{"id":"54da347b-d5a6-5123-90ad-b1c8fc58e9ee","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-mgpd-knockdown-phenocopy","predicate":"reproduces","statement":"Knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats produced a phenotype akin to chronic metformin treatment and abrogated metformin-mediated increases in cytosolic redox state and inhibition of endogenous glucose production.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"7bc4ebb6-6dd2-550e-9f94-b3958503ca20","mechanism_event_label":"Removing the enzyme both copied the drug and left it nothing further to do.","subject":{"id":"c53d2485-7cd0-5779-bc23-296fb5b1e7d0","slug":"rat-gpd2-knockdown","display_name":"Antisense-oligonucleotide knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats","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":"7bc4ebb6-6dd2-550e-9f94-b3958503ca20","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-mgpd-knockdown-phenocopy-event","event_type":"biochemical_relationship","label":"Removing the enzyme both copied the drug and left it nothing further to do.","description":"Knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats produced a phenotype akin to chronic metformin treatment and abrogated metformin-mediated increases in cytosolic redox state and inhibition of endogenous glucose production.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"e3a468b0-08ac-57a3-8df4-942934b35b2a","slug":"gpd2","display_name":"Human mitochondrial glycerol-3-phosphate dehydrogenase / GPD2","entity_type_key":"protein"},"role":"removed_enzyme","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":"occluded_actor","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"c53d2485-7cd0-5779-bc23-296fb5b1e7d0","slug":"rat-gpd2-knockdown","display_name":"Antisense-oligonucleotide knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats","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/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\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Acute and chronic low-dose metformin; mGPD knockdown and knockout","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"A redox-shuttle mechanism established in rodents at low doses; it does not by itself exclude complex I or AMPK contributions in other tissues.","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":"Rat and mouse","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Removing the enzyme both copied the drug and left it nothing further to do.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[metformin-p24847880] Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. (2014). https://pubmed.ncbi.nlm.nih.gov/24847880/ DOI: 10.1038/nature13270","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":"ed717c71-b54f-53e4-b795-d8d55ec02a02","evidence_kind":"source_excerpt","locator":"Lines 502-513","start_line":502,"end_line":513,"excerpt":"### metformin-mgpd-knockdown-phenocopy\nKnockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats produced a phenotype akin to chronic metformin treatment and abrogated metformin-mediated increases in cytosolic redox state and inhibition of endogenous glucose production.\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 enzyme both copied the drug and left it nothing further to do.\norganism: Rat and mouse\ntissue_or_cell_type: Liver\nexperimental_model: Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements\nlimitations: A redox-shuttle mechanism established in rodents at low doses; it does not by itself exclude complex I or AMPK contributions in other tissues.\nexposure: Acute and chronic low-dose metformin; mGPD knockdown and knockout\nevidence_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\"}\n[metformin-p24847880] Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. (2014). https://pubmed.ncbi.nlm.nih.gov/24847880/ DOI: 10.1038/nature13270","model_system":"Rat antisense-oligonucleotide knockdown, whole-body knockout mice and hepatic redox measurements","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [metformin-p24847880] Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. (2014). https://pubmed.ncbi.nlm.nih.gov/24847880/ DOI: 10.1038/nature13270","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":[],"corrections":[],"research":null}