Mechanisms of Exocytosis in Insulin‐Secreting B‐Cells and Glucagon‐Secreting A‐Cells

Abstract: In pancreatic B‐ and A‐cells, metabolic stimuli regulate biochemical and electrical processes that culminate in Ca 2+ ‐influx and release of insulin or glucagon, respectively. Like in other (neuro)endocrine cells, Ca 2+ ‐influx triggers the rapid exocytosis of hormone‐containing secretory granules. Only a small fraction of granules (<1% in insulin‐secreting B‐cells) can be released immediately, while the remainder requires translocation to the plasma membrane and further “priming” for release by several ATP‐ and Ca 2+ ‐dependent reactions. Such functional organization may account for systemic features such as the biphasic time course of glucose‐stimulated insulin secretion. Since this release pattern is altered in type‐2 diabetes mellitus, it is conceivable that disturbances in the exocytotic machinery underlie the disease. Here I will review recent data from our laboratory relevant for the understanding of these processes in insulin‐secreting B‐cells and glucagon‐secreting A‐cells and for the identification of novel targets for antidiabetic drug action. Two aspects are discussed in detail: 1) The importance of a tight interaction between L‐type Ca 2+ ‐channels and the exocytotic machinery for efficient secretion; and 2) the role of intragranular acidification for the priming of secretory granules and its regulation by a granular 65‐kDa sulfonylurea‐binding protein.