New Roles of Syntaxin-1A in Insulin Granule Exocytosis and Replenishment

In type-2 diabetes (T2D), severely reduced islet syntaxin-1A (Syn-1A) levels contribute to insulin secretory deficiency. We generated beta-cell-specific Syn-1A-KO (Syn-1A-beta KO) mice to mimic beta-cell Syn-1A deficiency in T2D. Glucose tolerance tests showed that Syn-1A-beta KO mice exhibited blood glucose elevation corresponding to reduced blood insulin levels. Perifusion of Syn-1A-beta KO islets showed impaired first-and second-phase glucose-stimulated insulin secretion (GSIS) resulting from reduction in readily releasable pool and granule pool refilling. To unequivocally determine the beta-cell exocytotic defects caused by Syn-1A deletion, EM and total internal reflection fluorescence microscopy showed that Syn-1A-KO beta-cells had a severe reduction in the number of secretory granules (SGs) docked onto the plasma membrane (PM) at rest and reduced SG recruitment to the PM after glucose stimulation, the latter indicating defects in replenishment of releasable pools required to sustain second-phase GSIS. Whereas reduced predocked SG fusion accounted for reduced first-phase GSIS, selective reduction of exocytosis of short-dock (but not no-dock) newcomer SGs accounted for the reduced second-phase GSIS. These Syn-1A actions on newcomer SGs were partly mediated by Syn-1A interactions with newcomer SG VAMP8.