title: Nitric oxide synthesis is reduced in subjects with type 2 diabetes and nephropathy.
abstract: OBJECTIVE
  Nitric oxide (NO) is a key metabolic and vascular regulator. Its production is stimulated by insulin. A reduced urinary excretion of NO products (NOx) is frequently found in type 2 diabetes, particularly in association with nephropathy. However, whether the decreased NOx excretion in type 2 diabetes is caused by a defective NOx production from arginine in response to hyperinsulinemia has never been studied.
  
  
  METHODS
  We measured NOx fractional (FSR) and absolute (ASR) synthesis rates in type 2 diabetic patients with diabetic nephropathy and in control subjects, after l-[(15)N(2)-guanidino]-arginine infusion, and use of precursor-product relationships. The study was conducted both before and after an euglycemic hyperinsulinemic ( approximately 1,000-1,200 pmol/l) clamp.
  
  
  RESULTS
  In type 2 diabetes, NOx FSR was reduced both under basal (19.3 +/- 3.9% per day, vs. 22.9 +/- 4.5% per day in control subjects) and hyperinsulinemic states (24.0 +/- 5.6% per day, vs. 37.9 +/- 6.4% per day in control subjects; P < 0.03 by ANOVA). Similarly, in type 2 diabetes, NOx ASR was lower than in control subjects under both conditions (basal, 0.32 +/- 0.06 vs. 0.89 +/- 0.34 mol per day; hyperinsulinemia, 0.35 +/- 0.07 vs. 1.15 +/- 0.38 mol per day; P = 0.01 by ANOVA). In type 2 diabetes, the ability of insulin to stimulate both the FSR (4.7 +/- 3.2% per day) and the ASR (0.03 +/- 0.04 mol per day) of NOx was several-fold lower than that in control subjects (15.0 +/- 2.9% per day and 0.25 +/- 0.07 mol per day, P < 0.03 and P < 0.02, respectively). Also the fraction of arginine flux converted to NOx (basal, 0.22 +/- 0.05% vs. 0.65 +/- 0.25%; hyperinsulinemia, 0.32 +/- 0.06% vs. 1.03 +/- 0.33%) was sharply reduced in the patients (P < 0.01 by ANOVA).
  
  
  CONCLUSIONS
  In type 2 diabetic patients with nephropathy, intravascular NOx synthesis from arginine is decreased under both basal and hyperinsulinemic states. This defect extends the concept of insulin resistance to NO metabolism.
authors.affiliation: Department of Clinical and Experimental Medicine, Metabolism Division, University of Padova, Italy. paolo.tessari@unipd.it
authors.forename: Paolo
authors.initials: P
authors.lastname: Tessari
authors.forename: Diego
authors.initials: D
authors.lastname: Cecchet
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cosma
authors.forename: Monica
authors.initials: M
authors.lastname: Vettore
authors.forename: Anna
authors.initials: A
authors.lastname: Coracina
authors.forename: Renato
authors.initials: R
authors.lastname: Millioni
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Iori
authors.forename: Lucia
authors.initials: L
authors.lastname: Puricelli
authors.forename: Angelo
authors.initials: A
authors.lastname: Avogaro
authors.forename: Monica
authors.initials: M
authors.lastname: Vedovato
mesh_terms: D000368:Aged; D000596:Amino Acids / Q000097:blood; D001120:Arginine / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis / Q000097:blood* / Q000378:metabolism; D012016:Reference Values
chemical_list: D000596:Amino Acids; D009569:Nitric Oxide; D001120:Arginine