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However, whether its expression and function are changed and what role it plays in type 2 diabetic cardiomyopathy (DCM) have not been reported. This study investigated the role and mechanism of Kir6.1 in DCM. We found that the cardiac function and the Kir6.1 expression in DCM mice were decreased. We generated mice overexpressing or lacking <jats:italic>Kir6.1<\/jats:italic> gene specifically in the heart. Kir6.1 overexpression improved cardiac dysfunction in DCM. Cardiac\u2010specific Kir6.1 knockout aggravated cardiac dysfunction. Kir6.1 regulated the phosphorylation of AKT and Foxo1 in DCM. We further found that Kir6.1 overexpression also improved cardiomyocyte dysfunction and up\u2010regulated the phosphorylation of AKT and FoxO1 in neonatal rat ventricular cardiomyocytes with insulin resistance. Furthermore, FoxO1 activation down\u2010regulated the expression of Kir6.1 and decreased the mitochondrial membrane potential (\u0394\u03a8m) in cardiomyocytes. FoxO1 inactivation up\u2010regulated the expression of Kir6.1 and increased the \u0394\u03a8m in cardiomyocytes. Chromatin immunoprecipitation assay demonstrated that the <jats:italic>Kir6.1<\/jats:italic> promoter region contains a functional FoxO1\u2010binding site. In conclusion, Kir6.1 improves cardiac dysfunction in DCM, probably through the AKT\u2010FoxO1 signalling pathway.<\/jats:p>","DOI":"10.1111\/jcmm.16346","type":"journal-article","created":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T18:21:04Z","timestamp":1612808464000},"page":"3935-3949","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Kir6.1 improves cardiac dysfunction in diabetic cardiomyopathy via the AKT\u2010FoxO1 signalling pathway"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2906-0504","authenticated-orcid":false,"given":"Jinxin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Cardiology Chinese PLA General Hospital Beijing China"},{"name":"Department of Geriatric Cardiology Chinese PLA General Hospital National Clinical Research Center for Geriatric Diseases Beijing 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