Abstract 17817: Impact of Aldose Reductase on Endothelial Function and Vascular Insulin Resistance in Diet-Induced Obesity
Obesity is a major risk factor for the development of type 2 diabetes and cardiovascular disease. It is associated with the induction of low grade inflammation that leads to insulin resistance and hyperglycemia. Under hyperglycemic conditions, excessive glucose, not utilized by glycolysis, is metabolized by the polyol pathway; however, the role of this pathway in diet-induced obesity has not been studied. To assess the contribution of this pathway of glucose metabolism, we studied high-fat induced obesity in male C57BL/6 mice and mice deficient in aldose reductase (AR), which catalyzes the first step of the polyol pathway. WT and AR-null mice were fed for 4 or 12 weeks with control diet (CD, 10–12 % kcal fat) or high-fat diet (HFD, 60% or 42% kcal fat, respectively). After 12 weeks of HFD (42%), AR-null mice gained significantly more weight (+14.9±0.9 g vs. +20.8±1.1 g; p<0.05) and displayed greater hypercholesterolemia (+133±213 mg/dl vs. +194±17 mg/dl; p<0.05) and hyperinsulinemia (+0.40±0.11 vs. +0.57±0.07 ng/ml; p<0.05) compared with WT mice. HFD feeding for 4 or 12 weeks significant decreased acetylcholine-induced relaxation of aorta ex vivo in AR-null mice by 23% (p<0.05, n=12) or 18%, (P<0.05, n=8), respectively, but not in WT mice. Insulin (100 nM, 15 min) stimulated the phosphorylation of Akt and eNOS by approximately 2-fold in aortas isolated from CD fed WT mice but not in AR-null mice. After 4 weeks on HFD aortas isolated from WT mice displayed decreased insulin sensitivity, as assessed by Akt and eNOS phosphorylation. HFD increased ERK phosphorylation in aortas of WT mice, but not of AR-null mice. In comparison with WT mice, HFD resulted in a significant increase in phosphorylation of IκBα (≈ 2-fold), abundance of IKKε (≈ 1.5-fold) and COX-2 (≈ 3-fold) in the hearts of AR-null mice. Deletion of AR did not affect these inflammatory markers in liver, adipose or skeletal muscle. Collectively, these data suggest that metabolism of excessive glucose via the polyol pathway prevents insulin resistance and endothelial dysfunction during diet-induced obesity.
- © 2010 by American Heart Association, Inc.