Insulin Control of Fat Regulation and Exercise in Teens

描述(申请人提供)：2型糖尿病(T2 DM)和肥胖在儿科人群中急剧增加，预示着并发症在更年轻的时候发展，并在美国人口中增加发病率和死亡率。这项拟议的研究计划将首次检查与成人T2 DM相关的心肌细胞内脂质(IMCL)沉积或运动能力下降是否已经在儿童T2 DM中发生，这些缺陷的潜在机制和相互关系，以及传统的胰岛素增敏技术如何影响这些缺陷。假设胰岛素抵抗增加的青少年将增加IMCL(可解释为胰岛素选择性地损害PI3-K信号，但ERK信号正常，导致骨骼肌SREBP-1增加，但脂肪SREBP-1减少)，运动能力下降(可解释为内皮功能障碍、舒张性功能障碍和IMCL增加)，并通过改善胰岛素抵抗和IMCL沉积的干预措施最大限度地提高运动能力。为了在体内探索这一假说，我们将解决以下具体目标。1：了解T2 DM对骨骼肌脂类分布和SREBP-1调节的影响，并与正常青少年和肥胖但没有T2 DM的青少年进行比较。2：以正常青少年和肥胖但无T2 DM青少年为对照，测定T2 DM青少年的基线运动能力及其相关性。3：研究三种不同的旨在改善胰岛素敏感性的治疗干预措施对SREBP-1调节和运动功能反应的影响，在青少年T2 DM患者中，有基础科学和临床研究相结合的培训，临床研究证书，在胰岛素信号转导、临床糖尿病研究和运动生理学方面的杰出导师，我处于成功的理想位置。K-23应用程序将帮助我实现成为儿科胰岛素抵抗和2型糖尿病领域的独立研究员的长期目标。

DESCRIPTION (provided by applicant):Type 2 diabetes (T2DM) and obesity are increasing dramatically in pediatric populations, forecasting the development of complications at younger ages, and increased morbidity and mortality in the US population. The proposed research plan will be the first to examine whether the intramyocellular lipid (IMCL) deposition or decreased exercise capacity associated with T2DM in adults already occurs in pediatric T2DM, the underlying mechanism and interrelation of such defects, and how traditional insulin sensitization techniques affect the defects. The hypothesis is that teens with increasing insulin resistance will have increased IMCL (explainable by insulin's selectively impaired PI3-kinase signaling, yet normal Erk signaling, resulting in increased skeletal muscle SREBP-1, yet decreased adipose SREBP-1), decreasing exercise capacity (explainable by endothelial dysfunction, diastolic dysfunction and increased IMCL), and greatest improvement in exercise capacity with interventions that improve both insulin resistance and IMCL deposition. To explore the hypothesis in vivo, we will address the following Specific Aims. 1: Understand the impact of T2DM upon skeletal muscle lipid distribution and SREBP-1 regulation, in comparison to normal adolescents and adolescents with obesity but without T2DM. 2: Determine the baseline exercise capacity and its correlates in adolescents with T2DM in comparison to normal adolescents and adolescents with obesity but without T2DM. 3: Examine the impact of three distinct therapeutic interventions directed at improvement of insulin sensitivity upon responses in SREBP-1 regulation and exercise function, in adolescents with T2DM With the combination of basic science and clinical research training, a clinical research certificate, outstanding mentors in insulin signaling, clinical diabetes research and exercise physiology, I am in an ideal position to be successful. The K-23 application will help me reach my long-term goal of being an independent investigator in the field of pediatric insulin resistance and type 2 diabetes.