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Diabetes 54:2852-2858, 2005
© 2005 by the American Diabetes Association, Inc.

Membrane Phosphoinositides Control Insulin Secretion Through Their Effects on ATP-Sensitive K+ Channel Activity

Chia-Wei Lin1, Feifei Yan1, Satoko Shimamura1, Sebastian Barg2, and Show-Ling Shyng1

1 Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, Oregon
2 Vollum Institute, Oregon Health & Science University, Portland, Oregon

ATP-sensitive K+ channels (KATP channels) of pancreatic ß-cells play key roles in glucose-stimulated insulin secretion by linking metabolic signals to cell excitability. Membrane phosphoinositides, in particular phosphatidylinositol 4,5-bisphosphates (PIP2), stimulate KATP channels and decrease channel sensitivity to ATP inhibition; as such, they have been postulated as critical regulators of KATP channels and hence of insulin secretion in ß-cells. Here, we tested this hypothesis by manipulating the interactions between KATP channels and membrane phospholipids in a ß-cell line, INS-1, and assessing how the manipulations affect membrane excitability and insulin secretion. We demonstrate that disruption of channel interactions with PIP2 by overexpressing PIP2-insensitive channel subunits leads to membrane depolarization and elevated basal level insulin secretion at low glucose concentrations. By contrast, facilitation of channel interactions with PIP2 by upregulating PIP2 levels via overexpression of a lipid kinase, phosphatidylinositol 4-phosphate 5 kinase, decreases the ATP sensitivity of endogenous KATP channels by ~26-fold and renders INS-1 cells hyperpolarized, unable to secrete insulin properly in the face of high glucose. Our results establish an important role of the interaction between membrane phosphoinositides and KATP channels in regulating insulin secretion.

Address correspondence and reprint requests to S.-L. Shyng, Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239. E-mail: shyngs{at}ohsu.edu

Abbreviations: GFP, green fluorescence protein; HA, influenza A virus hemagglutinin; HBSS, HEPES balanced salt solution; KATP channel, ATP-sensitive K+ channel; PIP2, phosphatidylinositol 4,5-bisphosphates; PIP5K, phosphatidylinositol 4-phosphate 5 kinase; RMP, resting membrane potential


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Copyright © 2005 by the American Diabetes Association.