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PLoS One. 2014 Apr 16;9(4):e95399. doi: 10.1371/journal.pone.0095399. eCollection 2014.

Regulation of insulin degrading enzyme activity by obesity-associated factors and pioglitazone in liver of diet-induced obese mice.

Author information

1
Department of Digestive Disease, Third Affiliated Hospital, Sun Yet-Sen University, Guangzhou, China; Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, United States of America.
2
Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, United States of America.

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.

PMID:
24740421
PMCID:
PMC3989328
DOI:
10.1371/journal.pone.0095399
[Indexed for MEDLINE]
Free PMC Article

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