Perspectives in Diabetes Diverse Roles of KAT P Channels Learned From Kir6.2 Genetically Engineered Mice

The regulation of insulin secretion from pancreatic -cells depends critically on the activities of their plasma membrane ion channels. ATP-sensitive K c h a nnels (KAT P channels) are present in many cells and regulate a variety of cellular functions by coupling cell metabolism with membrane potential. The activity of the KAT P channels in pancreatic -cells is regulated by changes in the ATP and ADP concentrations (AT P / A D P ratio) caused by glucose metabolism. Thus, the KAT P channels are the ATP and ADP sensors in the regulation of glucose-induced insulin secretion. KAT P channels are also the target of sulfonylureas, which are widely used in the treatment of type 2 diabetes. Molecular cloning of the two subunits of the pancreatic -cell KAT P c h a n n e l , Kir6.2 (an inward rectifier K channel member) and SUR1 (a receptor for sulfonylureas), has provided great insight into its structure and function. Kir6.2 subunits form the K ion-permeable pore and primarily confer inhibition of the channels by AT P, while SUR1 subunits confer activation of the channels by MgADP and K channel openers, such as diazoxide, as well as inhibition by sulfonylureas. The SUR1 subunits also enhance the sensitivity of the channels to AT P. To determine the physiological roles of KAT P channels directly, we have generated two kinds of genetically engineered mice: mice expressing a dominant-negative form of Kir6.2 s p e c i fically in the pancreatic -cells (Kir6.2G132S Tg mice) and mice lacking Kir6.2 (Kir6.2 knockout mice). Studies of these mice elucidated various roles of the KAT P channels in endocrine pancreatic function: 1) the KAT P channels are the major determinant of the resting membrane potential of pancreatic -cells, 2) both glucoseand sulfonylurea-induced membrane depolarization of -cells require closure of the KAT P channels, 3) both glucoseand sulfonylurea-induced rises in intracellular calcium concentration in -cells require closure of the KAT P channels, 4) both glucoseand sulfonylurea-induced insulin secretions are mediated principally by the KAT P channel–dependent pathway, 5) the KAT P channels are important for -cell survival and architecture of the islets, 6) the KAT P channels are important in the diff e rentiation of islet cells, and 7) the KAT P channels in glucose-responsive cells generally participate in coupling glucose sensing with cell excitability. Interestingly, despite the severe defect in glucose-induced insulin secretion, Kir6.2 knockout mice show only a very mild impairment in glucose tolerance. However, when the knockout mice become obese with age, they develop fasting hyperglycemia and glucose intolerance, while neither fasting hyperglycemia nor glucose intolerance is evident in the aged knockout mice without obesity, suggesting that both the genetic defect in glucose-induced insulin secretion and the acquired insulin resistance due to environmental factors are necessary to develop diabetes in Kir6.2 knockout mice. Thus, Kir6.2G132S Tg mice and Kir6.2 knockout mice provide a model of t y p e 2 diabetes and clarify the various roles of KAT P channels in endocrine pancreatic function. D i a b e t e s 4 9 :3 1 1–318, 2000