Insulin granule biogenesis and exocytosis
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Cellular and Molecular Life Sciences
REVIEW
Insulin granule biogenesis and exocytosis Muhmmad Omar‑Hmeadi1 · Olof Idevall‑Hagren1 Received: 22 July 2020 / Revised: 11 September 2020 / Accepted: 19 October 2020 © The Author(s) 2020
Abstract Insulin is produced by pancreatic β-cells, and once released to the blood, the hormone stimulates glucose uptake and suppresses glucose production. Defects in both the availability and action of insulin lead to elevated plasma glucose levels and are major hallmarks of type-2 diabetes. Insulin is stored in secretory granules that form at the trans-Golgi network. The granules undergo extensive modifications en route to their release sites at the plasma membrane, including changes in both protein and lipid composition of the granule membrane and lumen. In parallel, the insulin molecules also undergo extensive modifications that render the hormone biologically active. In this review, we summarize current understanding of insulin secretory granule biogenesis, maturation, transport, docking, priming and eventual fusion with the plasma membrane. We discuss how different pools of granules form and how these pools contribute to insulin secretion under different conditions. We also highlight the role of the β-cell in the development of type-2 diabetes and discuss how dysregulation of one or several steps in the insulin granule life cycle may contribute to disease development or progression. Keywords Diabetes · Lipids · β-Cell · Insulin
Introduction Insulin is the major blood-glucose lowering hormone, and it acts by promoting glucose uptake and storage and by suppressing glucose production. A single cell-type, the β-cell, is solely responsible for all insulin production and secretion. These cells are located within the islets of Langerhans, micro-organs scattered throughout the pancreas, where it is mixed with other endocrine cells involved in blood glucose regulation. Insulin is stored in large, dense-core granules and is released to the circulation in response to elevated plasma glucose concentrations. Insulin secretion is largely controlled at the level of the β-cell, and a single β-cell, taken out of the pancreas, retains the ability to release insulin in response to glucose. This process begins with glucose uptake and metabolism to ATP that subsequently closes ATP-sensitive K+-channels, resulting in membrane depolarization, opening of voltage-dependent C a2+ channels, C a2+ influx and insulin granule exocytosis. Insulin granules can be divided into two functionally distinct pools; one containing granules that * Olof Idevall‑Hagren [email protected] 1
Department of Medical Cell Biology, Uppsala University, Biomedical Centre, Husargatan 3, 75123 Uppsala, Sweden
are release competent and one containing granules that are not. The release competent granules are found immediately adjacent to the plasma membrane and their release gives rise to a sharp increase in plasma insulin known as the first phase of secretion. This granule pool is gradually depleted during prolonged
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