Leptin suppression of insulin secretion and gene expression in human pancreatic islets: Implications for the development of adipogenic diabetes mellitus

Previously we demonstrated the expression of the long form of the leptin re ceptor in rodent pancreatic beta-cells and an inhibition of insulin secreti on by leptin via activation of ATP-sensitive potassium channels. Here we ex amine pancreatic islets isolated from pancreata of human donors for their r esponses to leptin. The presence of leptin receptors on islet beta-cells wa s demonstrated by double fluorescence confocal microscopy after binding of a fluorescent derivative of human leptin (Cy3-leptin). Leptin (6.25 nM) sup pressed insulin secretion of normal islets by 20% at 5.6 mM glucose. Intrac ellular calcium responses to 16.7 mM glucose were rapidly reduced by leptin . Proinsulin messenger ribonucleic acid expression in islets was inhibited by leptin at 11.1 mM, but not at 5.6 mM glucose. Leptin also reduced proins ulin messenger ribonucleic acid levels that were increased in islets by tre atment with 10 nM glucagon-like peptide-1 in the presence of either 5.6 or 11.1 mM glucose. These findings demonstrate direct suppressive effects of l eptin on insulin-producing beta-cells in human islets at the levels of both stimulus-secretion coupling and gene expression. The findings also further indicate the existence of an adipoinsular axis in humans in which insulin stimulates leptin production in adipocytes and leptin inhibits the producti on of insulin in beta-cells. We suggest that dysregulation of the adipoinsu lar axis in obese individuals due to defective leptin reception by beta-cel ls may result in chronic hyperinsulinemia and may contribute to the pathoge nesis of adipogenic diabetes.