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Despite its extensive use, the mechanisms underlying many of its clinical effects, including attenuated postprandial glucose excursions, elevated intestinal glucose uptake, and increased production of lactate, Lac-Phe and GDF15, remain unclear. Here, we map these and other clinical effects of metformin to intestine-specific mitochondrial complex I inhibition. Using human metabolomic data and an orthogonal genetics approach in male mice, we demonstrate that metformin suppresses citrulline synthesis, a metabolite generated exclusively by small intestine mitochondria, and increases GDF15 by inhibiting the mitochondrial respiratory chain at complex I. This inhibition co-opts the intestines to function as a glucose sink, driving uptake of excess glucose and converting it to lactate and Lac-Phe. Notably, the glucose-lowering effect of another biguanide, phenformin, and berberine, a structurally unrelated nutraceutical, similarly depends on intestine-specific mitochondrial complex I inhibition, underscoring a shared therapeutic mechanism.<\/jats:p>","DOI":"10.1101\/2025.10.02.678294","type":"posted-content","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T07:25:18Z","timestamp":1759476318000},"source":"Crossref","is-referenced-by-count":3,"title":["Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycemic control"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2495-9083","authenticated-orcid":false,"given":"Zachary L.","family":"Sebo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5425-6306","authenticated-orcid":false,"given":"Ram P.","family":"Chakrabarty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0655-0882","authenticated-orcid":false,"given":"Rogan A.","family":"Grant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1572-1321","authenticated-orcid":false,"given":"Karis B.","family":"D\u2019Alessandro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4733-9007","authenticated-orcid":false,"given":"Alec R.","family":"Koss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7019-9174","authenticated-orcid":false,"given":"Jenna L. 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