Glucose & Lipid Metabolism in Obese Adolescents

描述(由申请人提供)：在过去的30年里，美国超重儿童(BMI和GT；第95个百分位数)(6-19岁)的患病率增加了3倍，2000年达到15%。伴随着儿童超重的增加，儿童(0-19岁)2型糖尿病的发病率增加了4倍(约占新诊断糖尿病的30%)。在非裔美国人和西班牙裔青少年中，肥胖和2型糖尿病占主导地位。儿童和青少年中肥胖症和2型糖尿病的迅速增加是一个重大的公共卫生问题，需要采取有效的治疗和预防战略。在这场战斗中，锻炼是一个潜在的有价值的工具。了解肥胖代谢影响的生理学，以及运动等干预措施对肥胖青少年葡萄糖代谢和胰岛素敏感性的影响，是制定预防胰岛素抵抗和糖代谢受损以及2型糖尿病发展战略的先决条件。在这项提案中，我们将使用最先进的稳定同位素和核磁共振技术来测量肌肉和肝脏的胰岛素敏感性、糖异生和细胞内脂肪含量。我们将研究96名西班牙裔青少年，在肥胖/非肥胖和性别方面进行均衡分布。基因混合将使用一组35个适当的标记来确定西班牙裔人口中欧洲人与土著基因的比例。受试者将在正式的锻炼计划之前和12周的计划之后进行研究。我们将确定1)肥胖相关的胰岛素敏感性降低和糖异生增加是否与肌肉和肝脏细胞内脂肪积累增加有关；2)正式的运动计划将提高胰岛素敏感性，减少糖异生；3)心肌细胞和/或肝内脂肪的变化是运动诱导代谢改善的1种可能机制；4)考虑到肥胖的影响，遗传混合物本身就对胰岛素敏感性和糖异生有影响；5)脂肪衍生蛋白脂联素的血浆浓度是肌肉和肝脏细胞内脂肪的有力标志。因此，通过拟议的研究可以获得的信息将增加我们对导致西班牙裔肥胖青少年胰岛素抵抗和糖代谢紊乱的生理因素的了解，以及运动诱导代谢影响的机制。这一信息可能导致确定预防和/或推迟青少年2型糖尿病发病的因素和潜在的新策略。

DESCRIPTION (provided by applicant): Over the past 30 y the prevalence of overweight children (BMI>95th percentile) (6-19 y) in the USA has increased 3-fold to reach 15% in 2000. Concomitant with the increase in childhood overweight, the incidence of type 2 diabetes in children (0-19 y) has increased 4-fold (to account for ~30% of newly diagnosed diabetes). There is a predominance of both obesity and type 2 diabetes in African American and Hispanic adolescents. The rapid increase in obesity and type 2 diabetes in children and adolescents is a major public health concern necessitating effective strategies for treatment and prevention. Exercise is a potentially valuable tool in this battle. Understanding the physiology of the metabolic effects of obesity and the effects of interventions e.g. exercise on glucose metabolism and insulin sensitivity in obese adolescents is a prerequisite in defining strategies for preventing insulin resistance and impaired glucose metabolism, and the development of type 2 diabetes. In this proposal we will use state of the art stable isotope and MRI techniques to measure insulin sensitivity, gluconeogenesis and intracellular fat content in muscle and liver. We will study 96 adolescents of Hispanic heritage with a balanced distribution with regard to obesity/non-obesity and gender. Genetic admixture will be determined using a panel of 35 markers appropriate to determine the proportion of European vs. Indigenous heritage in a Hispanic population. The subjects will be studied prior to a formalized exercise program and after 12 wks of the program. We will determine whether 1) obesity related decrease in insulin sensitivity and increase in gluconeogenesis are associated with increased intracellular fat accumulation in muscle and liver; 2) a formalized exercise program will improve insulin sensitivity and reduce gluconeogenesis; 3) changes in intramyocellular and/or intrahepatic fat are 1 likely mechanisms for exercise induced metabolic improvements; 4) genetic admixture in itself has an impact on insulin sensitivity and gluconeogenesis when the effects of obesity have been taken into account; 5) plasma concentrations of the fat derived protein adiponectin is a robust marker of intracellular fat in muscle and liver. Thus, the information that can be gained by the proposed studies will increase our understanding of the physiological factors leading to insulin resistance and disturbed glucose metabolism in Hispanic obese adolescents, and the mechanisms for exercise induced metabolic effects. This information is likely to lead to identifying factors and potentially new strategies to prevent and/or delay the onset of type 2 diabetes in adolescents.