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Secretory granule exocytosis and its amplification by cAMP in pancreatic β-cells

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Abstract

The sequence of events for secreting insulin in response to glucose in pancreatic β-cells is termed “stimulus-secretion coupling”. The core of stimulus-secretion coupling is a process which generates electrical activity in response to glucose uptake and causes Ca2+ oscillation for triggering exocytosis of insulin-containing secretory granules. Prior to exocytosis, the secretory granules are mobilized and docked to the plasma membrane and primed for fusion with the plasma membrane. Together with the final fusion with the plasma membrane, these steps are named the exocytosis process of insulin secretion. The steps involved in the exocytosis process are crucial for insulin release from β-cells and considered indispensable for glucose homeostasis. We recently confirmed a signature of defective exocytosis process in human islets and β-cells of obese donors with type 2 diabetes (T2D). Furthermore, cyclic AMP (cAMP) potentiates glucose-stimulated insulin secretion through mechanisms including accelerating the exocytosis process. In this mini-review, we aimed to organize essential knowledge of the secretory granule exocytosis and its amplification by cAMP. Then, we suggest the fatty acid translocase CD36 as a predisposition in β-cells for causing defective exocytosis, which is considered a pathogenesis of T2D in relation to obesity. Finally, we propose potential therapeutics of the defective exocytosis based on a CD36-neutralizing antibody and on Apolipoprotein A-I (ApoA-I), for improving β-cell function in T2D.

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Acknowledgements

We thank our present and former colleagues at Lund University Diabetes Centre (LUDC) and Nippon Medical School for contributions to the research introduced in this review and Yoshimi Nagao for supporting figure illustration. We acknowledge the human tissue laboratory at LUDC/Exodiab and the Nordic Centre for Islet Transplantation for the delivery of islets from human donors. We are grateful for support to our research in this area from the JSPS KAKENHI Grant Numbers 17KK0184, 19K23872 and 21K05453, the European Foundation for the Study of Diabetes and the Japan Diabetes Society, the Diabetes Wellness Sverige, the Uehara Memorial Foundation, the Scandinavia-Japan Sasakawa Foundation, the Sumitomo Life Welfare Foundation, the Ono Medical Research Foundation, the Swedish Research Council (LE project grant, JOL project grant, and an SRA grant SFO-EXODIAB (2009-1039)), ALF-Region Scania, Sweden, The Swedish Diabetes Foundation and the Swedish Foundation for Strategic Research (IRC-LUDC; IRC15-0067).

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Authors and Affiliations

  1. Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan

    Mototsugu Nagao

  2. Department of Clinical Sciences Malmö, Islet Cell Exocytosis, Lund University Diabetes Centre, Lund University, CRC 91-11, Jan Waldenströms Gata 35, 214 28, Malmö, Sweden

    Mototsugu Nagao, Jens O. Lagerstedt & Lena Eliasson

  3. Novo Nordisk A/S, Copenhagen, Denmark

    Jens O. Lagerstedt

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Correspondence to Mototsugu Nagao or Lena Eliasson.

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JOL is an employee of Novo Nordisk A/S, DK. The authors have no conflict of interest.

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The work using human islets was approved by the ethics committee in Malmö/Lund, Sweden: project No. 2011/263, date of approval 2011–05-03. All the procedures on the human islets were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and/or with the Helsinki Declaration of 1964 and later versions. Donors or their relatives had given their written consent to donate organs for biomedical research upon admission to the intensive care unit.

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Nagao, M., Lagerstedt, J.O. & Eliasson, L. Secretory granule exocytosis and its amplification by cAMP in pancreatic β-cells. Diabetol Int 13, 471–479 (2022). https://doi.org/10.1007/s13340-022-00580-3

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