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Transgenic Mouse Overexpressing Syntaxin-1A as a Diabetes Model

¹ Department of Medicine, University of Toronto, Toronto, Canada
² Department of Physiology, University of Toronto, Toronto, Canada
³ Program in Developmental Biology, Sick Kids Hospital, Toronto, Canada
⁴ Department of Molecular and Medical Genetics, University of Toronto, Toronto, Canada

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 ß-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, ß-cells from the STX-1A male mice also exhibited abnormal insulin tolerance. To unequivocally determine the ß-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 ß-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 ß-cell ion channels and the exocytotic machinery, collectively contributing to the impaired insulin secretion.

Abbreviations: Cm, membrane capacitance; GST, glutathione S-transferase; IPGTT, intraperitoneal glucose tolerance test; K_ATP channel, ATP-sensitive K⁺ channel; K_v channel, voltage-gated potassium channel; NSF, N-ethylmaleimide–sensitive factor; SNAP-25, synaptosome-associated protein of 25 kDa; SNARE, soluble NSF attachment protein receptor; STX-1A, syntaxin-1A; TEA, tetraethylammonium; VAMP-2, vesicle-associated membrane protein 2; WBS, Williams-Beuren syndrome

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