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Submitted on October 3, 2005
Accepted on January 23, 2006
-CELL FUNCTION BY REDUCING KATP CHANNEL SENSITIVITY TO ATP INHIBITION
Departments of Medicine and Physiology, University of Toronto, Toronto, Canada, M5S 1A8; Department of Physiology, China Medical University, Taichung, Taiwan, R.O.C.; Department of Medicine, University of Chicago, Chicago, IL 60637, USA
* To whom correspondence should be addressed. E-mail: yukman.leung{at}utoronto.ca.
Glucose regulates pancreatic islet 
-cell glucagon secretion directly by its metabolism to generate ATP in -cells, and indirectly via stimulation of paracrine release of 
-cell secretory products, particularly insulin. How the cellular substrates of these pathways converge in the -cell is not well known. We recently reported the use of the MIP-GFP (mouse insulin promoter-green fluorescent protein) mouse to reliably identify islet - (non-green cells) and -cells (green cells), and characterized their KATP channel properties, showing that -cell KATP channels exhibited a 5-fold higher sensitivity to ATP inhibition than -cell KATP channels. Here, we show that insulin exerted paracrine regulation of -cells by markedly reducing the sensitivity of -cell KATP channels to ATP (IC50 = 0.18 and 0.50 mM in absence and presence of insulin, respectively). Insulin also desensitized -cell KATP channels to ATP inhibition (IC50 = 0.84 and 1.23 mM in absence and presence of insulin, respectively). Insulin effects on both islet cell KATP channels were blocked by wortmannin, indicating that insulin acted on the insulin receptor-phosphatidylinositol 3-kinase signaling pathway. Insulin did not affect -cell A-type K+ currents. Glutamate, known to also inhibit -cell glucagon secretion, did not activate -cell KATP channel opening. We conclude that a major mechanism by which insulin exerts paracrine control on -cells is by modulating its KATP channel sensitivity to ATP block. This may be an underlying basis for the proposed sequential glucose-insulin regulation of -cell glucagon secretion, which becomes distorted in diabetes, leading to dysregulated glucagon secretion.
-cells •
islet -cells •
KATP channels •
insulin •
ATP
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