Rescuing the subprime meltdown in insulin exocytosis in diabetes

Neuroendocrine pancreatic islet beta-cells secrete the hormone insulin in response to glucose stimulation and adapt efficiently to increased demand by peripheral tissues to maintain glucose homeostasis. Insulin is packed within dense-core granules, which traffic and dock onto the plasma membrane whereby a Ca(2+) stimulus evokes exocytosis by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE), complex-mediated, membrane fusion. Recent studies have unveiled postdocking steps mediated by "priming" factors that influence SNARE complex assembly to confer fusion readiness to the docked granules. This review will summarize recent insights into the priming role for Munc13 in the exocytosis of insulin granules. We present evidence for the interaction of Munc13-1 with exocytotic substrates involved in cAMP-mediated potentiation of insulin release, the latter we show to mediate enhanced granule-to-granule fusion events underlying compound exocytosis. We thus also further review the current understanding of granule-to-granule fusion. As agents acting on cAMP signaling are clinically used to augment insulin release in diabetes, this better understanding of priming steps may reveal additional novel therapeutic strategies to increase the capacity for insulin release to improve the treatment of diabetes.