Hyperinsulinism induced by targeted suppression of beta cell K ATP channels

ATP-sensitive K + (K ATP ) channels couple cell metabolism to electrical activity. To probe the role of K ATP in glucose-induced insulin secretion, we have generated transgenic mice expressing a dominant-negative, GFP-tagged K ATP channel subunit in which residues 132–134 (Gly-Tyr-Gly) in the selectivity filter were replaced by Ala-Ala-Ala, under control of the insulin promoter. Transgene expression was confirmed by both beta cell-specific green fluorescence and complete suppression of channel activity in those cells (≈70%) that did fluoresce. Transgenic mice developed normally with no increased mortality and displayed normal body weight, blood glucose levels, and islet architecture. However, hyperinsulinism was evident in adult mice as ( i ) a disproportionately high level of circulating serum insulin for a given glucose concentration (≈2-fold increase in blood insulin), ( ii ) enhanced glucose-induced insulin release from isolated islets, and ( iii ) mild yet significant enhancement in glucose tolerance. Enhanced glucose-induced insulin secretion results from both increased glucose sensitivity and increased release at saturating glucose concentration. The results suggest that incomplete suppression of K ATP channel activity can give rise to a maintained hyper insulinism.