title: Effect of enhanced glycemic control with saxagliptin on endothelial nitric oxide release and CD40 levels in obese rats.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. rpmasaon@elucidaresearch.com
authors.forename: R Preston
authors.initials: RP
authors.lastname: Mason
authors.forename: Robert F
authors.initials: RF
authors.lastname: Jacob
authors.forename: Ruslan
authors.initials: R
authors.lastname: Kubant
authors.forename: Mary F
authors.initials: MF
authors.lastname: Walter
authors.forename: Aouatef
authors.initials: A
authors.lastname: Bellamine
authors.forename: Adam
authors.initials: A
authors.lastname: Jacoby
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Malinski
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001786:Blood Glucose / Q000032:analysis*; D019013:CD40 Antigens / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D002956:Citrulline / Q000097:blood; D004151:Dipeptides / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009765:Obesity / Q000097:blood* / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D019013:CD40 Antigens; D004151:Dipeptides; D007004:Hypoglycemic Agents; D007328:Insulin; D014280:Triglycerides; D002956:Citrulline; D002784:Cholesterol; C502994:saxagliptin; D052250:Nitric Oxide Synthase Type III; D000218:Adamantane