TY - JOUR
T1 - Potential protection against type 2 diabetes in obesity through lower CD36 expression and improved exocytosis in β-cells
AU - Nagao, Mototsugu
AU - Esguerra, Jonathan L.S.
AU - Asai, Akira
AU - Ofori, Jones K.
AU - Edlund, Anna
AU - Wendt, Anna
AU - Sugihara, Hitoshi
AU - Wollheim, Claes B.
AU - Oikawa, Shinichi
AU - Eliasson, Lena
N1 - Funding Information:
The authors thank Anna-Maria Veljanovska Ramsay and Britt-Marie Nilsson (both from Lund University Diabetes Centre, Malmö, Sweden) as well as Momoyo Kawahara and Miyuki Takatori (both from Nippon Medical School, Tokyo, Japan) for technical assistance. The authors also thank Anneli Björklund (Karolinska Institute, Stockholm, Sweden) for providing the CD36-overexpressing INS-1 cell line and EXODIAB and the Nordic Network for Clinical Islet Transplantation for providing human islets and human islet data. This study is financially supported by the Swedish Foundation for Strategic Research (IRC15-0067 to Lund University Diabetes Centre-Industrial Research Centre), Swedish Research Council (2009-1039 to EXODIAB; 349-2006-237 to Lund University Diabetes Centre; and project grants 2016-02124 and 2019-01406 to L.E.), Japan Society for the Promotion of Science (to M.N., J.L.S.E., and A.A.), European Foundation for the Study of Diabetes and Japan Diabetes Society (to M.N.), Insamlingsstiftelsen Diabetes Wellness Network Sverige (720-2964 JDWG to M.N.), Uehara Memorial Foundation (to M.N.), Scandinavia-Japan Sasakawa Foundation (to M.N.), Sumitomo Life Welfare Foundation (to M.N.), Nippon Medical School Alumni Association (to M.N.), Lotte Shigemitsu Prize (to A.A.), Albert Påhlsson Foundation (to J.L.S.E. and L.E.), Region Skåne-regional grant (ALF) (to L.E.), Novo Nordisk Foundation (to L.E.), and Swedish Diabetes Foundation (DIA2016-130 to L.E.).
Funding Information:
Acknowledgments. The authors thank Anna-Maria Veljanovska Ramsay and Britt-Marie Nilsson (both from Lund University Diabetes Centre, Malmö, Sweden) as well as Momoyo Kawahara and Miyuki Takatori (both from Nippon Medical School, Tokyo, Japan) for technical assistance. The authors also thank Anneli Björklund (Karolinska Institute, Stockholm, Sweden) for providing the CD36-overexpressing INS-1 cell line and EXODIAB and the Nordic Network for Clinical Islet Transplantation for providing human islets and human islet data. Funding. This study is financially supported by the Swedish Foundation for Strategic Research (IRC15-0067 to Lund University Diabetes Centre-Industrial Research Centre), Swedish Research Council (2009-1039 to EXODIAB; 349-2006-237 to Lund University Diabetes Centre; and project grants 2016-02124 and 2019-01406 to L.E.), Japan Society for the Promotion of Science (to M.N., J.L.S.E., and A.A.), European Foundation for the Study of Diabetes and Japan Diabetes Society (to M.N.), Insamlingsstiftelsen Diabetes Wellness Network Sverige (720-2964 JDWG to M.N.), Uehara Memorial Foundation (to M.N.), Scandinavia-Japan Sasakawa Foundation (to M.N.), Sumitomo Life Welfare Foundation (to M.N.), Nippon Medical School Alumni Association (to M.N.), Lotte Shigemitsu Prize (to A.A.), Albert Påhlsson Foundation (to J.L.S.E. and L.E.), Region Skåne-regional grant (ALF) (to L.E.), Novo Nordisk Foundation (to L.E.), and Swedish Diabetes Foundation (DIA2016-130 to L.E.). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. L.E. supervised the project. M.N. and L.E. designed experiments, conducted data analysis, and wrote the manuscript. M.N., A.A., J.K.O., A.E., and A.W. performed experiments. J.L.S.E. analyzed RNA-seq data. H.S., C.B.W., and S.O. contributed with discussion and edited the manuscript. L.E. and M.N. are the guarantors of this work and, as such, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Publisher Copyright:
© 2020 by the American Diabetes Association.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
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U2 - 10.2337/db19-0944
DO - 10.2337/db19-0944
M3 - Article
C2 - 32198214
AN - SCOPUS:85083490218
VL - 69
SP - 1193
EP - 1205
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 6
ER -
