ARGININE AND INSULIN SENSITIVITY

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 肥胖及其相关的胰岛素抵抗是儿童的重要健康问题。最近的研究已经确定一氧化氮（NO）作为一种介质在胰岛素抵抗的发病机制。精氨酸是NO的单一前体，补充精氨酸可改善动物模型中的胰岛素抵抗和血脂异常，这可能是通过表达过氧化物酶体增殖物激活受体γ（PPAR-gamma）辅激活因子-1 α实现的。本研究旨在确定补充L-精氨酸对肥胖青少年胰岛素抵抗和能量及蛋白质代谢的影响。 假设：对肥胖青少年补充精氨酸将改善这些受试者的胰岛素敏感性、血脂异常和蛋白质周转。 具体目标：通过在基线时和高胰岛素血症正常血糖钳夹（HEC）期间进行7小时持续静脉示踪输注L-[5，5，2 H2]亮氨酸、[13 C]葡萄糖、[2 H5]甘油和[2 H2]棕榈酸酯，评估7天口服补充300 mg/kg/天L-精氨酸对超重和肥胖青少年胰岛素敏感性的影响。 研究基线和补充精氨酸期间肥胖和超重青少年及健康对照者淋巴细胞中PPAR-gamma的表达。 背景和意义： 肥胖及其相关的胰岛素抵抗正在成为儿童的一个重要健康问题。肥胖的主要特征之一是胰岛素抵抗增加，具有较高的心血管风险，包括高血压、糖尿病、高脂血症等。胰岛素抵抗与内皮功能障碍相关，最近的研究已经确定一氧化氮在胰岛素抵抗的发病机制中起重要作用。 一氧化氮（NO）是由L-精氨酸通过NO合酶合成的，几乎在所有细胞类型中。越来越多的证据表明，NO调节哺乳动物的葡萄糖，脂肪酸和氨基酸的代谢。先前的研究表明，抑制NO合成导致大鼠高脂血症和脂肪堆积，而膳食精氨酸补充剂减少糖尿病肥胖大鼠的脂肪量。在动物研究中解释这些发现的机制包括：NO激活过氧化物酶体增殖物激活受体γ的表达;PPAR-gamma共激活因子-1 α，NO增加胰岛素敏感组织的血流量，促进底物摄取。精氨酸补充剂在动物模型中改善了胰岛素抵抗。 本研究旨在评估补充L-精氨酸对肥胖青少年的能量和蛋白质代谢、胰岛素抵抗和单核细胞过氧化物酶体增殖物激活受体-γ表达的影响，在基础条件下，在高胰岛素血症正葡萄糖钳夹（HEC）期间，在他们通常的摄入量和饮食补充精氨酸期间，持续14天。

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.