Therapeutic Adaptation of Insulin Action in Humans

人类胰岛素作用的治疗适应

• 批准号: 6861132
• 负责人: ROBERT H. COKER
• 金额: $ 13.39万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6861132
• 关键词: adipose tissue; caloric dietary content; calorimetry; cardiovascular stress test; clinical research; computed axial tomography; electrocardiography; exercise; glucose metabolism; glucose tolerance; human middle age (35-64); human old age (65+); human subject; human therapy evaluation; insulin sensitivity /resistance; lipid metabolism; northern blottings; polymerase chain reaction; questionnaires; striated muscles; weight loss

DESCRIPTION (provided by applicant): This Mentored Research Scientist Development Award will allow Dr. Coker to extend his work in glucose metabolism performed in animal models into the pathogenesis of insulin resistance in humans. Dr. William J. Evans and Dr. Philip A. Kern will serve as the Co-Mentors for this project. Excessive caloric intake or the lack of physical activity contributes to a positive caloric balance, leading to excess visceral adipose tissue deposition. The pathogenic consequences of visceral obesity usually includes hepatic and skeletal muscle insulin resistance, hyperglycemia, and hyperinsulinemia, and abnormal lipid metabolism eventually leading to type 2 diabetes (T2D). Although caloric restriction and/or exercise training are known to decrease risks associated with T2D, it has been difficult to separate the independent influence of weight loss from exercise training on insulin resistance. We propose to examine the effects of a caloric restriction and/or aerobic exercise training on hepatic and peripheral insulin action using a somatostatin, multi-stage, euglycemic clamp technique in overweight, glucose intolerant men and women. We will recruit 60, 50-80 y old women and men, who will be randomized into one of the following four groups: 1) caloric restriction with weight loss, 2) exercise training without weight loss, 3) exercise training with weight loss, and 4) controls (no dietary or exercise intervention). Dr. Evans has extensive experience in the management of dietary control and exercise training studies. In addition, Dr. Kern will provide specific training in cellular/molecular biology. We will test the hypotheses that 1) caloric restriction will improve hepatic and peripheral insulin action, 2) exercise training without weight loss will only improve peripheral insulin action, 3) exercise training with weight loss will improve hepatic and peripheral insulin action, 4) hepatic insulin action will improve in proportion to the decrease in visceral fat, and that 5) weight loss and exercise training will induce changes in skeletal muscle lipid metabolism through different mechanisms. Since people with impaired glucose tolerance are much more susceptible to the development of T2D, understanding the specific influence of the above mentioned therapeutic regimens on the pathogenesis of insulin resistance has extremely important public health implications. Furthermore, the proposed studies, mentors, co-investigators, and institutional commitment at the University of Arkansas for Medical Sciences provide an outstanding environment for Dr. Coker to develop into an independent basic scientist in diabetes research.

描述（由申请人提供）： 这项指导研究科学家发展奖将使 Coker 博士能够将他在动物模型中进行的葡萄糖代谢工作扩展到人类胰岛素抵抗的发病机制。 William J. Evans 博士和 Philip A. Kern 博士将担任该项目的联合导师。热量摄入过多或缺乏体力活动有助于热量正平衡，导致内脏脂肪组织沉积过多。内脏肥胖的致病后果通常包括肝脏和骨骼肌胰岛素抵抗、高血糖和高胰岛素血症以及最终导致2型糖尿病（T2D）的脂质代谢异常。尽管已知热量限制和/或运动训练可以降低与 T2D 相关的风险，但很难将减肥与运动训练对胰岛素抵抗的独立影响区分开来。我们建议在超重、葡萄糖不耐受的男性和女性中使用生长抑素、多阶段、正常血糖钳夹技术来检查热量限制和/或有氧运动训练对肝脏和外周胰岛素作用的影响。我们将招募 60 岁、50-80 岁的女性和男性，将他们随机分为以下四组之一：1）热量限制减肥组，2）不减肥运动训练，3）减肥运动训练， 4) 对照（无饮食或运动干预）。埃文斯博士在饮食控制和运动训练研究管理方面拥有丰富的经验。此外，克恩博士还将提供细胞/分子生物学方面的具体培训。我们将测试以下假设：1) 热量限制将改善肝脏和外周胰岛素作用，2) 不减肥的运动训练只会改善外周胰岛素作用，3) 减肥运动训练将改善肝脏和外周胰岛素作用，4) 肝脏胰岛素的作用会随着内脏脂肪的减少而成比例地提高，并且5）减肥和运动训练会通过不同的机制引起骨骼肌脂质代谢的变化。由于糖耐量受损的人更容易患上 T2D，因此了解上述治疗方案对胰岛素抵抗发病机制的具体影响具有极其重要的公共卫生意义。此外，阿肯色大学医学科学分校的拟议研究、导师、共同研究人员和机构承诺为 Coker 博士发展成为糖尿病研究领域的独立基础科学家提供了良好的环境。