Glucose & Lipid Metabolism in Obese Adolescents

描述（由申请人提供）：在过去的30年中，美国超重儿童（BMI>第95百分位数）（6-19岁）的患病率增加了3倍，2000年达到15%。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（占新诊断糖尿病的约30%）。肥胖和2型糖尿病在非洲裔美国人和西班牙裔青少年中占主导地位。儿童和青少年肥胖和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策略。在这场战斗中，锻炼是一个潜在的有价值的工具。了解肥胖代谢效应的生理学和干预措施（如运动）对肥胖青少年葡萄糖代谢和胰岛素敏感性的影响是确定预防胰岛素抵抗和葡萄糖代谢受损以及2型糖尿病发展策略的先决条件。在这项提议中，我们将使用最先进的稳定同位素和MRI技术来测量肌肉和肝脏中的胰岛素敏感性、胰岛素生成和细胞内脂肪含量。我们将研究96名西班牙裔青少年，这些青少年在肥胖/非肥胖和性别方面分布均衡。将使用一组35个标记物确定遗传混合物，以确定西班牙裔人群中欧洲与土著遗产的比例。受试者将在正式的运动计划之前和计划12周后进行研究。我们将确定1）肥胖相关的胰岛素敏感性降低和脂肪生成增加是否与肌肉和肝脏中细胞内脂肪积累增加有关; 2）正式的运动计划是否会改善胰岛素敏感性并减少脂肪生成; 3）肌细胞内和/或肝内脂肪的变化是否是运动诱导的代谢改善的可能机制; 4）当考虑到肥胖的影响时，遗传混合物本身对胰岛素敏感性和胰岛素生成有影响; 5）脂肪衍生蛋白脂联素的血浆浓度是肌肉和肝脏中细胞内脂肪的可靠标志物。因此，可以通过拟议的研究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以及运动诱导的代谢效应的机制的理解。这些信息可能会导致识别因素和潜在的新策略，以预防和/或延迟青少年2型糖尿病的发病。

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.