Nitric oxide synthesis is reduced in subjects with Type 2 diabetes and nephropathy

AbstractObjective.

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 T2DM, particularly in association with nephropathy. However, whether the decreased NOx excretion in T2DM is caused by a defective NOx production from arginine in response to hyperinsulinemia, has never been studied.

Research design and methods.

We measured NOx fractional (FSR) and absolute (ASR) synthesis rates in T2DM patients with diabetic nephropathy, and in control subjects, following L-[¹⁵N₂-guanidino]-arginine infusion, and use of precursor-product relationships. The study was conducted both before and following an euglycemic, hyperinsulinemic (1000-1200 pmol/L) clamp.

Results.

In T2DM, NOx FSR was reduced both under basal (19.3±3.9%/day, vs. 22.9±4.5%/day in controls) and hyperinsulinemic states (24.0±5.6%/day, vs. 37.9±6.4%/day in controls; p<0.03 by ANOVA). Similarly, in T2DM, NOx ASR was lower than in controls under both conditions (basal: 0.32±0.06 vs. 0.89±0.34 moles/day; hyperinsulinemia: 0.35±0.07 vs. 1.15±0.38 moles/day; p=0.01 by ANOVA). In T2DM, the ability of insulin to stimulate both the FSR (+4.7±3.2%/day) and the ASR (+0.03±0.04 moles/day) of NOx was several-fold lower than that in controls (+15.0±2.9%/day, and +0.25±0.07 moles/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).

Conclusion.

In T2DM 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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