Insulin Control of Fat Regulation and Exercise in Teens

青少年脂肪调节和运动的胰岛素控制

• 批准号: 7067575
• 负责人: KRISTEN Jane NADEAU
• 金额: $ 13.13万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7067575
• 关键词: adipose tissue; adolescence (12-20); biological signal transduction; biopsy; clinical research; disease /disorder proneness /risk; echocardiography; enzyme activity; exercise; glucose clamp technique; glucose tolerance test; hormone regulation /control mechanism; human subject; hyperinsulinism; insulin sensitivity /resistance; lipid biosynthesis; mitogen activated protein kinase; muscle function; noninsulin dependent diabetes mellitus; nuclear magnetic resonance spectroscopy; obesity; patient oriented research; phosphatidylinositol 3 kinase; photon absorptiometry; striated muscles; transcription factor

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.

描述（由申请人提供）：2 型糖尿病 (T2DM) 和肥胖症在儿科人群中急剧增加，预示着并发症会在年轻时出现，并导致美国人口的发病率和死亡率增加。拟议的研究计划将首次检查成人 T2DM 相关的肌细胞内脂质 (IMCL) 沉积或运动能力下降是否已经在儿童 T2DM 中发生、此类缺陷的潜在机制和相互关系，以及传统胰岛素增敏技术如何影响缺陷。假设胰岛素抵抗增加的青少年的 IMCL 增加（可以通过胰岛素选择性受损的 PI3 激酶信号传导来解释，但 Erk 信号传导正常，导致骨骼肌 SREBP-1 增加，但脂肪 SREBP-1 减少），运动能力下降。可以通过内皮功能障碍、舒张功能障碍和 IMCL 增加来解释），并且通过改善胰岛素抵抗和 IMCL 沉积的干预措施最大程度地提高运动能力。为了探索体内的假设，我们将实现以下具体目标。图 1：与正常青少年和肥胖但无 T2DM 的青少年相比，了解 T2DM 对骨骼肌脂质分布和 SREBP-1 调节的影响。图 2：确定患有 T2DM 的青少年与正常青少年和肥胖但不患有 T2DM 的青少年相比的基线运动能力及其相关性。 3：检查三种不同的治疗干预措施对 T2DM 青少年的胰岛素敏感性改善对 SREBP-1 调节和运动功能反应的影响。结合基础科学和临床研究培训、临床研究证书、杰出导师胰岛素信号传导、临床糖尿病研究和运动生理学，我处于成功的理想位置。 K-23 申请将帮助我实现成为儿科胰岛素抵抗和 2 型糖尿病领域独立研究者的长期目标。