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OBJECTIVENitric 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.RESEARCH DESIGN AND METHODSWe measured NOx fractional (FSR) and absolute (ASR) synthesis rates in type 2 diabetic patients with diabetic nephropathy and in control subjects, after l-[15N2-guanidino]-arginine infusion, and use of precursor–product relationships. The study was conducted both before and after an euglycemic hyperinsulinemic (∼1,000–1,200 pmol/l) clamp.RESULTSIn 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).CONCLUSIONSIn 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.

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]arginine enrichments in whole blood were performed in the first 3 h in the fasting state and then following a 3-h euglycemic-hyperinsulinemic clamp (with plasma insulin raised to Ϸ1,000 pmol/l). In the last 60 min of each experimental period, at Ϸsteady-state arginine enrichment, a linear increase of 15 NOx enrichment (mean r ϭ 0.9) was detected in both experimental periods. In the fasting state, NOx FSR was 27.4 Ϯ 4.3%/ day, whereas ASR was 0.97 Ϯ 0.36 mmol/day, accounting for 0.69 Ϯ 0.27% of arginine flux. Following hyperinsulinemia, both FSR and ASR of NOx increased (FSR by Ϸ50%, to 42.4 Ϯ 6.7%/day, P Ͻ 0.005; ASR by Ϸ25%, to 1.22 Ϯ 0.41 mmol/day, P ϭ 0.002), despite a Ϸ20 -30% decrease of arginine flux and concentration. The fraction of arginine flux used for NOx synthesis was doubled, to 1.13 Ϯ 0.35% (P Ͻ 0.003). In conclusion, whole body NOx synthesis can be directly measured over a short observation time with stable isotope methods in humans. Insulin acutely stimulates NOx synthesis from arginine. arginine;15 N nitrates; precursor pool; gas chromatography-combustion-isotope ratio mass spectrometry

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