In type-2 diabetes (T2D) severely reduced islet Syntaxin(Syn)-1A levels contribute to insulin secretory deficiency. We generated β-cell-specific Syn-1A KO(Syn-1A-βKO) mice to mimic β-cell Syn-1A deficiency in T2D. Glucose tolerance tests showed Syn-1A-βKO mice exhibited blood glucose elevation corresponding to reduced blood insulin levels. Perifusion of Syn-1A-βKO 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 β-cell exocytotic defects caused by Syn-1A deletion, EM and total internal reflection fluorescence microscopy showed Syn-1A-KO β-cells had severe reduction in number of SGs docked onto plasma membrane(PM) at rest and reduced SG recruitment to PM after glucose stimulation, the latter indicates 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.
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