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In this study, we aimed to investigate the cause of differential insulin secretion capacity of pancreatic islets from donors with T2D and non-T2D (ND), especially obese donors (BMI \u226530 kg\/m2). Islets from obese donors with T2D had reduced insulin secretion, decreased \u03b2-cell exocytosis, and higher expression of fatty acid translocase CD36. We tested the hypothesis that CD36 is a key molecule in the reduced insulin secretion capacity. Indeed, CD36 overexpression led to decreased insulin secretion, impaired exocytosis, and reduced granule docking. This was accompanied by reduced expression of the exocytotic proteins SNAP25, STXBP1, and VAMP2, likely because CD36 induced downregulation of the insulin receptor substrate (IRS) proteins, suppressed the insulin-signaling phosphatidylinositol 3-kinase\/AKT pathway, and increased nuclear localization of the transcription factor FoxO1. CD36 antibody treatment of the human \u03b2-cell line EndoC-\u03b2H1 increased IRS1 and exocytotic protein levels, improved granule docking, and enhanced insulin secretion. Our results demonstrate that \u03b2-cells from obese donors with T2D have dysfunctional exocytosis likely due to an abnormal lipid handling represented by differential CD36 expression. Hence, CD36 could be a key molecule to limit \u03b2-cell function in T2D associated with obesity.<\/jats:p>","DOI":"10.2337\/db19-0944","type":"journal-article","created":{"date-parts":[[2020,3,20]],"date-time":"2020-03-20T22:35:33Z","timestamp":1584743733000},"page":"1193-1205","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":54,"title":["Potential Protection Against Type 2 Diabetes in Obesity Through Lower CD36 Expression and Improved Exocytosis in \u03b2-Cells"],"prefix":"10.2337","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6880-5161","authenticated-orcid":false,"given":"Mototsugu","family":"Nagao","sequence":"first","affiliation":[{"name":"Department of Clinical Sciences, Malm\u00f6, Islet Cell Exocytosis, Lund University Diabetes Centre, Lund University, Clinical Research Centre, Malm\u00f6, Sweden"},{"name":"Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon 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