MON-LB031 Higher Insulin Degrading Enzyme Levels in Subjects with Metabolic Syndrome

Abstract

Background: With the growing prevalence of obesity, there is also a rise in the incidence of metabolic syndrome (MS). It is characterizes by hyperinsulinemia, increased fasting glucose, hypertriglyceridemia, low HDL, increased waist circumference and hypertension.Insulin-degrading enzyme (IDE) is the major enzyme responsible for insulin degradation among other proteins linked to glucose metabolism such as glucagon. Using genome wide associated studies, IDE was identified as a diabetes susceptibility gene. Furthermore, inhibition of IDE was suggested as therapeutic target for type 2 diabetes. Objectives: Study the difference in IDE levels between healthy and MetS subjects. Characterize metabolic parameters which correlate with IDE.Explore IDE levels in a mouse model of obesity/ insulin resistance. Methods: We developed highly specific anti IDE antibodies with the ability to detect human IDE levels using ELISA. IDE levels were measured in 45 MS subjects and 30 controls. Results: As expected, MS subjects had higher BMI, glucose, triglycerides and insulin levels, with lower HDL levels. IDE levels were higher in MS subjects (average 692 +/-464 vs 420 +/- 232 pg/microliter; p<0.01). We also found a strong correlation between IDE levels and triglyceride levels (r= 0.305; p<0.05), and negative correlation with HDL levels (r= -0.347; p<0.05). This difference remained significant even after multi-variant analysis.Of interest, IDE levels in MS subjects were clearly segregated into two different subgroups, subjects with "normal IDE", with value distribution and mean (n=25; 278+/-156 pg/ul) which were indistinguishable from the normal control group and subjects with high IDE (n=25; 1272+/-757 pg/ul<0.001 for the difference between normal and high IDE). The high IDE MS group was older and had higher glucose levels than the normal IDE MS group (54 +/- 10 vs 45+/-13 years; p=0.01; and (94+/-20 vs 80+/-8 mg/dl; p=0.01; respectively). Conclusions: IDE is higher in MS subjects and is related to age and fasting glucose. Whether or not this is a compensatory mechanism or contributes to disease progression remains to be explored. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Targeting Insulin-Degrading Enzyme in Insulin Clearance

“…Thus, Fosam and colleagues showed that in African Americans, who are at a higher risk for developing T2DM compared with non-Hispanic whites, lower IDE activity in the liver was associated with reduced insulin clearance and higher plasma insulin levels [ 111 ]. Sofer and colleagues found higher serum IDE levels in subjects with metabolic syndrome compared to control subjects [ 131 ]. Additionally, this group showed a direct correlation between circulating IDE levels and triglycerides, insulin, and C-peptide; whereas HDL-cholesterol was inversely associated [ 131 ].…”

“…Sofer and colleagues found higher serum IDE levels in subjects with metabolic syndrome compared to control subjects [ 131 ]. Additionally, this group showed a direct correlation between circulating IDE levels and triglycerides, insulin, and C-peptide; whereas HDL-cholesterol was inversely associated [ 131 ]. Pivovarova and colleagues, using gene expression profiling by microarrays, showed decreased hepatic Ide expression in subjects with T2DM [ 132 ].…”