{"id":"e6a90509-5a5a-5061-a01b-3e58a3590795","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-gdf15-dispensable","predicate":"preserves_measured_pool","statement":"Metformin increased circulating GDF15 in mice and humans, but studies in wild-type, GDF15-knockout and GFRAL-knockout mice suggested that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"neutral","is_public":true,"mechanism_event_id":"7ec4e8f6-26ab-5ede-9cf8-a8867ea9109f","mechanism_event_label":"A second group removed the same hormone and still saw the weight effect.","subject":{"id":"dd31a7a1-1d4c-55ec-afd9-7b078b04a367","slug":"mouse-gdf15-null","display_name":"Experimental Gdf15-null mouse genotype","entity_type_key":"protein_state"},"object":{"id":"b3d7bf48-4e59-59fd-9e60-752b9b2bcd26","slug":"body-weight","display_name":"Body weight","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"7ec4e8f6-26ab-5ede-9cf8-a8867ea9109f","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-gdf15-dispensable-event","event_type":"biochemical_relationship","label":"A second group removed the same hormone and still saw the weight effect.","description":"Metformin increased circulating GDF15 in mice and humans, but studies in wild-type, GDF15-knockout and GFRAL-knockout mice suggested that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"084f4aa7-a0f4-5ed9-808f-ad1decf5c6f0","slug":"gdf15","display_name":"Growth/differentiation factor 15 / GDF15","entity_type_key":"peptide"},"role":"removed_hormone","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"7fb6620e-34fd-5d0d-bc26-9c687c8fa41b","slug":"gfral","display_name":"GDNF family receptor alpha-like / GFRAL","entity_type_key":"protein"},"role":"removed_receptor","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"dd31a7a1-1d4c-55ec-afd9-7b078b04a367","slug":"mouse-gdf15-null","display_name":"Experimental Gdf15-null mouse genotype","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"b3d7bf48-4e59-59fd-9e60-752b9b2bcd26","slug":"body-weight","display_name":"Body weight","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/36001956.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"b326862a8ba767ce4e5c0a8cf5d480951464e1f95bf493ff226094b7ae29d457\", \"start_char\": 0, \"end_char\": 979, \"text_sha256\": \"b326862a8ba767ce4e5c0a8cf5d480951464e1f95bf493ff226094b7ae29d457\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Wild-type, GDF15-knockout and GFRAL-knockout mice with human measurements","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Metformin in knockout and wild-type mice","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"A direct replication attempt reaching the opposite conclusion on necessity, while confirming the GDF15 rise itself.","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 and human","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"A second group removed the same hormone and still saw the weight effect.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[metformin-p36001956] The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. (2022). https://pubmed.ncbi.nlm.nih.gov/36001956/ DOI: 10.1016/j.celrep.2022.111258","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Whole-body energy balance","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":"e5eacdb7-ee34-5ebc-b7d4-729a77ca7466","evidence_kind":"source_excerpt","locator":"Lines 814-825","start_line":814,"end_line":825,"excerpt":"### metformin-gdf15-dispensable\nMetformin increased circulating GDF15 in mice and humans, but studies in wild-type, GDF15-knockout and GFRAL-knockout mice suggested that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance.\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: A second group removed the same hormone and still saw the weight effect.\norganism: Mouse and human\ntissue_or_cell_type: Whole-body energy balance\nexperimental_model: Wild-type, GDF15-knockout and GFRAL-knockout mice with human measurements\nlimitations: A direct replication attempt reaching the opposite conclusion on necessity, while confirming the GDF15 rise itself.\nexposure: Metformin in knockout and wild-type mice\nevidence_span: {\"source_cache\": \"artifacts/metformin-research/36001956.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"b326862a8ba767ce4e5c0a8cf5d480951464e1f95bf493ff226094b7ae29d457\", \"start_char\": 0, \"end_char\": 979, \"text_sha256\": \"b326862a8ba767ce4e5c0a8cf5d480951464e1f95bf493ff226094b7ae29d457\"}\n[metformin-p36001956] The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. (2022). https://pubmed.ncbi.nlm.nih.gov/36001956/ DOI: 10.1016/j.celrep.2022.111258","model_system":"Wild-type, GDF15-knockout and GFRAL-knockout mice with human measurements","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [metformin-p36001956] The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. (2022). https://pubmed.ncbi.nlm.nih.gov/36001956/ DOI: 10.1016/j.celrep.2022.111258","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":"79fb1800-93e4-59d8-b7a7-ab861ece2c7c","title":"Is the GDF15-GFRAL pathway necessary for metformin to lower body weight?","kind":"contradiction","status":"open","why":"Both groups agree that metformin raises circulating GDF15 in mice and in people. They disagree on necessity: one reported that the weight effect is absent in Gdf15-null and Gfral-null mice and is reversed by a GFRAL-antagonist antibody, the other that weight and energy balance responses persist in the same knockouts. Diet composition, dose, duration and the degree of GDF15 induction differ between the studies. The reason for the difference 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/79fb1800-93e4-59d8-b7a7-ab861ece2c7c","sides":[{"conflict_id":"79fb1800-93e4-59d8-b7a7-ab861ece2c7c","ordinal":0,"label":"The weight effect travelled through that hormone and its brainstem receptor.","revision_id":"0405c75e-f06e-5af7-a642-1777802f6004","start_line":788,"end_line":799,"quote":"### metformin-gdf15-weight\nMetformin prevented high-fat-diet weight gain in wild-type mice but not in mice lacking GDF15 or its receptor GFRAL, and a GFRAL-antagonist antibody reversed the weight effect in obese mice.\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: The weight effect travelled through that hormone and its brainstem receptor.\norganism: Human and mouse\ntissue_or_cell_type: Distal intestine, kidney and brainstem receptor\nexperimental_model: Two randomised controlled trials in people plus wild-type, Gdf15-null and Gfral-null mice\nlimitations: The weight mechanism is separable from the glucose mechanism in this work; the mouse knockouts carry the causal claim, the human trials the GDF15 rise. A publisher correction was issued for this paper (Nature 2020;578:E24, PMID 32051582); its notice body was not available, so its impact on these records has not been assessed.\nexposure: Oral metformin; high-fat diet in mice; GFRAL-antagonist antibody\nevidence_span: {\"source_cache\": \"artifacts/metformin-research/31875646.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a\", \"start_char\": 0, \"end_char\": 1454, \"text_sha256\": \"a25b31ade3977aabe24159b0374c42fe4fb48ab1464ba9ae69c73e63f41e742a\"}\n[metformin-p31875646] GDF15 mediates the effects of metformin on body weight and energy balance. (2020). https://pubmed.ncbi.nlm.nih.gov/31875646/ DOI: 10.1038/s41586-019-1911-y","source_key":"import-8b3cf083-ea9c-54f5-b42b-bf1fef5b2978","source_title":"Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19)","claim_ids":["90a372f2-d318-50bc-b194-4aef4de9e52c"]},{"conflict_id":"79fb1800-93e4-59d8-b7a7-ab861ece2c7c","ordinal":1,"label":"A second group removed the same hormone and still saw the weight effect.","revision_id":"0405c75e-f06e-5af7-a642-1777802f6004","start_line":814,"end_line":825,"quote":"### metformin-gdf15-dispensable\nMetformin increased circulating GDF15 in mice and humans, but studies in wild-type, GDF15-knockout and GFRAL-knockout mice suggested that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance.\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: A second group removed the same hormone and still saw the weight effect.\norganism: Mouse and human\ntissue_or_cell_type: Whole-body energy balance\nexperimental_model: Wild-type, GDF15-knockout and GFRAL-knockout mice with human measurements\nlimitations: A direct replication attempt reaching the opposite conclusion on necessity, while confirming the GDF15 rise itself.\nexposure: Metformin in knockout and wild-type mice\nevidence_span: {\"source_cache\": \"artifacts/metformin-research/36001956.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"b326862a8ba767ce4e5c0a8cf5d480951464e1f95bf493ff226094b7ae29d457\", \"start_char\": 0, \"end_char\": 979, \"text_sha256\": \"b326862a8ba767ce4e5c0a8cf5d480951464e1f95bf493ff226094b7ae29d457\"}\n[metformin-p36001956] The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. (2022). https://pubmed.ncbi.nlm.nih.gov/36001956/ DOI: 10.1016/j.celrep.2022.111258","source_key":"import-8b3cf083-ea9c-54f5-b42b-bf1fef5b2978","source_title":"Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19)","claim_ids":["e6a90509-5a5a-5061-a01b-3e58a3590795"]}]}],"corrections":[],"research":null}