deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance删除降解酶抒发对映,年龄相关性对葡萄糖和胰岛素耐受性的影响.pdfVIP

Deletion of Insulin-Degrading Enzyme Elicits Antipodal, Age-Dependent Effects on Glucose and Insulin Tolerance 1 1 1 2 2 1,2 Samer O. Abdul-Hay , Dongcheul Kang , Melinda McBride , Lilin Li , Ji Zhao , Malcolm A. Leissring * 1 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, United States of America, 2 Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, United States of America Abstract Background: Insulin-degrading enzyme (IDE) is widely recognized as the principal protease responsible for the clearance and inactivation of insulin, but its role in glycemic control in vivo is poorly understood. We present here the first longitudinal characterization, to our knowledge, of glucose regulation in mice with pancellular deletion of the IDE gene (IDE-KO mice). Methodology: IDE-KO mice and wild-type (WT) littermates were characterized at 2, 4, and 6 months of age in terms of body weight, basal glucose and insulin levels, and insulin and glucose tolerance. Consistent with a functional role for IDE in insulin clearance, fasting serum insulin levels in IDE-KO mice were found to be ,3-fold higher than those in wild-type (WT) controls at all ages examined. In agreement with previous observations, 6-mo-old IDE-KO mice exhibited a severe diabetic phenotype characterized by increased body weight and pronounced glucose and insulin intolerance. In marked contrast, 2- mo-old IDE-KO mice exhibited multiple signs of improved glycemic control, including lower fasting glucose levels, lower body mass, and modestly enhanced insulin and glucose tolerance relative to WT controls. Biochemically, the