Leptin reduces glucose transport and cellular ATP levels in INS-1 beta-cells

Leptin suppresses insulin secretion by opening ATP-sensitive K(+) (K(ATP)) channels and hyperpolarizing beta-cells. We measured the intracellular concentration of ATP (ATP(i)) in tumor-derived beta-cells, INS-1, and found that leptin reduced ATP(i) by approximately 30%, suggesting that the opening of K(ATP) channels by leptin is mediated by decreased ATP(i). A reduction in glucose availability for metabolism may explain the decreased ATP(i), since leptin (30 min) reduced glucose transport into INS-1 cells by approximately 35%, compared to vehicle-treated cells. The twofold induction of GLUT2 phosphorylation by GLP-1, an insulin secretagogue, was abolished by leptin. Therefore, the acute effect of leptin could involve covalent modification of GLUT2. These findings suggest that leptin may inhibit insulin secretion by reducing ATP(i) as a result of reduced glucose availability for the metabolic pathway. In addition, leptin reduced glucose transport by 35% in isolated rat hepatocytes that also express GLUT2, suggesting that glucose transport may also be altered by leptin in other glucose-responsive tissues such as the liver.