title: Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance.
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).
  
  
  METHODS
  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 emergence of the diabetic phenotype in IDE-KO mice correlated with age-dependent reductions in insulin receptor (IR) levels in muscle, adipose, and liver tissue. Primary adipocytes harvested from 6-mo-old IDE-KO mice also showed functional impairments in insulin-stimulated glucose uptake.
  
  
  CONCLUSIONS
  Our results indicate that the diabetic phenotype in IDE-KO mice is not a primary consequence of IDE deficiency, but is instead an emergent compensatory response to chronic hyperinsulinemia resulting from complete deletion of IDE in all tissues throughout life. Significantly, our findings provide new evidence to support the idea that partial and/or transient inhibition of IDE may constitute a valid approach to the treatment of diabetes.
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, United States of America.
authors.forename: Samer O
authors.initials: SO
authors.lastname: Abdul-Hay
authors.forename: Dongcheul
authors.initials: D
authors.lastname: Kang
authors.forename: Melinda
authors.initials: M
authors.lastname: McBride
authors.forename: Lilin
authors.initials: L
authors.lastname: Li
authors.forename: Ji
authors.initials: J
authors.lastname: Zhao
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Leissring
mesh_terms: D000375:Aging / Q000097:blood*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications; D017353:Gene Deletion; D006946:Hyperinsulinism / Q000097:blood / Q000150:complications; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance; D007339:Insulysin / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype
chemical_list: D001786:Blood Glucose; D007328:Insulin; D007339:Insulysin