Transgenic mouse overexpressing syntaxin-1A as a diabetes model.
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 Ca(2+) 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 beta-cells by generating transgenic mice, which express a moderately increased level ( approximately 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, beta-cells from the STX-1A male mice also exhibited abnormal insulin tolerance. To unequivocally determine the beta-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 beta-cells. The STX-1A mouse also exhibited reduced currents through the Ca(2+) 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 beta-cell ion channels and the exocytotic machinery, collectively contributing to the impaired insulin secretion.
Lam
Patrick P L
PP
University of Toronto, Room 7226, Medical Science Building, 1 King's College Circle, Toronto, Ontario, Canada.
Leung
Yuk-Man
YM
Sheu
Laura
L
Ellis
James
J
Tsushima
Robert G
RG
Osborne
Lucy R
LR
Gaisano
Herbert Y
HY
D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D003920:Diabetes Mellitus / Q000235:genetics* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005089:Exocytosis / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015221:Potassium Channels / Q000502:physiology
D015220:Calcium Channels; D007328:Insulin; D015221:Potassium Channels