Hyperinsulinemia Precedes Insulin Resistance in Mice Lacking Pancreatic β-Cell Leptin Signaling

The adipocyte hormone leptin acts centrally and peripherally to regulate body weight and glucose homeostasis. The pancreatic beta-cell has been shown to be a key peripheral target of leptin, with leptin suppressing insulin synthesis and secretion from beta-cells both in vitro and in vivo. Mice with disrupted leptin signaling in beta-cells (lepr(flox/flox) RIPcre tg+ mice) display hyperinsulinemia, insulin resistance, glucose intolerance, obesity, and reduced fasting blood glucose. We hypothesized that hyperinsulinemia precedes the development of insulin resistance and increased adiposity in these mice with a defective adipoinsular axis. To determine the primary defect after impaired beta-cell leptin signaling, we treated lepr(flox/flox) RIPcre tg+ mice with the insulin sensitizer metformin or the insulin-lowering agent diazoxide with the rationale that pharmacological improvement of the primary defect would alleviate the secondary symptoms. We show that improving insulin sensitivity with metformin does not normalize hyperinsulinemia, whereas lowering insulin levels with diazoxide improves insulin sensitivity. Taken together, these results suggest that hyperinsulinemia precedes insulin resistance in beta-cell leptin receptor-deficient mice, with insulin resistance developing as a secondary consequence of excessive insulin secretion. Therefore, pancreatic beta-cell leptin receptor-deficient mice may represent a model of obesity-associated insulin resistance that is initiated by hyperinsulinemia.