{"id":"9a8c0fb4-b018-5b8b-b04e-2de9e4bd8022","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-b12-calcium-mechanism","predicate":"reduces","statement":"The authors attributed diminished B12 absorption and low serum B12 and transcobalamin-bound B12 during metformin to a calcium-dependent ileal membrane antagonism, since uptake of the B12-intrinsic factor complex by ileal cell surface receptors is calcium-dependent.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"1ddaf88f-9900-58eb-901c-e36e31714551","mechanism_event_label":"The proposed step is the calcium-dependent grab of the vitamin at the ileal cell surface.","subject":{"id":"519971b1-5aef-5ad7-8022-840144855cd0","slug":"metformin","display_name":"Metformin","entity_type_key":"drug"},"object":{"id":"8c0f397a-9cad-554f-ac5b-bb51bf1be2ac","slug":"intestinal-cobalamin-absorption","display_name":"Intestinal cobalamin absorption","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"1ddaf88f-9900-58eb-901c-e36e31714551","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-b12-calcium-mechanism-event","event_type":"biochemical_relationship","label":"The proposed step is the calcium-dependent grab of the vitamin at the ileal cell surface.","description":"The authors attributed diminished B12 absorption and low serum B12 and transcobalamin-bound B12 during metformin to a calcium-dependent ileal membrane antagonism, since uptake of the B12-intrinsic factor complex by ileal cell surface receptors is calcium-dependent.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"e359bc15-e675-5d83-b0fe-1d70814e130b","slug":"calcium-ion","display_name":"Calcium ion","entity_type_key":"ion"},"role":"required_cofactor","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"1e7fbe30-20c5-5229-97de-84ad5c3dde84","slug":"human-if-cobalamin","display_name":"Human intrinsic factor-cobalamin complex","entity_type_key":"protein_complex"},"role":"transported_complex","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"d67e8f26-bb42-5f02-af30-41f021cfd2d0","slug":"human-cubam","display_name":"Human cubilin-amnionless complex","entity_type_key":"protein_complex"},"role":"receptor_complex","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"519971b1-5aef-5ad7-8022-840144855cd0","slug":"metformin","display_name":"Metformin","entity_type_key":"drug"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"8c0f397a-9cad-554f-ac5b-bb51bf1be2ac","slug":"intestinal-cobalamin-absorption","display_name":"Intestinal cobalamin absorption","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"nutrient_deficiency","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/metformin-research/10977010.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b\", \"start_char\": 0, \"end_char\": 1267, \"text_sha256\": \"7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Metformin for three months, then oral calcium supplementation","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"A small, non-randomised comparative study. The calcium-dependent ileal mechanism is the authors’ interpretation of the reversal, not a direct measurement of receptor binding.","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":"Human","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"The proposed step is the calcium-dependent grab of the vitamin at the ileal cell surface.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[metformin-p10977010] Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. (2000). https://pubmed.ncbi.nlm.nih.gov/10977010/ DOI: 10.2337/diacare.23.9.1227","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Ileal absorption","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"nutrient_deficiency","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null}],"evidence":[{"id":"db20a6b0-6479-5172-8fdf-f645d853d82d","evidence_kind":"source_excerpt","locator":"Lines 1152-1163","start_line":1152,"end_line":1163,"excerpt":"### metformin-b12-calcium-mechanism\nThe authors attributed diminished B12 absorption and low serum B12 and transcobalamin-bound B12 during metformin to a calcium-dependent ileal membrane antagonism, since uptake of the B12-intrinsic factor complex by ileal cell surface receptors is calcium-dependent.\nCondition category: nutrient_deficiency\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 proposed step is the calcium-dependent grab of the vitamin at the ileal cell surface.\norganism: Human\ntissue_or_cell_type: Ileal absorption\nexperimental_model: Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation\nlimitations: A small, non-randomised comparative study. The calcium-dependent ileal mechanism is the authors’ interpretation of the reversal, not a direct measurement of receptor binding.\nexposure: Metformin for three months, then oral calcium supplementation\nevidence_span: {\"source_cache\": \"artifacts/metformin-research/10977010.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b\", \"start_char\": 0, \"end_char\": 1267, \"text_sha256\": \"7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b\"}\n[metformin-p10977010] Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. (2000). https://pubmed.ncbi.nlm.nih.gov/10977010/ DOI: 10.2337/diacare.23.9.1227","model_system":"Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [metformin-p10977010] Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. (2000). https://pubmed.ncbi.nlm.nih.gov/10977010/ DOI: 10.2337/diacare.23.9.1227","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":"43d9e458-1c34-5df6-8b48-fc855dc972b1","title":"Why does metformin lower vitamin B12: calcium-dependent ileal uptake, or bacterial overgrowth?","kind":"qualification","status":"open","why":"Both explanations come from human studies of the same effect. The 2000 study found that oral calcium reversed the fall in holotranscobalamin and attributed the effect to calcium-dependent antagonism at the ileal receptor. The 1977 study found deconjugation of bile acids and Schilling-test abnormalities that improved with antibiotics, and attributed the malabsorption to small-intestinal bacterial overgrowth. Neither study tested the other mechanism, the eras and methods differ, and the two are not mutually exclusive. 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/43d9e458-1c34-5df6-8b48-fc855dc972b1","sides":[{"conflict_id":"43d9e458-1c34-5df6-8b48-fc855dc972b1","ordinal":0,"label":"The proposed step is the calcium-dependent grab of the vitamin at the ileal cell surface.","revision_id":"0405c75e-f06e-5af7-a642-1777802f6004","start_line":1152,"end_line":1163,"quote":"### metformin-b12-calcium-mechanism\nThe authors attributed diminished B12 absorption and low serum B12 and transcobalamin-bound B12 during metformin to a calcium-dependent ileal membrane antagonism, since uptake of the B12-intrinsic factor complex by ileal cell surface receptors is calcium-dependent.\nCondition category: nutrient_deficiency\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 proposed step is the calcium-dependent grab of the vitamin at the ileal cell surface.\norganism: Human\ntissue_or_cell_type: Ileal absorption\nexperimental_model: Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation\nlimitations: A small, non-randomised comparative study. The calcium-dependent ileal mechanism is the authors’ interpretation of the reversal, not a direct measurement of receptor binding.\nexposure: Metformin for three months, then oral calcium supplementation\nevidence_span: {\"source_cache\": \"artifacts/metformin-research/10977010.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b\", \"start_char\": 0, \"end_char\": 1267, \"text_sha256\": \"7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b\"}\n[metformin-p10977010] Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. (2000). https://pubmed.ncbi.nlm.nih.gov/10977010/ DOI: 10.2337/diacare.23.9.1227","source_key":"import-8b3cf083-ea9c-54f5-b42b-bf1fef5b2978","source_title":"Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19)","claim_ids":["9a8c0fb4-b018-5b8b-b04e-2de9e4bd8022"]},{"conflict_id":"43d9e458-1c34-5df6-8b48-fc855dc972b1","ordinal":1,"label":"A second explanation: bacteria in the small bowel take up the vitamin before the body can.","revision_id":"0405c75e-f06e-5af7-a642-1777802f6004","start_line":1165,"end_line":1176,"quote":"### metformin-b12-bacterial-overgrowth\nVitamin B12 malabsorption was most prominent in patients on metformin, and pathological Schilling tests, increased glycocholic acid deconjugation and decreased faecal bile acid excretion normalised or improved after stopping the biguanide or giving antibiotics, suggesting small-intestinal bacterial overgrowth binding the intrinsic-factor-B12 complex.\nCondition category: nutrient_deficiency\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 explanation: bacteria in the small bowel take up the vitamin before the body can.\norganism: Human\ntissue_or_cell_type: Small intestine\nexperimental_model: Breath test, faecal bile acid measurement and Schilling tests in maturity-onset diabetics on biguanides\nlimitations: A 1977 study using the Schilling test. It proposes bacterial overgrowth as the mechanism; the antibiotic reversal is suggestive rather than definitive, and it competes with the calcium-dependent explanation.\nexposure: Phenformin, buformin or metformin, with antibiotic treatment as a test\nevidence_span: {\"source_cache\": \"artifacts/metformin-research/873086.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"1889488dcc83ec22842eccf766b842761a6c10643dbf7d8e6f8308331dfdf01c\", \"start_char\": 0, \"end_char\": 1442, \"text_sha256\": \"1889488dcc83ec22842eccf766b842761a6c10643dbf7d8e6f8308331dfdf01c\"}\n[metformin-p873086] Alteration of bile acid metabolism and vitamin-B12-absorption in diabetics on biguanides. (1977). https://pubmed.ncbi.nlm.nih.gov/873086/ DOI: 10.1007/bf01219698","source_key":"import-8b3cf083-ea9c-54f5-b42b-bf1fef5b2978","source_title":"Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19)","claim_ids":["eff15cb5-16ae-5173-8b66-4d3cb840f25f"]}]}],"corrections":[],"research":null}