LEPTIN SUPPRESSION OF INSULIN-SECRETION BY THE ACTIVATION OF ATP-SENSITIVE K-CELLS( CHANNELS IN PANCREATIC BETA)

In the genetic mutant mouse models ob/ob or db/db, leptin deficiency o r resistance, respectively, results in severe obesity and the developm ent of a syndrome resembling NIDDM, One of the earliest manifestations in these mutant mice is hyperinsulinemia, suggesting that leptin may normally directly suppress the secretion of insulin. Here, we show tha t pancreatic islets express a long (signal-transducing) form of leptin -receptor mRNA and that beta-cells bind a fluorescent derivative of le ptin (Cy3-leptin). The expression of leptin receptors on insulin-secre ting beta-cells was also visualized utilizing antisera generated again st an extracellular epitope of the receptor, A functional role for the beta-cell leptin receptor is indicated by our observation that leptin (100 ng/ml) suppressed the secretion of insulin from islets isolated from ob/ob mice, Furthermore, leptin produced a marked lowering of [Ca 2+](i) in ob/ob beta-cells, which was accompanied by cellular hyperpol arization and increased membrane conductance. Cell-attached patch meas urements of ob/ob beta-cells demonstrated that leptin activated ATP-se nsitive potassium channels (K-ATP) by increasing the open channel prob ability, while exerting no effect on mean open time, These effects wer e reversed by the sulfonylurea tolbutamide, a specific inhibitor of K- ATP. Taken together, these observations indicate an important physiolo gical role for leptin as an inhibitor of insulin secretion and lead us to propose that the failure of leptin to inhibit insulin secretion fr om the beta-cells of ob/ob and db/db mice may explain, in part, the de velopment of hyperinsulinemia, insulin resistance, and the progression to NIDDM.