Journal
CANADIAN JOURNAL OF DIABETES
Volume 41, Issue 1, Pages 41-51Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jcjd.2016.06.003
Keywords
11 beta-hydroxysteroid dehydrogenase type 1; glucocorticoid; glucocorticoid receptor; insulin resistance; lipid accumulation; RU486
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Funding
- University Grants Commission, New Delhi [F.7-10/2007 (BSR), F.7-10/2007]
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Objectives: High intake of dietary fructose causes perturbation in lipid metabolism and provokes lipid-induced insulin resistance. A rise in glucocorticoids (GCs) has recently been suggested to be involved in fructose-induced insulin resistance. The objective of the study was to investigate the effect of GC blockade on lipid abnormalities in insulin-resistant mice. Methods: Insulin resistance was induced in mice by administering a high-fructose diet (HFrD) for 60 days. Mifepristone (RU486), a GC antagonist, was administered to HFrD-fed mice for the last 18 days, and the intracellular and extracellular GC levels, the glucocorticoid receptor (GR) activation and the expression of GC-regulated genes involved in lipid metabolism were examined. Results: HFrD elevated the intracellular GC content in both liver and adipose tissue and enhanced the GR nuclear translocation. The plasma GC level remained unchanged. The levels of free fatty acids and tri-glycerides in plasma were elevated, accompanied by increased plasma insulin and glucose levels and decreased hepatic glycogen content. Treatment with RU486 reduced plasma lipid levels, tissue GC levels and the expression of GC-targeted genes involved in lipid accumulation, and it improved insulin sensitivity. Conclusions: This study demonstrated that HFrD-induced lipid accumulation and insulin resistance are mediated by enhanced GC in liver and adipose tissue and that GC antagonism might reduce fructose-induced lipid abnormalities and insulin resistance. (C) 2016 Canadian Diabetes Association.
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