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Both insulin dependent and insulin independent skeletal muscle glucose uptake are however reduced in individuals with diabetes. We here show that AMPK activator O304 stimulates insulin independent glucose uptake and utilization in skeletal muscle and heart in vivo, while preventing glycogen accumulation. Combined glucose uptake and utilization requires an increased metabolic demand and we show that O304 acts as a mitochondrial uncoupler, i.e., generates a metabolic demand. O304 averts gene expression changes associated with metabolic inflexibility in skeletal muscle and heart of diabetic mice and reverts diabetic cardiomyopathy. In Type 2 diabetes, insulin resistance elicits compensatory insulin hypersecretion, provoking \u03b2-cell stress and eventually compensatory failure. In db\/db mice O304 preserves \u03b2-cell function by preventing decline in insulin secretion, \u03b2-cell mass, and pancreatic insulin content. Thus, as a dual AMPK activator and mitochondrial uncoupler O304 mitigates two central defects of T2D; impaired glucose uptake\/utilization and \u03b2-cell failure, which today lack effective treatment.<\/jats:p>","DOI":"10.1038\/s42003-023-05255-6","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T19:02:35Z","timestamp":1692990155000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving \u03b2-cell function"],"prefix":"10.1038","volume":"6","author":[{"given":"Stefan","family":"Norlin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Axelsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madelene","family":"Ericsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3553-7348","authenticated-orcid":false,"given":"Helena","family":"Edlund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"key":"5255_CR1","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.2337\/diab.30.12.1000","volume":"30","author":"RA DeFronzo","year":"1981","unstructured":"DeFronzo, R. 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