Nitric Oxide Synthesis Is Reduced in Subjects With Type 2 Diabetes and Nephropathy

• Published in: Diabetes (New York, N.Y.) Vol. 59; no. 9; pp. 2152 - 2159
• Main Authors: Tessari, Paolo, Cecchet, Diego, Cosma, Alessandra, Vettore, Monica, Coracina, Anna, Millioni, Renato, Iori, Elisabetta, Puricelli, Lucia, Avogaro, Angelo, Vedovato, Monica
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.09.2010
• Subjects: Aged; Amino Acids - blood; Antidiabetics; Arginine - blood; Biological and medical sciences; Care and treatment; Diabetes; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - metabolism; Diabetes. Impaired glucose tolerance; Diabetic nephropathies; Diabetic Nephropathies - metabolism; Diabetic nephropathy; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glomerular Filtration Rate; Glucose; Health aspects; Humans; Insulin resistance; Kinases; Male; Medical sciences; Metabolism; Middle Aged; Nitrates; Nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide - blood; Nitric Oxide - metabolism; Patients; Physiological aspects; Reference Values; Research design; Type 2 diabetes; Endocrinopathy; Kidney disease; Type 2 diabetes; Human; Urinary system disease; Nephropathy; Nitric oxide; Metabolic diseases; Biosynthesis
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db09-1772

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. 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. 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). 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.