New insights into the molecular mechanisms of priming of insulin exocytosis

• Published in: Diabetes, obesity & metabolism Vol. 9; no. s2; pp. 99 - 108
• Main Authors: Kwan, E.P, Gaisano, H.Y
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.11.2007; Blackwell Publishing Ltd
• Subjects: Animals; Diabetes Mellitus, Type 2 - metabolism; diacylglycerol; Exocytosis - physiology; Insulin - metabolism; insulin exocytosis; Islets of Langerhans - metabolism; Mice; Munc13-1; Nerve Tissue Proteins; priming; readily releasable pool; SNARE Proteins; soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE); Vesicular Transport Proteins
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/j.1463-1326.2007.00788.x

Exocytosis of insulin vesicles in the pancreatic β-cell involves a sequence of regulated events, whose normal function and efficient adaptation to increased demand are essential for the maintenance of glucose homeostasis. These exocytotic events comprise the trafficking and docking of vesicles to the plasma membrane, followed by fusion triggered by Ca²⁺. Recent studies have unravelled post-docking steps mediated by novel factors, which, by their interactions with soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)- and SNARE-associated proteins, confer the docked vesicles fusion competence. These priming steps define the releasable pool of insulin vesicles, which accounts for the first phase of insulin secretion, and controls the rate at which vesicles are replenished for the second phase of secretion. This article aims to summarize what is currently known about the mechanisms that underlie the priming activity of these proteins, focusing on Munc13, a topic to which we have made some recent contributions. Abnormal glucose homeostasis in type 2 diabetes is because of the failure of islet β-cells to augment insulin secretion sufficiently to compensate for reduced insulin sensitivity. A better understanding of the priming steps may help develop novel approaches to increase insulin secretory capacity and thereby prevent the progression to type 2 diabetes.