Long-term leptin treatment of ob/ob mice improves glucose-induced insulin secretion

OBJECTIVE: Previous studies have demonstrated that leptin inhibits glucose- stimulated insulin secretion from isolated islets, although a lack of lepti n effect on insulin secretion has also been reported. The effect of long te rm in vivo leptin treatment of insulin secretion has, however, not been est ablished. Therefore, in the present study, we have evaluated the effect of long term in vivo treatment of leptin on glucose-induced insulin secretion in ob/ob mice. METHODS: After 7 days' treatment of leptin (100 mug daily s.c.), insulin re lease was measured in isolated islets by batch incubation followed by radio immunoassay. Glucose utilization and oxidation were measured by measuring t he formation of (H2O)-H-3 and (CO2)-C-14 from [5-H-3] and [U-C-14] glucose, respectively. Glucose-6-phosphatase activity was measured by measuring the conversion of C-14-glucose-6-P to C-14-glucose. In addition, immunohistoch emistry of pancreatic specimens was undertaken for study of expression of i nsulin, GLUT-2 and hormone-sensitive lipase (HSL). RESULTS: Leptin treatment significantly improved insulin secretion both at 5.5 mM (by 15%; P < 0.05) and 16.7 mM (by 85%; P < 0.001) glucose, compared to vehicle-treated controls. Furthermore, whereas leptin treatment did not affect islet. insulin or DNA contents, a significant decrease in islet tri glyceride content and glucose-6-phosphatase activity was observed. Moreover , the immunocytochemical data revealed an increased immunostaining for insu lin, GLUT-2 and hormone-sensitive lipase (HSL) in islets from leptin-treate d ob/ob mice. CONCLUSION: The results suggest that long-term leptin treatment of ob/ob mi ce improves glucose-stimulated insulin secretion in parallel with reduced g lucose-6-phosphatase activity, increased HSL and decreased triglyceride lev els in islets. These perturbations may explain the improvement of glucose-s timulated insulin secretion induced by leptin.