Abstract 165: Saxagliptin Restores Vascular Mitochondrial Exercise Response in Diabetes

Abstract

Exercise decreases cardiovascular disease (CVD) risk and all-cause mortality. We and others have defined that exercise stimulates mitochondrial biogenesis via upstream signaling through endothelial nitric oxide synthase (eNOS), sirtuins (SIRTs), and/or PPARγ co-activator alpha (PGC1-α). Further, this response is absent in diabetes and hypertension. We tested the hypothesis that pharmacological restoration of vascular signaling with the dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin will improve vascular mitochondrial adaptation to exercise through activation of eNOS, SIRTs, and/or PGC1-α. We examined the impact of an 8 day treadmill exercise intervention in the Goto-Kakizaki (GK) rat, a model of lean, type 2 diabetes (T2DM), and Wistar control rats. Four groups were examined: sedentary or exercise groups with or without saxagliptin. Twenty-four hours post-bout, aortas were probed for mitochondrial complexes I-V, as well upstream signaling molecules. In Wistar rats, the expression of mitochondrial complexes III, IV, and V, along with SIRT3 (p<0.05), eNOS, and PCG1-α, increased with exercise. Conversely, in GK animals, exercise led to a decrease of complexes I, III, and IV, a decrease in the expression of COX IV (p<0.05) and AMPK, and no effect on eNOS or SIRT3. In exercised GK rats treated with saxagliptin, the expression of all mitochondrial complexes increased, complex IV significantly (p<0.05). Significant increases (p<0.05) were also observed in cytochrome c, eNOS and nNOS, PGC1-α, and UCP3 protein content in GK rats treated with both exercise and saxagliptin. Body weight and insulin and glucose concentrations were not significantly different in GK animals across experimental groups, indicating that the effects observed are independent of changes in these parameters. In addition, saxagliptin added to a three week exercise intervention improved running time significantly compared to an exercise intervention alone. In summary, our data suggest that saxagliptin restores vascular mitochondrial adaptation to exercise in a rodent model of diabetes. In conclusion, these data are proof of concept of a targetable mitochondrial defect in the diabetic vasculature.