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Here, we show that combination treatment with metformin ameliorates negative effects of rapamycin while maintaining its benefits. From 12 to 30\u2009weeks of age, NcZ10 males were fed a control diet or diets supplemented with rapamycin, metformin, or a combination of both. Rapamycin alone reduced weight gain, adiposity, HOMA\u2010IR, and inflammation, and prevented hyperinsulinemia and pre\u2010steatotic hepatic lipidosis, but exacerbated hyperglycemia, hypertriglyceridemia, and pancreatic islet degranulation. Metformin alone reduced hyperinsulinemia and circulating c\u2010reactive protein, but exacerbated nephropathy. Combination treatment retained the benefits of both while preventing many of the deleterious effects. Importantly, the combination treatment reversed effects of rapamycin on markers of hepatic insulin resistance and normalized systemic insulin sensitivity in this inherently insulin\u2010resistant model. In adipose tissue, rapamycin attenuated the expression of genes associated with adipose tissue expansion (<jats:italic>Mest, Gpam<\/jats:italic>), inflammation (<jats:italic>Itgam<\/jats:italic>, <jats:italic>Itgax<\/jats:italic>, <jats:italic>Hmox1, Lbp<\/jats:italic>), and cell senescence (<jats:italic>Serpine1<\/jats:italic>). In liver, the addition of metformin counteracted rapamycin\u2010induced alterations of <jats:italic>G6pc, Ppara<\/jats:italic>, and <jats:italic>Ldlr<\/jats:italic> expressions that promote hyperglycemia and hypertriglyceridemia. Both rapamycin and metformin treatment reduced hepatic <jats:italic>Fasn<\/jats:italic> expression, potentially preventing lipidosis. These results delineate a state of \u201cinsulin signaling restriction\u201d that withdraws endocrine support for further adipogenesis, progression of the metabolic syndrome, and the development of its comorbidities. Our results are relevant for the treatment of T2D, the optimization of current rapamycin\u2010based treatments for posttransplant rejection and various cancers, and for the development of treatments for healthy aging.<\/jats:p>","DOI":"10.1111\/acel.13666","type":"journal-article","created":{"date-parts":[[2022,8,20]],"date-time":"2022-08-20T06:40:02Z","timestamp":1660977602000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Rapamycin\/metformin co\u2010treatment normalizes insulin sensitivity and reduces complications of metabolic syndrome in type 2 diabetic mice"],"prefix":"10.1111","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5666-8040","authenticated-orcid":false,"given":"Peter C.","family":"Reifsnyder","sequence":"first","affiliation":[{"name":"The Jackson Laboratory  Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Flurkey","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory  Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalinda","family":"Doty","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory  Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel A.","family":"Calcutt","sequence":"additional","affiliation":[{"name":"Department of Pathology University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Koza","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine Maine Medical Center Research Institute  Scarborough Maine USA"},{"name":"Graduate School of Biomedical Sciences and Engineering University of Maine  Orono Maine USA"},{"name":"Pennington Biomedical Research Center  Baton Rouge Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2298-0954","authenticated-orcid":false,"given":"David E.","family":"Harrison","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory  Bar Harbor Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,8,19]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOL.0b013e32814e6d29"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.12958"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0179879"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glw090"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12405"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.2337\/DB12\u20101474"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.2337\/db13\u20100106"},{"issue":"1","key":"e_1_2_10_9_1","first-page":"4","article-title":"Recent advances in the relationship between obesity, inflammation, and insulin resistance","volume":"17","author":"Bastard J. 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