ARGININE AND INSULIN SENSITIVITY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity and its associated insulin resistance are an important health problem in children. Recent studies have identified Nitric Oxide (NO) as a mediator in the pathogenesis of insulin resistance. Arginine is the single precursor for NO and arginine supplementation has improved insulin resistance and dyslipidemia in animal models, possibly through the expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) coactivator-1alpha. This study seeks to determine the effect of L-arginine supplementation on insulin resistance and energy and protein metabolism in obese adolescents. HYPOTHESIS: Arginine supplementation to obese adolescents will improve insulin sensitivity, dyslipidemia and protein turnover in these subjects. SPECIFIC AIMS: To assess the effect of a 7 day oral supplementation with 300mg/kg/day of L-arginine on insulin sensitivity in overweight and obese adolescents by conducting a 7hour, constant intravenous tracer infusion of L-[5,5,2H2] leucine, [13C] glucose, [2H5] glycerol, and [2H2]palmitate at baseline, and during a Hyperinsulinemic Euglycemic Clamp (HEC). To investigate the expression of PPAR-gamma in lymphocytes of obese and overweight adolescents and healthy controls, at baseline and during arginine supplementation. BACKGROUND AND SIGNIFICANCE: Obesity and its associated insulin resistance are becoming an important health concern in children. Among the main features of obesity is increased insulin resistance with a higher cardiovascular risk including hypertension, diabetes, hyperlipidemia, etc. Insulin resistance is associated with endothelial dysfunction, and recent studies have identified an important role for Nitric oxide in the pathogenesis of insulin resistance. Nitric oxide (NO) is synthesized from L-arginine by NO synthase in virtually all cell types. Emerging evidence shows that NO regulates the metabolism of glucose, fatty acids and amino acids in mammals. Previous studies have shown that an inhibition of NO synthesis causes hyperlipidemia and fat accretion in rats, whereas dietary arginine supplementation reduces fat mass in diabetic fatty rats. Among the mechanisms that explain these findings in animal studies include: NO activates the expression of peroxisome proliferator-activated receptor gamma;PPAR-gamma coactivator-1alpha, NO increases blood flow to insulin-sensitive tissues, promoting substrate uptake. Arginine supplementation has improved insulin resistance in animal models. This study seeks to evaluate the effect of L-arginine supplementation in energy and protein metabolism, insulin resistance and the expression of peroxisome proliferator-activated receptor-gamma in monocytes of obese adolescents, under basal conditions and during a hyperinsulinemic euglycemic clamp (HEC) during their usual intake and during dietary arginine supplementation for 14 days.