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Here, we report a neural mechanism via the small guanosine triphosphatase Ras-related protein 1 (Rap1). Mice with forebrain-specific\n            <jats:italic toggle=\"yes\">Rap1<\/jats:italic>\n            knockout exhibited resistance to the antidiabetic effects of low-dose metformin while remaining sensitive to other antidiabetic agents. Centrally administered metformin inhibited brain Rap1 and reduced hyperglycemia. Conversely, forced activation of brain Rap1 increased glycemia and abolished the glycemic effect of metformin. Metformin activated a specific subset of neurons in the ventromedial hypothalamic nucleus (VMH) that requires Rap1. Both loss-of-function and gain-of-function studies suggest that VMH Rap1 is indispensable for the antidiabetic effects of metformin. These findings highlight the VMH Rap1 pathway as a critical mediator of metformin action.\n          <\/jats:p>","DOI":"10.1126\/sciadv.adu3700","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T17:59:27Z","timestamp":1753898367000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["Low-dose metformin requires brain Rap1 for its antidiabetic action"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5408-5578","authenticated-orcid":true,"given":"Hsiao-Yun","family":"Lin","sequence":"first","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7504-5316","authenticated-orcid":true,"given":"Weisheng","family":"Lu","sequence":"additional","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5471-9016","authenticated-orcid":true,"given":"Yanlin","family":"He","sequence":"additional","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Brain Glycemic and Metabolism Control Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9864-3286","authenticated-orcid":true,"given":"Yukiko","family":"Fu","sequence":"additional","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5003-2460","authenticated-orcid":true,"given":"Kentaro","family":"Kaneko","sequence":"additional","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Department of Agricultural Chemistry, School of Agriculture, Meiji University, Kanagawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peimeng","family":"Huang","sequence":"additional","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3520-021X","authenticated-orcid":true,"given":"Ana B.","family":"De la Puente-Gomez","sequence":"additional","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8104-6892","authenticated-orcid":true,"given":"Chunmei","family":"Wang","sequence":"additional","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2354-4727","authenticated-orcid":true,"given":"Yongjie","family":"Yang","sequence":"additional","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9680-4614","authenticated-orcid":true,"given":"Feng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology &amp; Immunology Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4908-1572","authenticated-orcid":true,"given":"Yong","family":"Xu","sequence":"additional","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0112-9925","authenticated-orcid":true,"given":"Makoto","family":"Fukuda","sequence":"additional","affiliation":[{"name":"USDA\/ARS Children\u2019s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02000097"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/cber.19290620605"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc11-1299"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3372"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199508313330903"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1911-y"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-019-0146-4"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-019-0242-2"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-013-2991-0"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnaa023"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.01.003"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-017-4343-y"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-017-4361-9"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.3805"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/213203a0"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.49.12.2063"},{"key":"e_1_3_2_18_2","first-page":"4059","article-title":"Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus","volume":"81","author":"Cusi K.","year":"1996","unstructured":"K. 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