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Acute effect of insulin on nitric oxide synthesis in humans: a precursor-product isotopic study

Department of Clinical and Experimental Medicine, Metabolism Division, University of Padova, Padua, Italy

Submitted 8 September 2006 ; accepted in final form 17 May 2007

Nitric oxide (NO) is a key regulatory molecule with wide vascular, cellular, and metabolic effects. Insulin affects NO synthesis in vitro. No data exist on the acute effect of insulin on NO kinetics in vivo. By employing a precursor-product tracer method in humans, we have directly estimated the acute effect of insulin on intravascular NO_x (i.e., the NO oxidation products) fractional (FSR) and absolute (ASR) synthesis rates in vivo. Nine healthy male volunteers were infused iv with L-[¹⁵N₂-guanidino]arginine ([¹⁵N₂]arginine) for 6 h. Timed measurements of ¹⁵NO_x and [¹⁵N₂]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 1,000 pmol/l). In the last 60 min of each experimental period, at steady-state arginine enrichment, a linear increase of ¹⁵NO_x enrichment (mean r = 0.9) was detected in both experimental periods. In the fasting state, NO_x FSR was 27.4 ± 4.3%/day, whereas ASR was 0.97 ± 0.36 mmol/day, accounting for 0.69 ± 0.27% of arginine flux. Following hyperinsulinemia, both FSR and ASR of NO_x increased (FSR by 50%, to 42.4 ± 6.7%/day, P < 0.005; ASR by 25%, to 1.22 ± 0.41 mmol/day, P = 0.002), despite a 20–30% decrease of arginine flux and concentration. The fraction of arginine flux used for NO_x synthesis was doubled, to 1.13 ± 0.35% (P < 0.003). In conclusion, whole body NO_x synthesis can be directly measured over a short observation time with stable isotope methods in humans. Insulin acutely stimulates NO_x synthesis from arginine.

arginine; ¹⁵N nitrates; precursor pool; gas chromatography-combustion-isotope ratio mass spectrometry