The insulin-degrading enzyme (IDE) is a metalloendopeptidase with a high affinity for insulin . Human genetic polymorphisms in Ide have been linked to increased risk for T2DM . In mice, hepatic Ide ablation causes glucose intolerance and insulin resistance when mice are fed a regular diet .
OBJECTIVE These studies were undertaken to further investigate its regulatory role in glucose homeostasis and insulin sensitivity in diet-induced obesity .
METHODS To this end, we have compared the metabolic effects of loss versus gain of IDE function in mice fed a high-fat diet (HFD).
RESULTS We demonstrate that loss of IDE function in liver (L-IDE-KO mouse) exacerbates hyperinsulinemia and insulin resistance without changes in insulin clearance but in parallel to an increase in pancreatic β-cell function . Insulin resistance was associated with increased FoxO1 activation and a ~2-fold increase of GLUT2 protein levels in the liver of HFD-fed mice in response to an intraperitoneal injection of insulin . Conversely, gain of IDE function (adenoviral delivery) improves glucose tolerance and insulin sensitivity, in parallel to a reciprocal ~2-fold reduction in hepatic GLUT2 protein levels . Furthermore, in response to insulin, IDE co-immunoprecipitates with the insulin receptor in liver lysates of mice with adenoviral-mediated liver overexpression of IDE .
CONCLUSIONS We conclude that IDE regulates hepatic insulin action and whole-body glucose metabolism in diet-induced obesity via insulin receptor levels.