New insights into the molecular mechanisms of priming of insulin exocytosis.
Exocytosis of insulin vesicles in the pancreatic beta-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 Ca(2+). 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 beta-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.
Kwan
E P
EP
Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada.
Gaisano
H Y
HY
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005089:Exocytosis / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins; D050600:SNARE Proteins; D033921:Vesicular Transport Proteins
D007328:Insulin; D009419:Nerve Tissue Proteins; D050600:SNARE Proteins; C503321:Unc13a protein, mouse; D033921:Vesicular Transport Proteins