketolase activation, lactate and selected neuroimaging.

exposure

Consumption of a formula with thiamine below the assay detection limit

limitations

The paper reports blood without specifying plasma in the accessible results. All nine infants had concurrent infections, so lactate is not a specific deficiency test.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Homo sapiens

plain_language

Severe infant deficiency could present with lactate accumulation alongside neurological signs.

primary_references

[fattal-valevski-2005-formula-outbreak] Outbreak of life-threatening thiamine deficiency in infants in Israel caused by a defective soy-based formula. (2005). https://pubmed.ncbi.nlm.nih.gov/15687431/ DOI: 10.1542/peds.2004-1255

tissue_or_cell_type

Blood and cerebrospinal fluid

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1479–1491

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nine Israeli infants aged 2-12 months exposed to a defective soy-based formula in the 2003 outbreak; clinical examination, erythrocyte transketolase activation, lactate and selected neuroimaging. · source_derived_draft · unverified_draft

### thiamine-def-infant-neurologic-lactate All three infants with ophthalmoplegia-related neurological manifestations had blood lactic acidosis; two also had high cerebrospinal-fluid lactate. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Severe infant deficiency could present with lactate accumulation alongside neurological signs. organism: Homo sapiens tissue_or_cell_type: Blood and cerebrospinal fluid experimental_model: Nine Israeli infants aged 2-12 months exposed to a defective soy-based formula in the 2003 outbreak; clinical examination, erythrocyte transketolase activation, lactate and selected neuroimaging. limitations: The paper reports blood without specifying plasma in the accessible results. All nine infants had concurrent infections, so lactate is not a specific deficiency test. evidence_location: Results: three neurologically affected infants evidence_span: All 3 had blood lactic acidosis exposure: Consumption of a formula with thiamine below the assay detection limit [fattal-valevski-2005-formula-outbreak] Outbreak of life-threatening thiamine deficiency in infants in Israel caused by a defective soy-based formula. (2005). https://pubmed.ncbi.nlm.nih.gov/15687431/ DOI: 10.1542/peds.2004-1255

evidence_span

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experimental_model

Cultured human lens epithelial cells exposed to extreme hyperbaric oxygen with enzyme assays and real-time PCR

exposure

99% oxygen at 50 atmospheres for 3 hours, then normal culture for up to 11 days

limitations

Fifty atmospheres is an extreme experimental exposure far above therapy, chosen to probe which defences matter. The selenoenzyme result is the informative part; the pressure is not clinically relevant.

nutrient_topic

Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Hyperbaric oxygen therapy

organism

Human cells

plain_language

The damage landed on the mitochondria, and the cell could not make up the energy by fermenting.

primary_references

[hbot-p15642322] Thioredoxin reductase may be essential for the normal growth of hyperbaric oxygen-treated human lens epithelial cells. (2004). https://pubmed.ncbi.nlm.nih.gov/15642322/ DOI: 10.1016/j.exer.2004.07.001

tissue_or_cell_type

Lens epithelium

Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19) · lines 413–424

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cultured human lens epithelial cells exposed to extreme hyperbaric oxygen with enzyme assays and real-time PCR · source_derived_draft · unverified_draft

### hbot-mito-damage-and-atp Cell death appeared to be caused by loss of ATP, with a 31% decrease immediately after exposure despite a 46% increase in lactate production, and damage occurred primarily in the mitochondria rather than the cytoplasm. Condition category: normal nutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: The damage landed on the mitochondria, and the cell could not make up the energy by fermenting. organism: Human cells tissue_or_cell_type: Lens epithelium experimental_model: Cultured human lens epithelial cells exposed to extreme hyperbaric oxygen with enzyme assays and real-time PCR limitations: Fifty atmospheres is an extreme experimental exposure far above therapy, chosen to probe which defences matter. The selenoenzyme result is the informative part; the pressure is not clinically relevant. exposure: 99% oxygen at 50 atmospheres for 3 hours, then normal culture for up to 11 days evidence_span: {"source_cache": "artifacts/hbot-research/15642322.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e3bc035a17e4e19dd92d4fadb1a79f8e3801619dac24fb91dcf985728afaf995", "start_char": 0, "end_char": 2646, "text_sha256": "e3bc035a17e4e19dd92d4fadb1a79f8e3801619dac24fb91dcf985728afaf995"} [hbot-p15642322] Thioredoxin reductase may be essential for the normal growth of hyperbaric oxygen-treated human lens epithelial cells. (2004). https://pubmed.ncbi.nlm.nih.gov/15642322/ DOI: 10.1016/j.exer.2004.07.001

evidence_access

Primary full text

experimental_model

Human metabolomics and endurance/sprint/resistance comparisons.

limitations

A biomarker rise is not evidence that taking phenylalanine reproduces exercise benefits.

nutrient_topic

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

plain_language

Phenylalanine can join lactate in a metabolite that rises after exercise.

primary_references

An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5

L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 398–404

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human metabolomics and endurance/sprint/resistance comparisons. · source_derived_draft · unverified_draft

## l-phenylalanine-lacphe-exercise Phenylalanine can join lactate in a metabolite that rises after exercise. Lac-Phe rose after exercise in human cohorts of 36 and 8 participants; in the modality comparison, changes tracked lactate and were greatest after sprint exercise. Model: Human metabolomics and endurance/sprint/resistance comparisons. Limitations: A biomarker rise is not evidence that taking phenylalanine reproduces exercise benefits. Evidence access: Primary full text An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse global Cndp2 knockout; repeated treadmill exercise with high-fat feeding.

limitations

Cndp2 has other substrates; the phenotype was conditional on exercise and diet and did not establish a human deficiency syndrome.

nutrient_topic

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

plain_language

Removing a production enzyme weakened one part of the exercise response.

primary_references

An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 414–420

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse global Cndp2 knockout; repeated treadmill exercise with high-fat feeding. · source_derived_draft · unverified_draft

## l-phenylalanine-lacphe-genetic Removing a production enzyme weakened one part of the exercise response. Global Cndp2 knockout markedly reduced circulating Lac-Phe and attenuated the food-intake and weight response to chronic exercise on a high-fat diet. Model: Mouse global Cndp2 knockout; repeated treadmill exercise with high-fat feeding. Limitations: Cndp2 has other substrates; the phenotype was conditional on exercise and diet and did not establish a human deficiency syndrome. Evidence access: Primary full text An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5

evidence_access

Primary full text

experimental_model

Intraperitoneal pharmacological dosing in diet-induced obese mice.

limitations

Oral dosing did not reproduce the effect; lean mice did not respond even up to 150 mg/kg. Lactate and phenylalanine separately did not reproduce it.

nutrient_topic

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

plain_language

The combined metabolite changed feeding in a specific mouse model.

primary_references

An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5

L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 406–412

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Intraperitoneal pharmacological dosing in diet-induced obese mice. · source_derived_draft · unverified_draft

## l-phenylalanine-lacphe-obese-mice The combined metabolite changed feeding in a specific mouse model. Injected Lac-Phe at 50 mg/kg reduced food intake in diet-induced obese mice; daily injection for ten days reduced intake, adiposity and weight. Model: Intraperitoneal pharmacological dosing in diet-induced obese mice. Limitations: Oral dosing did not reproduce the effect; lean mice did not respond even up to 150 mg/kg. Lactate and phenylalanine separately did not reproduce it. Evidence access: Primary full text An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5

evidence_span

{"source_cache": "artifacts/berberine-research/25072399.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "aa8c67580ab0a69c335873a80e94bbe418ac93b88bcad42c72e1eeb564ff828a", "start_char": 0, "end_char": 1385, "text_sha256": "aa8c67580ab0a69c335873a80e94bbe418ac93b88bcad42c72e1eeb564ff828a"}

experimental_model

Pharmacological inhibition, siRNA and dominant-negative AMPK experiments

exposure

Berberine concentration-response; 20 micromolar in phosphorylation experiments

limitations

AMPK is not necessary for every glucose response. This does not show that all other berberine actions are AMPK-independent; cell concentrations may exceed circulating parent drug.

nutrient_topic

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

organism

Human HepG2 hepatocytes and mouse C2C12 myotubes

plain_language

More glycolytic use of glucose can increase lactate production; this is not a clinical lactic-acidosis incidence estimate.

primary_references

[berberine-p25072399] Berberine promotes glucose consumption independently of AMP-activated protein kinase activation. (2014). https://pubmed.ncbi.nlm.nih.gov/25072399/ DOI: 10.1371/journal.pone.0103702

tissue_or_cell_type

Glucose consumption, lactate release and mitochondrial respiration

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 363–374

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Pharmacological inhibition, siRNA and dominant-negative AMPK experiments · source_derived_draft · unverified_draft

### berberine-glycolytic-lactate Berberine increased lactate release in HepG2 and C2C12 cells, including during AMPK-pathway blockade. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: More glycolytic use of glucose can increase lactate production; this is not a clinical lactic-acidosis incidence estimate. organism: Human HepG2 hepatocytes and mouse C2C12 myotubes tissue_or_cell_type: Glucose consumption, lactate release and mitochondrial respiration experimental_model: Pharmacological inhibition, siRNA and dominant-negative AMPK experiments limitations: AMPK is not necessary for every glucose response. This does not show that all other berberine actions are AMPK-independent; cell concentrations may exceed circulating parent drug. exposure: Berberine concentration-response; 20 micromolar in phosphorylation experiments evidence_span: {"source_cache": "artifacts/berberine-research/25072399.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "aa8c67580ab0a69c335873a80e94bbe418ac93b88bcad42c72e1eeb564ff828a", "start_char": 0, "end_char": 1385, "text_sha256": "aa8c67580ab0a69c335873a80e94bbe418ac93b88bcad42c72e1eeb564ff828a"} [berberine-p25072399] Berberine promotes glucose consumption independently of AMP-activated protein kinase activation. (2014). https://pubmed.ncbi.nlm.nih.gov/25072399/ DOI: 10.1371/journal.pone.0103702

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/metformin-research/7555503.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301", "start_char": 0, "end_char": 2221, "text_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301"}

experimental_model

Plasma metformin measurement by HPLC in 14 people with lactic acidosis during metformin treatment

exposure

Chronic metformin with intercurrent renal failure

limitations

A case series in an intensive-care setting. It argues against a simple dose-toxicity relationship; the numbers are small.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human

plain_language

The drug level alone did not decide who developed the acidosis or who survived it.

primary_references

[metformin-p7555503] Role of metformin accumulation in metformin-associated lactic acidosis. (1995). https://pubmed.ncbi.nlm.nih.gov/7555503/ DOI: 10.2337/diacare.18.6.779

tissue_or_cell_type

Whole body

trigger_kind

biomarker_context Imported condition classification; unverified.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1438–1449

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Plasma metformin measurement by HPLC in 14 people with lactic acidosis during metformin treatment · source_derived_draft · unverified_draft

### metformin-acidosis-not-only-accumulation Metformin-associated lactic acidosis was not necessarily due to metformin accumulation, true type B aerobic lactic acidosis seemed exceptional, and neither the severity of the clinical picture nor the degree of accumulation predicted survival. Condition category: biomarker_context nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The drug level alone did not decide who developed the acidosis or who survived it. organism: Human tissue_or_cell_type: Whole body experimental_model: Plasma metformin measurement by HPLC in 14 people with lactic acidosis during metformin treatment limitations: A case series in an intensive-care setting. It argues against a simple dose-toxicity relationship; the numbers are small. exposure: Chronic metformin with intercurrent renal failure evidence_span: {"source_cache": "artifacts/metformin-research/7555503.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301", "start_char": 0, "end_char": 2221, "text_sha256": "c960785146be30aa07921ceef25600c044dd421566e708cdc5c45bffccb0e301"} [metformin-p7555503] Role of metformin accumulation in metformin-associated lactic acidosis. (1995). https://pubmed.ncbi.nlm.nih.gov/7555503/ DOI: 10.2337/diacare.18.6.779

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/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_access

Primary full text

experimental_model

Human cancer-cell nutrient manipulation and NAD+/NADH measurements.

limitations

Reaction-level LDH activity is recorded without assigning an untested isoform.

nutrient_topic

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

plain_language

An electron acceptor can restore NAD without making new NAD molecules.

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 348–354

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cancer-cell nutrient manipulation and NAD+/NADH measurements. · source_derived_draft · unverified_draft

## nad-plus-ldh-redox An electron acceptor can restore NAD without making new NAD molecules. In the tested human A549 and HeLa cancer cells, net pyruvate-to-lactate conversion provided an alternative route to regenerate NAD+ from NADH during complex-I inhibition. Model: Human cancer-cell nutrient manipulation and NAD+/NADH measurements. Limitations: Reaction-level LDH activity is recorded without assigning an untested isoform. 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 abstract and PMC full-text Figure 2 and CRISPR methods

experimental_model

Human RT4 cell knockout and 25 mM lactate treatment for 24 hours; Figure 2.

limitations

This is a shared-enzyme connection, not proof that carnosine changes appetite.

nutrient_topic

Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine

plain_language

The peptide-processing enzyme also participates in another metabolic pathway.

primary_references

An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5

Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 172–178

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human RT4 cell knockout and 25 mM lactate treatment for 24 hours; Figure 2. · source_derived_draft · unverified_draft

## carnosine-cndp2-lacphe The peptide-processing enzyme also participates in another metabolic pathway. Deleting CNDP2 in human RT4 bladder epithelial cells reduced Lac-Phe production; extracellular lactate stimulated production in the control cells. Model: Human RT4 cell knockout and 25 mM lactate treatment for 24 hours; Figure 2. Limitations: This is a shared-enzyme connection, not proof that carnosine changes appetite. Evidence access: Primary abstract and PMC full-text Figure 2 and CRISPR methods An exercise-inducible metabolite that suppresses feeding and obesity. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35705806/ · DOI 10.1038/s41586-022-04828-5

evidence_access

Primary abstract

experimental_model

Rat hepatocytes; simultaneous synthase and phosphorylase activation.

limitations

Context-dependent null result, not an unexplained contradiction.

nutrient_topic

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

plain_language

Changing the starting substrate changed the outcome.

primary_references

Lithium restores glycogen synthesis from glucose in hepatocytes from diabetic rats. · 1993 · https://pubmed.ncbi.nlm.nih.gov/8460950/ · DOI 10.1006/abbi.1993.1164

Lithium: metal-sensitive enzymes, transport and cross-nutrient mechanisms (2026-09-19) · lines 312–318

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat hepatocytes; simultaneous synthase and phosphorylase activation. · source_derived_draft · unverified_draft

## lithium-glycogen-substrate-null Changing the starting substrate changed the outcome. LiCl did not increase glycogen accumulation with lactate and pyruvate in the same hepatocyte study. Model: Rat hepatocytes; simultaneous synthase and phosphorylase activation. Limitations: Context-dependent null result, not an unexplained contradiction. Evidence access: Primary abstract Lithium restores glycogen synthesis from glucose in hepatocytes from diabetic rats. · 1993 · https://pubmed.ncbi.nlm.nih.gov/8460950/ · DOI 10.1006/abbi.1993.1164