AMP-activated protein kinase complexes

evidence_span

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experimental_model

Crystal structures of the human ACC2 biotin-carboxylase domain after AMPK phosphorylation

exposure

Phosphorylation and soraphen A comparison

limitations

Domain structures explain a regulatory mechanism; the construct uses Ser222 numbering and must not be silently relabeled with another isoform numbering scheme.

nutrient_topic

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

organism

Homo sapiens

plain_language

An energy-sensing kinase can switch ACC2 down even when biotin is available.

primary_references

[b7-p19900410] Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK. (2010). https://pubmed.ncbi.nlm.nih.gov/19900410/ DOI: 10.1016/j.bbrc.2009.11.029

tissue_or_cell_type

Purified ACC2 domain

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 702–713

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structures of the human ACC2 biotin-carboxylase domain after AMPK phosphorylation · source_derived_draft · unverified_draft

### b7-acc2-ampk In the studied human ACC2 domain, phosphorylated Ser222 occupied the putative dimer interface, disrupting polymerization and explaining AMPK-mediated inactivation. Condition category: normal nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: An energy-sensing kinase can switch ACC2 down even when biotin is available. organism: Homo sapiens tissue_or_cell_type: Purified ACC2 domain experimental_model: Crystal structures of the human ACC2 biotin-carboxylase domain after AMPK phosphorylation limitations: Domain structures explain a regulatory mechanism; the construct uses Ser222 numbering and must not be silently relabeled with another isoform numbering scheme. exposure: Phosphorylation and soraphen A comparison evidence_span: {"source_cache": "artifacts/biotin-research/19900410.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3d7161fb1a281c68bbe3b8d4738b26d5ed762ca2bea3d9621ee6c8946a7fa71c", "start_char": 0, "end_char": 870, "text_sha256": "3d7161fb1a281c68bbe3b8d4738b26d5ed762ca2bea3d9621ee6c8946a7fa71c"} [b7-p19900410] Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK. (2010). https://pubmed.ncbi.nlm.nih.gov/19900410/ DOI: 10.1016/j.bbrc.2009.11.029

evidence_span

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experimental_model

Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model

exposure

Metformin and other AMPK activators with FXR agonists

limitations

An adverse-direction finding: in a cholestasis model metformin worsened liver injury. Recorded because a mechanism record should not be filtered for favourable outcomes.

nutrient_topic

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

organism

Human cells and mouse

plain_language

The energy sensor directly switches down the bile-acid receptor.

primary_references

[metformin-p24531544] Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. (2014). https://pubmed.ncbi.nlm.nih.gov/24531544/ DOI: 10.1172/jci68815

tissue_or_cell_type

Liver and intestine

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 996–1007

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model · source_derived_draft · unverified_draft

### metformin-ampk-fxr AMPK interacted with FXR in the cytoplasm and phosphorylated it in its hinge domain, inhibiting FXR transcriptional activity and preventing coactivator recruitment. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The energy sensor directly switches down the bile-acid receptor. organism: Human cells and mouse tissue_or_cell_type: Liver and intestine experimental_model: Mass-spectrometry interaction screen in human hepatoma cells with mouse liver, intestine and a cholestasis model limitations: An adverse-direction finding: in a cholestasis model metformin worsened liver injury. Recorded because a mechanism record should not be filtered for favourable outcomes. exposure: Metformin and other AMPK activators with FXR agonists evidence_span: {"source_cache": "artifacts/metformin-research/24531544.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad", "start_char": 0, "end_char": 1358, "text_sha256": "9e34abf954452e017d254058f7e611697560bba87a53cf726c88f0b77d6673ad"} [metformin-p24531544] Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. (2014). https://pubmed.ncbi.nlm.nih.gov/24531544/ DOI: 10.1172/jci68815

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

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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 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

evidence_access

Primary abstract

experimental_model

Several cultured cell lines under prolonged amino-acid withdrawal.

limitations

Different stress from glucose withdrawal; a universal AMPK-on/autophagy-on rule is unsupported.

nutrient_topic

Fasting physiological-state collection; human protocols, cellular deprivation and refeeding are distinguished. · Fasting / abstention from energy intake

plain_language

Loss of this sensor did not shut down all autophagy.

primary_references

Unexpected roles for AMPK in the suppression of autophagy and the reactivation of MTORC1 signaling during prolonged amino acid deprivation. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38744665/ · DOI 10.1080/15548627.2024.2355074

Fasting: fuel switching, nutrient sensing, ketone signaling, nutrient dependencies and refeeding (2026-09-18) · lines 312–318

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Several cultured cell lines under prolonged amino-acid withdrawal. · source_derived_draft · unverified_draft

## fast-ampk-context Loss of this sensor did not shut down all autophagy. Autophagy remained unimpaired in AMPK-deficient cells during amino-acid deprivation; ULK1 signaling and LC3B lipidation increased. Model: Several cultured cell lines under prolonged amino-acid withdrawal. Limitations: Different stress from glucose withdrawal; a universal AMPK-on/autophagy-on rule is unsupported. Evidence access: Primary abstract Unexpected roles for AMPK in the suppression of autophagy and the reactivation of MTORC1 signaling during prolonged amino acid deprivation. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38744665/ · DOI 10.1080/15548627.2024.2355074

evidence_access

Primary abstract

experimental_model

Cultured nutrient-stressed cells.

limitations

Cell survival and autophagy readouts must be distinguished.

nutrient_topic

Fasting physiological-state collection; human protocols, cellular deprivation and refeeding are distinguished. · Fasting / abstention from energy intake

plain_language

The same sensor can support recovery during persistent stress.

primary_references

Unexpected roles for AMPK in the suppression of autophagy and the reactivation of MTORC1 signaling during prolonged amino acid deprivation. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38744665/ · DOI 10.1080/15548627.2024.2355074

Fasting: fuel switching, nutrient sensing, ketone signaling, nutrient dependencies and refeeding (2026-09-18) · lines 320–326

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Cultured nutrient-stressed cells. · source_derived_draft · unverified_draft

## fast-ampk-reactivation The same sensor can support recovery during persistent stress. AMPK loss impaired mTORC1 reactivation during prolonged amino-acid deprivation and increased apoptosis. Model: Cultured nutrient-stressed cells. Limitations: Cell survival and autophagy readouts must be distinguished. Evidence access: Primary abstract Unexpected roles for AMPK in the suppression of autophagy and the reactivation of MTORC1 signaling during prolonged amino acid deprivation. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38744665/ · DOI 10.1080/15548627.2024.2355074

evidence_access

Primary abstract

experimental_model

Mammalian cell experiments with study Ulk1 constructs; mouse residue numbering.

limitations

Do not transfer residue numbers to human ULK1 or infer a fasting-hour threshold.

nutrient_topic

Fasting physiological-state collection; human protocols, cellular deprivation and refeeding are distinguished. · Fasting / abstention from energy intake

plain_language

Energy stress can act on the autophagy-starting machinery.

primary_references

AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21258367/ · DOI 10.1038/ncb2152

Fasting: fuel switching, nutrient sensing, ketone signaling, nutrient dependencies and refeeding (2026-09-18) · lines 296–302

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mammalian cell experiments with study Ulk1 constructs; mouse residue numbering. · source_derived_draft · unverified_draft

## fast-ampk-ulk Energy stress can act on the autophagy-starting machinery. Under glucose starvation AMPK directly activated Ulk1 through Ser317 and Ser777 phosphorylation. Model: Mammalian cell experiments with study Ulk1 constructs; mouse residue numbering. Limitations: Do not transfer residue numbers to human ULK1 or infer a fasting-hour threshold. Evidence access: Primary abstract AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21258367/ · DOI 10.1038/ncb2152

evidence_span

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experimental_model

Lysosome isolation, genetic perturbation and coimmunoprecipitation

exposure

Low-dose berberine experiments; AXIN1 loss, PEN2 perturbation and UHRF1 overexpression

limitations

Cancer-cell signaling model; low laboratory concentration is not proof of a mechanism at every human tissue exposure. Different dose/context from respiratory inhibition studies.

nutrient_topic

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

organism

Human HCT-116 cells

plain_language

Increasing the negative regulator prevented the observed response.

primary_references

[berberine-p37144221] Berberine stimulates lysosomal AMPK independent of PEN2 and maintains cellular AMPK activity through inhibiting the dephosphorylation regulator UHRF1. (2023). https://pubmed.ncbi.nlm.nih.gov/37144221/ DOI: 10.3389/fphar.2023.1148611

tissue_or_cell_type

Lysosomal AMPK and UHRF1 regulation

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 428–439

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Lysosome isolation, genetic perturbation and coimmunoprecipitation · source_derived_draft · unverified_draft

### berberine-uhrf1-overexpression UHRF1 overexpression abolished berberine-induced AMPK activation in the tested cells. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Increasing the negative regulator prevented the observed response. organism: Human HCT-116 cells tissue_or_cell_type: Lysosomal AMPK and UHRF1 regulation experimental_model: Lysosome isolation, genetic perturbation and coimmunoprecipitation limitations: Cancer-cell signaling model; low laboratory concentration is not proof of a mechanism at every human tissue exposure. Different dose/context from respiratory inhibition studies. exposure: Low-dose berberine experiments; AXIN1 loss, PEN2 perturbation and UHRF1 overexpression evidence_span: {"source_cache": "artifacts/berberine-research/37144221.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e146553474cca4ec8441b54580959225dcf3dfee60a50ea519ccac5e2cb6488d", "start_char": 0, "end_char": 1212, "text_sha256": "e146553474cca4ec8441b54580959225dcf3dfee60a50ea519ccac5e2cb6488d"} [berberine-p37144221] Berberine stimulates lysosomal AMPK independent of PEN2 and maintains cellular AMPK activity through inhibiting the dephosphorylation regulator UHRF1. (2023). https://pubmed.ncbi.nlm.nih.gov/37144221/ DOI: 10.3389/fphar.2023.1148611

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

evidence_span

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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

evidence_span

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experimental_model

Liver-specific LKB1 deletion in adult mice with adenoviral TORC2 knockdown

exposure

Metformin in LKB1-deficient livers

limitations

A genetic requirement in this model. The same year’s consensus was later challenged by AMPK-independent findings recorded in this collection.

nutrient_topic

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

organism

Mouse

plain_language

The upstream kinase is what turns the energy sensor on in the liver.

primary_references

[metformin-p16308421] The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. (2005). https://pubmed.ncbi.nlm.nih.gov/16308421/ DOI: 10.1126/science.1120781

tissue_or_cell_type

Liver

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 567–578

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Liver-specific LKB1 deletion in adult mice with adenoviral TORC2 knockdown · source_derived_draft · unverified_draft

### metformin-lkb1-ampk-axis Deletion of LKB1 in adult mouse liver resulted in a nearly complete loss of AMPK activity, with hyperglycaemia and increased gluconeogenic and lipogenic gene expression. Condition category: normal nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The upstream kinase is what turns the energy sensor on in the liver. organism: Mouse tissue_or_cell_type: Liver experimental_model: Liver-specific LKB1 deletion in adult mice with adenoviral TORC2 knockdown limitations: A genetic requirement in this model. The same year’s consensus was later challenged by AMPK-independent findings recorded in this collection. exposure: Metformin in LKB1-deficient livers evidence_span: {"source_cache": "artifacts/metformin-research/16308421.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e4762199db357f0f8002a9da8ff2ecad8e9bfcb48c963eb4b2cde7ffa363eec4", "start_char": 0, "end_char": 1103, "text_sha256": "e4762199db357f0f8002a9da8ff2ecad8e9bfcb48c963eb4b2cde7ffa363eec4"} [metformin-p16308421] The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. (2005). https://pubmed.ncbi.nlm.nih.gov/16308421/ DOI: 10.1126/science.1120781

evidence_span

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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

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/metformin-research/24961373.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70", "start_char": 0, "end_char": 1270, "text_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70"}

experimental_model

Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake

exposure

Metformin and phenformin against thiamine uptake; acute metformin in wild-type mice

limitations

Identifies thiamine as an endogenous OCT1 substrate and shows competitive inhibition by metformin. The steatosis phenotype is a mouse phenotype.

nutrient_topic

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

organism

Mouse and human transporter

plain_language

Short vitamin B1 switches on the same energy sensor the drug does.

primary_references

[metformin-p24961373] OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. (2014). https://pubmed.ncbi.nlm.nih.gov/24961373/ DOI: 10.1073/pnas.1314939111

tissue_or_cell_type

Liver and intestine

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1269–1280

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake · source_derived_draft · unverified_draft

### metformin-oct1-loss-ampk-thiamine Loss of Oct1 raised the AMP to ATP ratio and activated AMPK, and thiamine deficiency itself enhanced phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Short vitamin B1 switches on the same energy sensor the drug does. organism: Mouse and human transporter tissue_or_cell_type: Liver and intestine experimental_model: Oct1-knockout and human OCT1 transgenic mice, metabolomics and isotopic uptake limitations: Identifies thiamine as an endogenous OCT1 substrate and shows competitive inhibition by metformin. The steatosis phenotype is a mouse phenotype. exposure: Metformin and phenformin against thiamine uptake; acute metformin in wild-type mice evidence_span: {"source_cache": "artifacts/metformin-research/24961373.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70", "start_char": 0, "end_char": 1270, "text_sha256": "77be4a228b3d067ca1e7ba44e8148f5fbda7956a23b42fb8281e9faf451a0e70"} [metformin-p24961373] OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. (2014). https://pubmed.ncbi.nlm.nih.gov/24961373/ DOI: 10.1073/pnas.1314939111

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

evidence_span

{"source_cache": "artifacts/acetate-research/16630552.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8e99fe94e17c850602d0da9607212293dfc8d773e356b73ef37c4b071bbeabea", "start_char": 0, "end_char": 914, "text_sha256": "8e99fe94e17c850602d0da9607212293dfc8d773e356b73ef37c4b071bbeabea"}

experimental_model

KK-Ay diabetic mice fed for 8 weeks, with rat hepatocyte experiments

exposure

0.3% dietary acetic acid for 8 weeks; sodium acetate as neutralised acetic acid applied to rat hepatocytes

limitations

The hepatocyte arm used the neutralised salt and still activated AMPK, which does not sit easily beside the human finding that the acid rather than the salt lowered glucose. Both are recorded.

nutrient_topic

Acetic acid research collection; topical membership is not evidence of a direct clinical effect, and the ingested acid is recorded separately from the circulating acetate anion. · Acetic acid

organism

Mouse and rat cells

plain_language

The neutralised salt switched on the liver cell energy sensor directly.

primary_references

[acetate-p16630552] Acetic acid activates hepatic AMPK and reduces hyperglycemia in diabetic KK-A(y) mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16630552/ DOI: 10.1016/j.bbrc.2006.03.176

tissue_or_cell_type

Liver

Acetic acid: the ingested acid, the receptors acetate binds, the acetyl-CoA it becomes, and the acetyl groups that reach histones (2026-09-21) · lines 420–431

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · KK-Ay diabetic mice fed for 8 weeks, with rat hepatocyte experiments · source_derived_draft · unverified_draft

### acetate-sodium-acetate-hepatocyte Sodium acetate, in the form of neutralised acetic acid, directly activated AMPK and lowered the expression of genes such as glucose-6-phosphatase and sterol regulatory element binding protein 1 in rat hepatocytes, leading the authors to conclude that the hypoglycaemic effect might be due to activation of AMPK in the liver. Condition category: normal nutrient_topic: Acetic acid research collection; topical membership is not evidence of a direct clinical effect, and the ingested acid is recorded separately from the circulating acetate anion. plain_language: The neutralised salt switched on the liver cell energy sensor directly. organism: Mouse and rat cells tissue_or_cell_type: Liver experimental_model: KK-Ay diabetic mice fed for 8 weeks, with rat hepatocyte experiments limitations: The hepatocyte arm used the neutralised salt and still activated AMPK, which does not sit easily beside the human finding that the acid rather than the salt lowered glucose. Both are recorded. exposure: 0.3% dietary acetic acid for 8 weeks; sodium acetate as neutralised acetic acid applied to rat hepatocytes evidence_span: {"source_cache": "artifacts/acetate-research/16630552.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8e99fe94e17c850602d0da9607212293dfc8d773e356b73ef37c4b071bbeabea", "start_char": 0, "end_char": 914, "text_sha256": "8e99fe94e17c850602d0da9607212293dfc8d773e356b73ef37c4b071bbeabea"} [acetate-p16630552] Acetic acid activates hepatic AMPK and reduces hyperglycemia in diabetic KK-A(y) mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16630552/ DOI: 10.1016/j.bbrc.2006.03.176

evidence_span

{"source_cache": "artifacts/dihydrocapsaicin-research/36681810.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "14c4f7752262c5a27fb7b848664015595f598cb51edcc2d5df96f1140be143cb", "start_char": 0, "end_char": 1600, "text_sha256": "14c4f7752262c5a27fb7b848664015595f598cb51edcc2d5df96f1140be143cb"}

experimental_model

3T3-L1 adipocytes assayed for viability, lipid accumulation, AMPK activity, lipolysis and glucose uptake

exposure

8-methyl nonanoic acid applied during 48-hour nutrient starvation or 5-day maturation

limitations

A cell-line study of the metabolite. The two exposure windows give different effects, which is recorded rather than averaged.

nutrient_topic

Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin. · Dihydrocapsaicin

organism

Mouse cells

plain_language

In fat cells under starvation the fragment switches on the energy sensor and less fat accumulates.

primary_references

[dhc-p36681810] Cellular responses to 8-methyl nonanoic acid, a degradation by-product of dihydrocapsaicin, in 3T3-L1 adipocytes. (2023). https://pubmed.ncbi.nlm.nih.gov/36681810/ DOI: 10.1186/s12906-023-03844-w

tissue_or_cell_type

Adipocytes

Dihydrocapsaicin: the second capsaicinoid, the hypothermia it is used to induce, what the gut and liver do to it, and what it does without TRPV1 (2026-09-21) · lines 621–632

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 3T3-L1 adipocytes assayed for viability, lipid accumulation, AMPK activity, lipolysis and glucose uptake · source_derived_draft · unverified_draft

### dhc-8-mna-activates-ampk In 3T3-L1 adipocytes 8-methyl nonanoic acid caused no impact on cell viability, and during nutrient starvation it decreased lipid amounts in association with AMP-activated protein kinase activation, a molecular event that suppresses lipogenic processes. Condition category: normal nutrient_topic: Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin. plain_language: In fat cells under starvation the fragment switches on the energy sensor and less fat accumulates. organism: Mouse cells tissue_or_cell_type: Adipocytes experimental_model: 3T3-L1 adipocytes assayed for viability, lipid accumulation, AMPK activity, lipolysis and glucose uptake limitations: A cell-line study of the metabolite. The two exposure windows give different effects, which is recorded rather than averaged. exposure: 8-methyl nonanoic acid applied during 48-hour nutrient starvation or 5-day maturation evidence_span: {"source_cache": "artifacts/dihydrocapsaicin-research/36681810.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "14c4f7752262c5a27fb7b848664015595f598cb51edcc2d5df96f1140be143cb", "start_char": 0, "end_char": 1600, "text_sha256": "14c4f7752262c5a27fb7b848664015595f598cb51edcc2d5df96f1140be143cb"} [dhc-p36681810] Cellular responses to 8-methyl nonanoic acid, a degradation by-product of dihydrocapsaicin, in 3T3-L1 adipocytes. (2023). https://pubmed.ncbi.nlm.nih.gov/36681810/ DOI: 10.1186/s12906-023-03844-w

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/aspirin-research/22517326.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1a48863bf252421416f67d62acb18c9f44f170075c5aff6f775eba14bba2b1b4", "start_char": 0, "end_char": 887, "text_sha256": "1a48863bf252421416f67d62acb18c9f44f170075c5aff6f775eba14bba2b1b4"}

experimental_model

Allosteric activation and dephosphorylation assays with AMP-activated protein kinase knockout mice

exposure

Salicylate at concentrations reached in plasma after salsalate or high-dose aspirin, against the synthetic activator A-769662

limitations

The knockout arm ties the whole-animal effect to the kinase. The concentrations are those of high-dose salicylate therapy, not of antiplatelet aspirin, which the authors state explicitly.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Human enzyme and mouse

plain_language

The old plant compound switches on the cell’s energy sensor directly, at doses far above a daily aspirin.

primary_references

[asa-p22517326] The ancient drug salicylate directly activates AMP-activated protein kinase. (2012). https://pubmed.ncbi.nlm.nih.gov/22517326/ DOI: 10.1126/science.1215327

tissue_or_cell_type

AMP-activated protein kinase

trigger_kind

biomarker_context Imported condition classification; unverified.

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 494–505

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Allosteric activation and dephosphorylation assays with AMP-activated protein kinase knockout mice · source_derived_draft · unverified_draft

### asa-salicylate-activates-ampk At concentrations reached in plasma after administration of salsalate or of aspirin at high doses, salicylate activates AMP-activated protein kinase by binding at the same site as the synthetic activator A-769662 to cause allosteric activation and inhibition of dephosphorylation of the activating phosphorylation site threonine-172, and in knockout mice the effects of salicylate to increase fat utilisation and to lower plasma fatty acids in vivo were lost. Condition category: biomarker_context nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: The old plant compound switches on the cell’s energy sensor directly, at doses far above a daily aspirin. organism: Human enzyme and mouse tissue_or_cell_type: AMP-activated protein kinase experimental_model: Allosteric activation and dephosphorylation assays with AMP-activated protein kinase knockout mice limitations: The knockout arm ties the whole-animal effect to the kinase. The concentrations are those of high-dose salicylate therapy, not of antiplatelet aspirin, which the authors state explicitly. exposure: Salicylate at concentrations reached in plasma after salsalate or high-dose aspirin, against the synthetic activator A-769662 evidence_span: {"source_cache": "artifacts/aspirin-research/22517326.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1a48863bf252421416f67d62acb18c9f44f170075c5aff6f775eba14bba2b1b4", "start_char": 0, "end_char": 887, "text_sha256": "1a48863bf252421416f67d62acb18c9f44f170075c5aff6f775eba14bba2b1b4"} [asa-p22517326] The ancient drug salicylate directly activates AMP-activated protein kinase. (2012). https://pubmed.ncbi.nlm.nih.gov/22517326/ DOI: 10.1126/science.1215327

evidence_span

{"source_cache": "artifacts/ala-research/15195087.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6fcce42055285979267d9a0f58b3c7e9fb221b549db47d2f508b3fb2112ad493", "start_char": 0, "end_char": 1001, "text_sha256": "6fcce42055285979267d9a0f58b3c7e9fb221b549db47d2f508b3fb2112ad493"}

experimental_model

Rodent feeding, energy expenditure and hypothalamic AMPK manipulation

exposure

Alpha-lipoic acid with central AMPK manipulation

limitations

Central effects must not be generalized to AMPK in all tissues or to human weight-loss outcomes.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Rodents

plain_language

The brain’s feeding-control AMPK response decreased in this setting.

primary_references

[ala-p15195087] Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. (2004). https://pubmed.ncbi.nlm.nih.gov/15195087/ DOI: 10.1038/nm1061

tissue_or_cell_type

Hypothalamus and whole-animal energy balance

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 975–986

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rodent feeding, energy expenditure and hypothalamic AMPK manipulation · source_derived_draft · unverified_draft

### ala-hypothalamic-ampk Lipoic acid suppressed hypothalamic AMPK activity in the rodent experiments. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The brain’s feeding-control AMPK response decreased in this setting. organism: Rodents tissue_or_cell_type: Hypothalamus and whole-animal energy balance experimental_model: Rodent feeding, energy expenditure and hypothalamic AMPK manipulation limitations: Central effects must not be generalized to AMPK in all tissues or to human weight-loss outcomes. exposure: Alpha-lipoic acid with central AMPK manipulation evidence_span: {"source_cache": "artifacts/ala-research/15195087.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6fcce42055285979267d9a0f58b3c7e9fb221b549db47d2f508b3fb2112ad493", "start_char": 0, "end_char": 1001, "text_sha256": "6fcce42055285979267d9a0f58b3c7e9fb221b549db47d2f508b3fb2112ad493"} [ala-p15195087] Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. (2004). https://pubmed.ncbi.nlm.nih.gov/15195087/ DOI: 10.1038/nm1061

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

Cells can use more glucose even when this proposed signaling route is blocked.

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 350–361

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-ampk-independent-glucose Berberine still increased glucose utilization after AMPK inhibition, AMPK-alpha silencing or dominant-negative AMPK expression. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cells can use more glucose even when this proposed signaling route is blocked. 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

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/metformin-research/20577053.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f6019de6b5a35f860f55b39d91656e5fd1077d34e301d244a1ea498b96faac14", "start_char": 0, "end_char": 1707, "text_sha256": "f6019de6b5a35f860f55b39d91656e5fd1077d34e301d244a1ea498b96faac14"}

experimental_model

Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression

exposure

Metformin dose-response in hepatocytes lacking AMPK or LKB1

limitations

A direct challenge to the AMPK requirement. The measured correlate is intracellular ATP, so this is an energy-state mechanism rather than a signalling one.

nutrient_topic

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

organism

Mouse

plain_language

Removing the sensor did not remove the drug effect, and in these cells it made it larger.

primary_references

[metformin-p20577053] Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. (2010). https://pubmed.ncbi.nlm.nih.gov/20577053/ DOI: 10.1172/jci40671

tissue_or_cell_type

Liver

trigger_kind

machinery_impairment Imported condition classification; unverified.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 593–604

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression · source_derived_draft · unverified_draft

### metformin-ampk-independent-glucose In mice lacking AMPK in the liver, blood glucose was comparable to wild type and the hypoglycaemic effect of metformin was maintained; metformin-induced inhibition of glucose production was amplified in both AMPK- and LKB1-deficient hepatocytes. Condition category: machinery_impairment nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Removing the sensor did not remove the drug effect, and in these cells it made it larger. organism: Mouse tissue_or_cell_type: Liver experimental_model: Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression limitations: A direct challenge to the AMPK requirement. The measured correlate is intracellular ATP, so this is an energy-state mechanism rather than a signalling one. exposure: Metformin dose-response in hepatocytes lacking AMPK or LKB1 evidence_span: {"source_cache": "artifacts/metformin-research/20577053.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f6019de6b5a35f860f55b39d91656e5fd1077d34e301d244a1ea498b96faac14", "start_char": 0, "end_char": 1707, "text_sha256": "f6019de6b5a35f860f55b39d91656e5fd1077d34e301d244a1ea498b96faac14"} [metformin-p20577053] Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. (2010). https://pubmed.ncbi.nlm.nih.gov/20577053/ DOI: 10.1172/jci40671

evidence_span

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experimental_model

KK-Ay diabetic mice fed for 8 weeks, with rat hepatocyte experiments

exposure

0.3% dietary acetic acid for 8 weeks; sodium acetate as neutralised acetic acid applied to rat hepatocytes

limitations

The hepatocyte arm used the neutralised salt and still activated AMPK, which does not sit easily beside the human finding that the acid rather than the salt lowered glucose. Both are recorded.

nutrient_topic

Acetic acid research collection; topical membership is not evidence of a direct clinical effect, and the ingested acid is recorded separately from the circulating acetate anion. · Acetic acid

organism

Mouse

plain_language

Eight weeks of dietary acid lowered fasting glucose and long-term glucose control, and turned down the liver genes that make glucose and fat.

primary_references

[acetate-p16630552] Acetic acid activates hepatic AMPK and reduces hyperglycemia in diabetic KK-A(y) mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16630552/ DOI: 10.1016/j.bbrc.2006.03.176

tissue_or_cell_type

Liver

Acetic acid: the ingested acid, the receptors acetate binds, the acetyl-CoA it becomes, and the acetyl groups that reach histones (2026-09-21) · lines 407–418

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · KK-Ay diabetic mice fed for 8 weeks, with rat hepatocyte experiments · source_derived_draft · unverified_draft

### acetate-acetic-acid-ampk Fasting plasma glucose and HbA1c levels were lower in KK-Ay mice fed 0.3% acetic acid for 8 weeks than in control mice, and acetic acid also reduced the expression of genes involved in gluconeogenesis and lipogenesis, which is in part regulated by AMP-activated protein kinase in the liver. Condition category: normal nutrient_topic: Acetic acid research collection; topical membership is not evidence of a direct clinical effect, and the ingested acid is recorded separately from the circulating acetate anion. plain_language: Eight weeks of dietary acid lowered fasting glucose and long-term glucose control, and turned down the liver genes that make glucose and fat. organism: Mouse tissue_or_cell_type: Liver experimental_model: KK-Ay diabetic mice fed for 8 weeks, with rat hepatocyte experiments limitations: The hepatocyte arm used the neutralised salt and still activated AMPK, which does not sit easily beside the human finding that the acid rather than the salt lowered glucose. Both are recorded. exposure: 0.3% dietary acetic acid for 8 weeks; sodium acetate as neutralised acetic acid applied to rat hepatocytes evidence_span: {"source_cache": "artifacts/acetate-research/16630552.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8e99fe94e17c850602d0da9607212293dfc8d773e356b73ef37c4b071bbeabea", "start_char": 0, "end_char": 914, "text_sha256": "8e99fe94e17c850602d0da9607212293dfc8d773e356b73ef37c4b071bbeabea"} [acetate-p16630552] Acetic acid activates hepatic AMPK and reduces hyperglycemia in diabetic KK-A(y) mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16630552/ DOI: 10.1016/j.bbrc.2006.03.176

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Human NSCLC cell cultures including H1299, H460, and A549

limitations

Abrupt medium depletion; no direct lysine-binding sensor established; no supplementation benefit inferred for healthy humans.

organism

Homo sapiens

plain_language

These cultured cancer cells needed available lysine for full nutrient-and-growth-factor signaling.

primary_references

[jang2020] Lysine is required for growth factor-induced mTORC1 activation (2020). https://pubmed.ncbi.nlm.nih.gov/33008594/ DOI: 10.1016/j.bbrc.2020.09.100

tissue_or_cell_type

Cultured lung cancer cells

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 819–827

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human NSCLC cell cultures including H1299, H460, and A549 · source_derived_draft · unverified_draft

### lysine-deprivation-mtorc1 Lysine withdrawal suppressed mTORC1 activity in NSCLC cell lines, and lysine restoration reversed the suppression; GCN2 and AMPK contributed to this response. Plain language: These cultured cancer cells needed available lysine for full nutrient-and-growth-factor signaling. Condition category: nutrient_deficiency organism: Homo sapiens tissue_or_cell_type: Cultured lung cancer cells experimental_model: Human NSCLC cell cultures including H1299, H460, and A549 limitations: Abrupt medium depletion; no direct lysine-binding sensor established; no supplementation benefit inferred for healthy humans. [jang2020] Lysine is required for growth factor-induced mTORC1 activation (2020). https://pubmed.ncbi.nlm.nih.gov/33008594/ DOI: 10.1016/j.bbrc.2020.09.100

evidence_access

Primary abstract

experimental_model

Cellular kinase and autophagy assays; mouse Ulk1 numbering.

limitations

Specific signaling mechanism, not a whole-body autophagic-flux measurement.

nutrient_topic

Fasting physiological-state collection; human protocols, cellular deprivation and refeeding are distinguished. · Fasting / abstention from energy intake

plain_language

Nutrient sufficiency can restrain this initiation route.

primary_references

AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21258367/ · DOI 10.1038/ncb2152

Fasting: fuel switching, nutrient sensing, ketone signaling, nutrient dependencies and refeeding (2026-09-18) · lines 304–310

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Cellular kinase and autophagy assays; mouse Ulk1 numbering. · source_derived_draft · unverified_draft

## fast-mtor-ulk Nutrient sufficiency can restrain this initiation route. High mTOR activity phosphorylated Ulk1 Ser757 and disrupted its interaction with AMPK. Model: Cellular kinase and autophagy assays; mouse Ulk1 numbering. Limitations: Specific signaling mechanism, not a whole-body autophagic-flux measurement. Evidence access: Primary abstract AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21258367/ · DOI 10.1038/ncb2152

availability_state

machinery_impairment Imported condition classification; unverified.

dose

Hydroxytyrosol with compound C or cyclosporine

duration

Cell assay accompanying fish feeding

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

Zebrafish liver cell line with an eight-week spotted-seabass feeding arm

limitations

This fish/cell mechanism is not direct evidence for human liver disease or a clinical drug interaction.

nutrient_topic

Hydroxytyrosol chapter; interacting nutrients, drugs, peptides and proteins retain their experimental settings. · Hydroxytyrosol

organism

Zebrafish liver cell line with an eight-week spotted-seabass feeding arm

plain_language

Compound C blocked hydroxytyrosol-associated PINK1 mitophagy in zebrafish liver cells, and cyclosporine blocked the measured mitochondrial benefits.

primary_references

Hydroxytyrosol Promotes the Mitochondrial Function through Activating Mitophagy. (2022). https://pubmed.ncbi.nlm.nih.gov/35624756/ DOI: 10.3390/antiox11050893

route

In vitro perturbation

tissue

AMPK/PINK1 mitophagy and mitochondrial function

trigger_kind

machinery_impairment Imported condition classification; unverified.

Hydroxytyrosol: mechanism of action and interactions (2026-09-20) · lines 121–130

Original AI-assisted source-specific curation with primary-study citations, model, exposure, route, duration, negative findings and limitations preserved. Not publisher full text. · supports · Zebrafish liver cell line with an eight-week spotted-seabass feeding arm · source_derived_draft · unverified_draft

## hydroxytyrosol-ampk-pink1-mitophagy Compound C blocked hydroxytyrosol-associated PINK1 mitophagy in zebrafish liver cells, and cyclosporine blocked the measured mitochondrial benefits. Model/species: Zebrafish liver cell line with an eight-week spotted-seabass feeding arm Tissue/system: AMPK/PINK1 mitophagy and mitochondrial function Exposure: Hydroxytyrosol with compound C or cyclosporine Route: In vitro perturbation Duration: Cell assay accompanying fish feeding Limits: This fish/cell mechanism is not direct evidence for human liver disease or a clinical drug interaction. Primary reference: Hydroxytyrosol Promotes the Mitochondrial Function through Activating Mitophagy. (2022). https://pubmed.ncbi.nlm.nih.gov/35624756/ DOI: 10.3390/antiox11050893 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

availability_state

machinery_impairment Imported condition classification; unverified.

dose

Naringenin with AMPK inhibition, Atg5 silencing or chloroquine

duration

Acute cell assay

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

LPS-stimulated RAW264.7 macrophages with a collagen-induced-arthritis mouse arm

limitations

The inhibitor and silencing experiments support pathway dependence in this model, not rheumatoid-arthritis efficacy in humans.

nutrient_topic

Naringenin chapter; interacting nutrients, drugs, peptides and proteins retain their experimental settings. · Naringenin

organism

LPS-stimulated RAW264.7 macrophages with a collagen-induced-arthritis mouse arm

plain_language

AMPK inhibition reversed naringenin-induced autophagy in LPS-stimulated macrophages, while Atg5 silencing or chloroquine counteracted its cytokine effect.

primary_references

Naringenin ameliorates collagen-induced arthritis through activating AMPK-mediated autophagy in macrophages. (2023). https://pubmed.ncbi.nlm.nih.gov/37904715/ DOI: 10.1002/iid3.983

route

In vitro perturbation

tissue

AMPK/ULK1 autophagic flux and cytokines

trigger_kind

machinery_impairment Imported condition classification; unverified.

Naringenin: mechanism of action and interactions (2026-09-20) · lines 132–141

Original AI-assisted source-specific curation with primary-study citations, model, exposure, route, duration, negative findings and limitations preserved. Not publisher full text. · supports · LPS-stimulated RAW264.7 macrophages with a collagen-induced-arthritis mouse arm · source_derived_draft · unverified_draft

## naringenin-ampk-autophagy-dependence AMPK inhibition reversed naringenin-induced autophagy in LPS-stimulated macrophages, while Atg5 silencing or chloroquine counteracted its cytokine effect. Model/species: LPS-stimulated RAW264.7 macrophages with a collagen-induced-arthritis mouse arm Tissue/system: AMPK/ULK1 autophagic flux and cytokines Exposure: Naringenin with AMPK inhibition, Atg5 silencing or chloroquine Route: In vitro perturbation Duration: Acute cell assay Limits: The inhibitor and silencing experiments support pathway dependence in this model, not rheumatoid-arthritis efficacy in humans. Primary reference: Naringenin ameliorates collagen-induced arthritis through activating AMPK-mediated autophagy in macrophages. (2023). https://pubmed.ncbi.nlm.nih.gov/37904715/ DOI: 10.1002/iid3.983 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_span

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experimental_model

Ethanol-fed mice with hepatic AMPK and SREBP-1 measurement

exposure

Chronic ethanol feeding

limitations

A signalling route to steatosis measured in mice. It sits alongside, not instead of, the redox explanation for fatty liver.

nutrient_topic

Alcohol research collection; topical membership is not evidence of a direct clinical effect, and ethanol is recorded separately from the acetaldehyde it becomes. · Ethanol

organism

Mouse

plain_language

Alcohol rewires the liver’s fat-building programme through the energy sensor.

primary_references

[alcohol-p21953514] Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice. (2012). https://pubmed.ncbi.nlm.nih.gov/21953514/ DOI: 10.1002/hep.24708

tissue_or_cell_type

Liver

Alcohol: ethanol clearance, acetaldehyde, the channels it binds, organ injury and nutrient collisions (2026-09-21) · lines 436–447

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ethanol-fed mice with hepatic AMPK and SREBP-1 measurement · source_derived_draft · unverified_draft

### alcohol-lipin1-srebp Ethanol regulated hepatic lipin-1 through AMP-activated protein kinase and sterol regulatory element-binding protein 1 signalling in mice. Condition category: normal nutrient_topic: Alcohol research collection; topical membership is not evidence of a direct clinical effect, and ethanol is recorded separately from the acetaldehyde it becomes. plain_language: Alcohol rewires the liver’s fat-building programme through the energy sensor. organism: Mouse tissue_or_cell_type: Liver experimental_model: Ethanol-fed mice with hepatic AMPK and SREBP-1 measurement limitations: A signalling route to steatosis measured in mice. It sits alongside, not instead of, the redox explanation for fatty liver. exposure: Chronic ethanol feeding evidence_span: {"source_cache": "artifacts/alcohol-research/21953514.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "acfcd2656e45aab9abcf367ed27e447001ddaa55ac143e9cc2f24b0958ea15a7", "start_char": 0, "end_char": 1626, "text_sha256": "acfcd2656e45aab9abcf367ed27e447001ddaa55ac143e9cc2f24b0958ea15a7"} [alcohol-p21953514] Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice. (2012). https://pubmed.ncbi.nlm.nih.gov/21953514/ DOI: 10.1002/hep.24708