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Media type:
E-Article
Title:
Transgenic Mouse Overexpressing Syntaxin-1A as a Diabetes Model
Contributor:
Lam, Patrick P.L.;
Leung, Yuk-Man;
Sheu, Laura;
Ellis, James;
Tsushima, Robert G.;
Osborne, Lucy R.;
Gaisano, Herbert Y.
imprint:
American Diabetes Association, 2005
Published in:
Diabetes, 54 (2005) 9, Seite 2744-2754
Language:
English
DOI:
10.2337/diabetes.54.9.2744
ISSN:
0012-1797;
1939-327X
Origination:
Footnote:
Description:
<jats:p>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.</jats:p>