Abstract

Soluble N-ethylmaleimide–sensitive factor (NSF) attachment protein receptor (SNARE) protein syntaxin-1A (STX-1A) plays a role not only in exocytosis, but also binds and regulates Ca²⁺ and K⁺ (voltage-gated K⁺ and ATP-sensitive K⁺ channels) to influence the sequence of events leading to secretion. Islet levels of STX-1A and cognate SNARE proteins are reduced in type 2 diabetic rodents, suggesting their role in dysregulated insulin secretion contributing to the abnormal glucose homeostasis. We investigated the specific role of STX-1A in pancreatic β-cells by generating transgenic mice, which express a moderately increased level (∼30% higher) of STX-1A in pancreatic islets (hereafter called STX-1A mice). The STX-1A mice displayed fasting hyperglycemia and a more sustained elevation of plasma glucose levels after an intraperitoneal glucose tolerance test, with correspondingly reduced plasma insulin levels. Surprisingly, β-cells from the STX-1A male mice also exhibited abnormal insulin tolerance. To unequivocally determine the β-cell secretory defects, we used single-cell analyses of exocytosis by patch clamp membrane capacitance measurements and ion channel recordings. Depolarization-evoked membrane capacitance increases were reduced in the STX-1A mouse islet β-cells. The STX-1A mouse also exhibited reduced currents through the Ca²⁺ channels but little change in the voltage-gated K⁺ channel or ATP-sensitive K⁺ channel. These results suggest that fluctuation of islet STX-1A levels in diabetes could influence the pathological and differential regulation of β-cell ion channels and the exocytotic machinery, collectively contributing to the impaired insulin secretion.