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Potential protection against type 2 diabetes in obesity through lower CD36 expression and improved exocytosis in β-cells

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posted on 27.03.2020 by Ada Admin, Mototsugu Nagao, Jonathan L.S. Esguerra, Akira Asai, Jones K. Ofori, Anna Edlund, Anna Wendt, Hitoshi Sugihara, Claes B. Wollheim, Shinichi Oikawa, Lena Eliasson
Obesity is a risk factor for type 2 diabetes (T2D), however not all obese individuals develop the disease. In this study, we aimed to investigate the cause of differential insulin secretion capacity of pancreatic islets from T2D and non-T2D (ND) especially obese donors (BMI ≥30 kg/m2). Islets from obese T2D donors had reduced insulin secretion, decreased B-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 with reduced expression of the exocytotic proteins, SNAP25, STXBP1 and VAMP2, likely because CD36 induced down-regulation of the IRS proteins, suppressed insulin signaling PI3K-AKT pathway and increased nuclear localization of the transcription factor FoxO1. CD36 antibody treatment of the human B-cell line, EndoC-BH1, increased IRS1 and exocytotic protein levels, improved granule docking and enhanced insulin secretion. Our results demonstrate that B-cells from obese T2D donors have dysfunctional exocytosis likely due to an abnormal lipid handling represented by differential CD36 expression. Hence, CD36 could be a key molecule to limit B-cell function in T2D associated with obesity.

Funding

The study is financially supported by Swedish Foundation for Strategic Research (LUDC-IRC, IRC15-0067), Swedish Research Council (EXODIAB, 2009-1039; LUDC, 349-2006-237; L.E., project grant 2016-02124), Japan Society for the Promotion of Science (M.N., J.L.S.E. and A.A.), European Foundation for the Study of Diabetes and Japan Diabetes Society (M.N.), Diabetes Wellness Sverige (M.N., 720-2964 JDWG), Uehara Memorial Foundation (M.N.), Scandinavia-Japan Sasakawa Foundation (M.N.), Sumitomo Life Welfare Foundation (M.N.), Nippon Medical School Alumni Association (M.N.), Lotte Shigemitsu Prize (A.A.), Albert Påhlsson Foundation (J.L.S.E. and L.E.), Region Skåne-ALF (L.E.), Novo Nordisk Foundation (L.E.) and Swedish Diabetes Foundation (L.E., DIA2016-130).

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