Abstract
Insulin degrading enzyme (IDE) is a potential drug target in the treatment of type 2 diabetes (T2D). IDE controls circulating insulin through a degradation-dependent clearance mechanism in multiple tissues. However, there is not sufficient information about IDE regulation in obesity. In this study, we test obesity-associated factors and pioglitazone in the regulation of IDE in diet-induced obese (DIO) C57BL/6 mice. The enzyme activity and protein level of IDE were increased in the liver of DIO mice. Pioglitazone (10 mg/kg/day) administration for 2 months significantly enhanced the enzyme activity (75%), protein (180%) and mRNA (100%) of IDE in DIO mice. The pioglitazone-induced changes were coupled with 50% reduction in fasting insulin and 20% reduction in fasting blood glucose. The mechanism of IDE regulation in liver was investigated in the mouse hepatoma cell line (Hepa 1c1c7 cells), in which pioglitazone (5 µM) increased IDE protein and mRNA in a time-dependent manner in an 8 h study. Free fatty acid (palmitate 300 µM) induced IDE protein, but reduced the mRNA. Glucagon induced, and TNF-α decreased IDE protein. Insulin did not exhibit any activity in the same condition. In summary, pioglitazone, FFA and glucagon directly increased, but TNF-α decreased the IDE activity in hepatocytes. The results suggest that IDE activity is regulated in liver by multiple factors in obesity and pioglitazone may induce IDE activity in the control of T2D.
Highlights
Hyperinsulinemia is associated with obesity and is a risk factor for insulin resistance
Induction of Hepatic Insulin degrading enzyme (IDE) by high fat diet (HFD) We investigated insulin clearance in diet-induced obese (DIO) model by examining hepatic IDE activity
Our study suggests that pioglitazone has a potential activity in the induction of IDE activity
Summary
Hyperinsulinemia is associated with obesity and is a risk factor for insulin resistance. Circulating insulin is determined by the balance of insulin clearance and secretion. The role of insulin clearance is less investigated in the pathogenesis of hyperinsulinemia relative to insulin secretion in the obese models. Insulin clearance was claimed as a target in the treatment of T2D given the role of hyperinsulinemia in the pathogenesis of insulin resistance [1,2,3]. Insulin resistance occurs after activation of the negative feedback loop of insulin receptor pathway in response to the high level insulin [1]. Induction of IDE activity is expected to prevent the negative feedback by lowering circulating insulin. We investigated IDE activity in response to obesity-associated factors and pioglitazone
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
