ABNORMALITIES OF PANCREATIC-ISLETS BY TARGETED EXPRESSION OF A DOMINANT-NEGATIVE K-ATP CHANNEL

ATP-sensitive K+ (K-ATP) channels are known to play important roles in various cellular functions: but the direct consequences of disruption of K-ATP channel function are largely unknown. We have generated tran sgenic mice expressing a dominant-negative form of the K-ATP channel s ubunit Kir6.2 (Kir6.2G132S, substitution of glycine with serine at pos ition 132) in pancreatic beta cells. Kir6.2G132S transgenic mice devel op hypoglycemia with hyperinsulinemia in neonates and hyperglycemia wi th hypoinsulinemia and decreased beta cell population in adults, K-ATP channel function is found to be impaired in the beta cells of transge nic mice with hyperglycemia. In addition, both resting membrane potent ial and basal calcium concentrations are shown to be significantly ele vated in the beta cells of transgenic mice. We also found a high frequ ency of apoptotic beta cells before the appearance of hyperglycemia in the transgenic mice, suggesting that the K-ATP channel might play a s ignificant role in beta cell survival in addition to its role in the r egulation of insulin secretion.