Leptin Suppression of Insulin Secretion and Gene Expression in Human Pancreatic Islets: Implications for the Development of Adipogenic Diabetes Mellitus1

Abstract

Previously we demonstrated the expression of the long form of the leptin receptor in rodent pancreatic beta-cells and an inhibition of insulin secretion by leptin via activation of ATP-sensitive potassium channels. Here we examine pancreatic islets isolated from pancreata of human donors for their responses to leptin. The presence of leptin receptors on islet beta-cells was demonstrated by double fluorescence confocal microscopy after binding of a fluorescent derivative of human leptin (Cy3-leptin). Leptin (6.25 nM) suppressed insulin secretion of normal islets by 20% at 5.6 mM glucose. Intracellular 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 proinsulin messenger ribonucleic acid levels that were increased in islets by treatment 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 leptin 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 production of insulin in beta-cells. We suggest that dysregulation of the adipoinsular axis in obese individuals due to defective leptin reception by beta-cells may result in chronic hyperinsulinemia and may contribute to the pathogenesis of adipogenic diabetes.

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“…This is easily understood, since leptin has been proven to regulate insulin secretion and action through LEPRs in pancreatic β cells [31]. Chiu et al [30] found that subjects with at least one G allele had insulin-resistant phenotypes, with higher total LDL-C and higher plasma insulin concentrations.…”

Leptin modulates β cell expression of IL-1 receptor antagonist and release of IL-1β in human islets

“…␤ cells express leptin receptors, and leptin inhibits insulin secretion in vivo and in vitro (17)(18)(19)(20)(21)(22)(23). In rodent islets, leptin induces ␤ cell proliferation and protects from FFAinduced ␤ cell apoptosis (24)(25)(26)(27).…”

Essential Role of Phosphoinositide 3-Kinase in Leptin-inducedK ATP Channel Activation in the Rat CRI-G1 Insulinoma Cell Line

“…Although the hypothalamus is considered the main target for leptin, particularly with respect to body weight regulation, it is clear that this hormone has distinct actions on other peripheral, target organs. There have been several reports that leptin reduces insulin secretion from pancreatic beta cells (3)(4)(5)(6), although this view is not shared by all investigators (7). One mechanism proposed to explain the leptin-induced reduction in insulin secretion is via activation of ATP-sensitive K ϩ (K ATP ) channels (8,9).…”