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Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance.

Abdul-Hay SO, Kang D, McBride M, Li L, Zhao J, Leissring MA - PLoS ONE (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, 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 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.

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Constitutive hyperinsulinemia in IDE-KO mice.Insulin levels in serum of 2-, 4- and 6-mo-old wild-type (WT) and IDE-KO (KO) mice following overnight fasting. Data are mean ± SEM of 10–12 mice per group. *P<0.05 determined by 2-tailed Student's t test.
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pone-0020818-g001: Constitutive hyperinsulinemia in IDE-KO mice.Insulin levels in serum of 2-, 4- and 6-mo-old wild-type (WT) and IDE-KO (KO) mice following overnight fasting. Data are mean ± SEM of 10–12 mice per group. *P<0.05 determined by 2-tailed Student's t test.

Mentions: As expected given the known role of IDE in insulin catabolism, and consistent with previous findings [4], fasting serum insulin levels in IDE-KO mice were found to be approximately 3-fold higher than those in WT controls at all ages examined (Fig. 1). By contrast, the effects of IDE deficiency on virtually all other parameters varied in an age-dependent manner. Relative to age-matched controls, basal glucose levels were significantly lower in 2-mo-old IDE-KO mice, unchanged in 4-mo-old animals, and significantly increased in 6-mo-old IDE-KO mice (Fig. 2A). Body mass followed a corresponding trend, with 2-mo-old IDE-KO mice being significantly lighter, and 6-mo-old IDE-KO mice significantly heavier, than age-matched WT controls (Fig. 2B).


Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance.

Abdul-Hay SO, Kang D, McBride M, Li L, Zhao J, Leissring MA - PLoS ONE (2011)

Constitutive hyperinsulinemia in IDE-KO mice.Insulin levels in serum of 2-, 4- and 6-mo-old wild-type (WT) and IDE-KO (KO) mice following overnight fasting. Data are mean ± SEM of 10–12 mice per group. *P<0.05 determined by 2-tailed Student's t test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111440&req=5

pone-0020818-g001: Constitutive hyperinsulinemia in IDE-KO mice.Insulin levels in serum of 2-, 4- and 6-mo-old wild-type (WT) and IDE-KO (KO) mice following overnight fasting. Data are mean ± SEM of 10–12 mice per group. *P<0.05 determined by 2-tailed Student's t test.
Mentions: As expected given the known role of IDE in insulin catabolism, and consistent with previous findings [4], fasting serum insulin levels in IDE-KO mice were found to be approximately 3-fold higher than those in WT controls at all ages examined (Fig. 1). By contrast, the effects of IDE deficiency on virtually all other parameters varied in an age-dependent manner. Relative to age-matched controls, basal glucose levels were significantly lower in 2-mo-old IDE-KO mice, unchanged in 4-mo-old animals, and significantly increased in 6-mo-old IDE-KO mice (Fig. 2A). Body mass followed a corresponding trend, with 2-mo-old IDE-KO mice being significantly lighter, and 6-mo-old IDE-KO mice significantly heavier, than age-matched WT controls (Fig. 2B).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, 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 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.

Show MeSH
Related in: MedlinePlus