{"id":"ae3d493f-60e7-58e6-af38-1c2fda4a0b30","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-ampk-independent-glucose","predicate":"preserves_measured_pool","statement":"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.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"ac83d306-58e5-556b-898b-fef0622457d8","mechanism_event_label":"Removing the sensor did not remove the drug effect, and in these cells it made it larger.","subject":{"id":"ccfd9bed-e1fa-510e-914d-8e62e72a4b6a","slug":"mouse-liver-ampk-null","display_name":"Liver-specific AMPK-deficient mouse hepatocytes in the 2010 study","entity_type_key":"protein_state"},"object":{"id":"827a1499-8877-52c0-b837-0c944dab8fef","slug":"hepatic-glucose-production","display_name":"Hepatic glucose production / endogenous glucose production","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"ac83d306-58e5-556b-898b-fef0622457d8","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-ampk-independent-glucose-event","event_type":"biochemical_relationship","label":"Removing the sensor did not remove the drug effect, and in these cells it made it larger.","description":"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.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"8128eec0-61cc-51ef-8d4e-5ec9678e8dfa","slug":"ampk-complexes","display_name":"AMP-activated protein kinase complexes","entity_type_key":"protein_family"},"role":"deleted_sensor","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"519971b1-5aef-5ad7-8022-840144855cd0","slug":"metformin","display_name":"Metformin","entity_type_key":"drug"},"role":"retained_actor","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"ccfd9bed-e1fa-510e-914d-8e62e72a4b6a","slug":"mouse-liver-ampk-null","display_name":"Liver-specific AMPK-deficient mouse hepatocytes in the 2010 study","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"827a1499-8877-52c0-b837-0c944dab8fef","slug":"hepatic-glucose-production","display_name":"Hepatic glucose production / endogenous glucose production","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"evidence_span","value_text":"{\"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\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Metformin dose-response in hepatocytes lacking AMPK or LKB1","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"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.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake.","comparator":null,"unit":null,"notes":"","entity":{"slug":"metformin","display_name":"Metformin","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Mouse","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Removing the sensor did not remove the drug effect, and in these cells it made it larger.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[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","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Liver","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null}],"evidence":[{"id":"117dfd17-8b03-5631-aee9-0612f119ad9e","evidence_kind":"source_excerpt","locator":"Lines 593-604","start_line":593,"end_line":604,"excerpt":"### metformin-ampk-independent-glucose\nIn 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.\nCondition category: machinery_impairment\nnutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake.\nplain_language: Removing the sensor did not remove the drug effect, and in these cells it made it larger.\norganism: Mouse\ntissue_or_cell_type: Liver\nexperimental_model: Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression\nlimitations: 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.\nexposure: Metformin dose-response in hepatocytes lacking AMPK or LKB1\nevidence_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\"}\n[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","model_system":"Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study 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","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"d0474bd9-7cfd-5695-a152-12f3633a6813","stable_key":"import-8b3cf083-ea9c-54f5-b42b-bf1fef5b2978","title":"Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"0b51d0759aeeb88ac5b3a6277245a196b2bb024d7c32ec89379ed428fb06bfb5","revision_id":"0405c75e-f06e-5af7-a642-1777802f6004","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"64f54fc5-a8a0-5cfe-ace6-cf30e74b4c79","title":"Does metformin need AMPK and LKB1 to lower hepatic glucose production?","kind":"contradiction","status":"open","why":"Two laboratories using liver-specific genetic models reported opposite answers. Compound C inhibition in rat hepatocytes and liver-specific LKB1 deletion in mice supported a requirement, while liver-specific AMPK deletion and LKB1 deletion in a later study left the effect intact and even amplified it, with the fall in hepatocyte ATP tracking the effect instead. The models differ in how AMPK was removed, in the dose of metformin used, and in whether an inhibitor or a genetic deletion was used, and the later study measured energy state directly. Which difference accounts for the disagreement is not established.","resolution":"Unresolved; needs review.","created_at":"2026-09-19 23:24:31","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/64f54fc5-a8a0-5cfe-ace6-cf30e74b4c79","sides":[{"conflict_id":"64f54fc5-a8a0-5cfe-ace6-cf30e74b4c79","ordinal":0,"label":"In this experiment, blocking the sensor removed the drug effect on glucose output.","revision_id":"0405c75e-f06e-5af7-a642-1777802f6004","start_line":554,"end_line":565,"quote":"### metformin-ampk-required-hepatocyte\nUsing an AMPK inhibitor, AMPK activation was found to be required for the inhibitory effect of metformin on glucose production by hepatocytes.\nCondition category: normal\nnutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake.\nplain_language: In this experiment, blocking the sensor removed the drug effect on glucose output.\norganism: Rat\ntissue_or_cell_type: Liver and skeletal muscle\nexperimental_model: Rat hepatocytes, isolated rat skeletal muscle and metformin-treated rats with an AMPK inhibitor\nlimitations: The inhibitor experiment supports a requirement for AMPK in these hepatocytes; later work in AMPK-deficient mice reached a different conclusion, recorded separately.\nexposure: Metformin in hepatocytes and in vivo; compound C AMPK inhibition\nevidence_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\"}\n[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","source_key":"import-8b3cf083-ea9c-54f5-b42b-bf1fef5b2978","source_title":"Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19)","claim_ids":["119db90f-2bbe-57e4-a544-992aafc602e0"]},{"conflict_id":"64f54fc5-a8a0-5cfe-ace6-cf30e74b4c79","ordinal":1,"label":"Removing the sensor did not remove the drug effect, and in these cells it made it larger.","revision_id":"0405c75e-f06e-5af7-a642-1777802f6004","start_line":593,"end_line":604,"quote":"### metformin-ampk-independent-glucose\nIn 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.\nCondition category: machinery_impairment\nnutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake.\nplain_language: Removing the sensor did not remove the drug effect, and in these cells it made it larger.\norganism: Mouse\ntissue_or_cell_type: Liver\nexperimental_model: Liver-specific AMPK-deficient and LKB1-deficient mouse hepatocytes with PGC-1alpha overexpression\nlimitations: 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.\nexposure: Metformin dose-response in hepatocytes lacking AMPK or LKB1\nevidence_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\"}\n[metformin-p20577053] Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. 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