Metformin and saxagliptin combination treatment reduces nitroxidative stress and restores nitric oxide release in the endothelium of obese rats (ADA 2012) - May 25, 2012 - Presentation time: 6/10/2012 3:00:00 PM; Saxagliptin was found to increase aortic and glomerular endothelial NO release by 20% (299 ± 57 nM to 360 ± 29 nM) and 21% (110 ± 14 nM to 133 ± 24 nM), respectively, while decreasing ONOO- release by 11% and 16%, respectively, as compared to vehicle-treated controls
Preclinical-animal • Diabetes
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American Diabetes Association - 72nd Scientific Sessions June 8 - 12, 2012, Philadelphia, PA
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Abstract Number: 214-OR
Endothelial cell (EC) dysfunction in diabetes is characterized by reduced nitric oxide (NO) and increased peroxynitrite (ONOO-) levels, an imbalance causally related to atherothrombotic disease. In this study, we hypothesized that EC dysfunction in diabetic rats is reversed with combination treatment using a DPP4 inhibitor (saxagliptin) and metformin due to their distinct and beneficial effects on endothelial NO synthase (eNOS) activity. To test this hypothesis, obese Zucker rats were fed a high-fat diet and treated with saxagliptin (10 mg/kg/day), with or without metformin (300 mg/kg/day), for 4 weeks. Aortic and glomerular ECs were then assayed ex vivo for NO and ONOO- release using amperometric nanosensors. Changes in EC function were correlated with fasting glucose levels. Saxagliptin was found to increase aortic and glomerular endothelial NO release by 20% (299 ± 57 nM to 360 ± 29 nM) and 21% (110 ± 14 nM to 133 ± 24 nM), respectively, while decreasing ONOO- release by 11% and 16%, respectively, as compared to vehicle-treated controls. Combination treatment with metformin increased aortic and glomerular NO release by 45% (435 ± 81 nM) and 53% (168 ± 32 nM), respectively, with comparable reductions in ONOO- levels. The NO/ONOO- ratio, an indicator of eNOS coupling, increased more than two-fold with the combination treatment and was significantly greater than that observed with saxagliptin alone. Reversal of EC dysfunction with the combination was observed prior to reductions in elevated fasting glucose levels (156 ± 14 mg/dL). These data indicate that saxagliptin and metformin combination therapy has direct effects on arterial and renal EC function in obese rats, including enhanced NO bioavailability and reduced nitroxidative stress, independent of changes on fasting glucose levels.
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