Effect of Enhanced Glycemic Control with Saxagliptin on Endothelial Nitric Oxide Release and CD40 Levels in Obese Rats

Abstract

Aim: Endothelial cell (EC) dysfunction contributes to insulin resistance in diabetes and is characterized by reduced nitric oxide (NO) release, increased nitroxidative stress and enhanced inflammation. The purpose of this study was to test the effect of improved postprandial glucose control on EC function in insulin-resistant rats as compared to fasting glucose (FG) changes. Methods: Obese Zucker rats were treated with 10 mg/kg/day saxagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, for 4 or 8 weeks and compared to lean rats. NO and peroxynitrite (ONOO ) release from aortic and glomerular ECs was measured ex vivo using amperometric approaches and correlated with FG, postprandial glucose, insulin, soluble CD40 (sCD40) and L-citrulline levels. Results: Saxagliptin treatment improved NO production and reduced ONOO release prior to any observed changes in FG levels. In untreated obese animals, NO release from aortic and glomerular ECs decreased by 22% and 31%, respectively, while ONOO release increased by 26% and 40%. Saxagliptin increased aortic and glomerular NO release by 18% and 31%, respectively, with comparable reductions in ONOO levels; the NO/ONOO ratio, an indicator of NO synthase coupling, increased by 40%. Improved glycemic control was further associated with a reduction in sCD40 levels by more than ten-fold (from 300 206 to 22 22 pg/mL, p 0.001). Conclusion: These findings indicate that enhanced glycemic control with DPP4 inhibition improved NO release and reduced inflammation in a manner not predicted by FG changes alone. J Atheroscler Thromb, 2011; 18:774-783.

Efficacy of sitagliptin on blood glucose fluctuation in Japanese type 2 diabetic patients with basal-supported oral therapy

“…However, it has been pointed out that the therapy can mainly control fasting glucose levels but cannot necessarily correct blood glucose fluctuation, especially when sulfo-months glycemic control by DPP-4 inhibition improved nitric oxide release and reduced inflammation in rats, accompanying corrected postprandial hyperglycemia [23]. Although endothelial function and atherosclerosis were not evaluated in the current study, it is possible that BOT with DPP-4 inhibitor provides some favorable effect on them in human patients.…”

The Incretin Axis in Cardiovascular Disease

“…6,7,28 Recurring themes reported in the effects of GLP1 and DPPIV inhibitors are changes in nuclear factor-B and nitric oxide production. 29 Regulation of K ATP channels and cAMP levels may also be involved. Manipulating the incretin axis may improve vasoreactivity in both rodents and humans.…”

Asymmetric dimethylarginine, a biomarker of cardiovascular complications in diabetes mellitus

“…Ojima et al [97] showed that GLP-1 receptor agonist would inhibit ADMA development in the kidney of streptozotocin-induced DM rats. In addition, serum concentration of ADMA was sought with the DPP-4 inhibitor saxagliptin in an animal experiment [98] . The discoveries of that study indicate that the DPP-4 inhibitors could impact serum concentrations of ADMA.…”