Type 2 diabetes has been coined "a two-hit disease," as it involves specific defects of
glucose-stimulated insulin secretion from the pancreatic beta cells in addition to defects in peripheral tissue
insulin action required for
glucose uptake. Both of these processes, insulin secretion and
glucose uptake, are mediated by SNARE (
soluble N-ethylmaleimide-sensitive factor attachment protein receptor)
protein core complexes composed of
syntaxin, SNAP-23/25, and VAMP
proteins. The SNARE core complex is regulated by the Sec1/Munc18 (SM) family of
proteins, which selectively bind to their cognate
syntaxin isoforms with high affinity. The process of insulin secretion uses multiple Munc18-syntaxin
isoform pairs, whereas
insulin action in the peripheral tissues appears to use only the Munc18c-syntaxin 4 pair. Importantly, recent reports have linked
obesity and
Type 2 diabetes in humans with changes in
protein levels and single nucleotide polymorphisms (SNPs) of Munc18 and
syntaxin isoforms relevant to these exocytotic processes, although the molecular mechanisms underlying the observed phenotypes remain incomplete (5, 104, 144). Given the conservation of these
proteins in two seemingly disparate processes and the need to design and implement novel and more effective clinical interventions, it will be vitally important to delineate the mechanisms governing these conserved SNARE-mediated exocytosis events. Thus, we provide here an up-to-date historical review of advancements in defining the roles and molecular mechanisms of Munc18-syntaxin complexes in the pathophysiology of
Type 2 diabetes.