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Insulin Regulates Islet -Cell Function by Reducing K_ATP Channel Sensitivity to Adenosine 5'-Triphosphate Inhibition

Departments of Medicine and Physiology (Y.M.L., I.A., L.S., X.G., R.G.T., N.E.D., H.Y.G.), University of Toronto, Toronto, Canada M5S 1A8; Department of Physiology (Y.M.L.), China Medical University, Taichung 404, Taiwan, R.O.C.; and Department of Medicine (M.H.), University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Drs. Yuk M. Leung and Herbert Y. Gaisano, Room 7226, Medical Sciences Building, 1 King’s College Circle, University of Toronto, Toronto, Ontario, Canada M5S 1A8. E-mail: yukman.leung{at}utoronto.ca or herbert.gaisano{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 ß-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 ß-cells (green cells), and characterized their ATP-sensitive K⁺ (K_ATP) channel properties, showing that -cell K_ATP channels exhibited a 5-fold higher sensitivity to ATP inhibition than ß-cell K_ATP channels. Here, we show that insulin exerted paracrine regulation of -cells by markedly reducing the sensitivity of -cell K_ATP channels to ATP (IC₅₀ = 0.18 and 0.50 mM in absence and presence of insulin, respectively). Insulin also desensitized ß-cell K_ATP channels to ATP inhibition (IC₅₀ = 0.84 and 1.23 mM in absence and presence of insulin, respectively). Insulin effects on both islet cell K_ATP 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 K_ATP channel opening. We conclude that a major mechanism by which insulin exerts paracrine control on -cells is by modulating its K_ATP 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.

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