Potential Protection Against Type 2 Diabetes in Obesity Through Lower CD36 Expression and Improved Exocytosis in β-Cells

Author:

Nagao Mototsugu12ORCID,Esguerra Jonathan L.S.1,Asai Akira123,Ofori Jones K.1,Edlund Anna1,Wendt Anna1,Sugihara Hitoshi2,Wollheim Claes B.4,Oikawa Shinichi2,Eliasson Lena1ORCID

Affiliation:

1. Department of Clinical Sciences, Malmö, Islet Cell Exocytosis, Lund University Diabetes Centre, Lund University, Clinical Research Centre, Malmö, Sweden

2. Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan

3. Food and Health Science Research Unit, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan

4. Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland

Abstract

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 donors with T2D and non-T2D (ND), especially obese donors (BMI ≥30 kg/m2). Islets from obese donors with T2D had reduced insulin secretion, decreased β-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 β-cell line EndoC-βH1 increased IRS1 and exocytotic protein levels, improved granule docking, and enhanced insulin secretion. Our results demonstrate that β-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 β-cell function in T2D associated with obesity.

Funder

Swedish Foundation for Strategic Research

Swedish Research Council

European Foundation for the Study of Diabetes

Insamlingsstiftelsen Diabetes Wellness Network Sverige

Region Skåne

Novo Nordisk Foundation

Swedish Diabetes Foundation

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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