Abstract 13129: Age-Dependent Insulin Resistance in Aldose Reductase-Null Mice
Obesity is a major risk factor for the development of type 2 diabetes and cardiovascular disease. A hallmark of the cardiometabolic syndrome is visceral adiposity, insulin resistance, hyperinsulinemia, hyperglycemia and cardiovascular inflammation. Under hyperglycemic conditions, excessive glucose not utilized by glycolysis is diverted by aldose reductase (AR) to sorbitol in the polyol pathway. Although AR inhibitors are beneficial in Type I diabetes models against neuropathy, nephropathy, retinopathy and caractogenesis, whether AR is involved in Type II diabetes and insulin resistance is unclear. To assess the contribution of AR, we studied age-dependent (12, 18, and 22 weeks) development of insulin resistance in male C57BL/6 mice and mice deficient in aldose reductase (AR). AR-null mice gained significantly more weight (8-22 weeks, +10.7±0.5 vs. +8.4±0.9 g, p=0.038) than WT mice. Blood glucose levels were significantly elevated in AR-null mice at all age groups compared with WT mice. Aged AR-null mice had increased plasma insulin levels (WT: 0.38±0.01, AR-null 0.50±0.03ng/mL, p=0.007) and were insulin resistant (HOMA-IR: WT: 2.54±0.07, AR-null: 3.48±0.19, p=0.003) compared with WT mice. AR-null mice had an age-dependent decrease in insulin sensitivity as measured by glucose tolerance test (GTT) and insulin tolerance test (ITT). In contrast, aging did not influence insulin sensitivity in WT mice. To test organ specific insulin sensitivity, insulin-dependent signaling (15min, 1.5U/kg in vivo or 100nM ex vivo) was measured by Western blot (phosphorylation of Akt, and endothelial specific eNOS) in aorta, heart, muscle, liver and adipose tissue of 12-, 18-, 22-week old mice. Deletion of AR significantly decreased insulin-dependent phosphorylation of Akt and eNOS in cardiac and skeletal muscle at an age of 18 weeks. Surprisingly, aortic endothelium insulin resistance was detected in 12-week old AR-null mice indicating a potential endothelial origin of age-dependent systemic insulin resistance. In contrast, insulin sensitivity of liver or adipose tissue was not affected by aging. Collectively, these data suggest that AR protects against age-dependent insulin resistance perhaps by metabolism of excess glucose via the polyol pathway.
- © 2011 by American Heart Association, Inc.