Exercise Training in Insulin Resistant Non-Diabetics

描述（由申请人提供）：本提案的目的是研究运动训练对具有胰岛素抵抗但葡萄糖耐量正常的瘦非糖尿病个体的影响。胰岛素抵抗是大多数2型糖尿病（T2D）患者的主要特征。然而，在高达25%的葡萄糖耐量正常的精瘦非糖尿病个体中也存在类似性质和程度的胰岛素抵抗。在这一组中，在没有高血糖的情况下，胰岛素抵抗使他们易患：1)T2D；2)代谢综合征X（高血压、血脂异常、冠状动脉疾病）；3)癌症。然而，在这些非糖尿病患者中，干预策略尚未制定，胰岛素抵抗的生化机制尚未得到广泛研究。有两个主要原因，因此我们建议调查这个胰岛素抵抗组。首先，因为他们比胰岛素敏感的人患临床疾病的风险更高，所以清楚地证明锻炼对他们是一种有益的干预是很重要的。其次，在这一组中，对胰岛素抵抗的分析没有被肥胖或高血糖引起的代谢异常所混淆（如在通常的t2dm患者中）。因此，在这些受试者中，我们计划通过胰岛素钳测量全身胰岛素敏感性，以及运动训练前后肌肉中胰岛素信号系统的主要成分。要研究的成分有：胰岛素受体；国税局蛋白质;π3-kinase;PKB / AKT;和GLUT 4。此外，我们将研究该系统的主要已知调节因子：脂联素；PTP - 1 b;PC-l;IKK;NF-KB;和PKC。接下来，这些抵抗者将接受14周的运动训练，以提高胰岛素敏感性。训练后，他们将被重新研究，并将结果与两个对照组进行比较：未运动的胰岛素抵抗组；以及胰岛素敏感的受试者。我们相信这些研究将：1)记录运动训练对胰岛素抵抗、非糖尿病受试者胰岛素敏感性的有益改善；2)进一步了解胰岛素抵抗背后的生化缺陷；3)有潜力揭示治疗干预的新细胞靶点。

DESCRIPTION (provided by applicant): The purpose of this proposal is to investigate the effects of exercise training in lean, non diabetic individuals who have insulin resistance, but normal glucose tolerance. Insulin resistance is a major feature of most patients with type 2 diabetes mellitus (T2D). It is not appreciated, however, that insulin resistance of a similar nature and magnitude also occurs in up to 25% of lean, non-diabetic individuals with normal glucose tolerance. In this group, insulin resistance, in the absence of hyperglycemia, predisposes them to: 1) T2D; 2) the Metabolic Syndrome X (hypertension, dyslipidemia, and coronary artery disease); and 3) cancer. However, in these non diabetics, intervention strategies have not been developed, and the biochemical mechanisms of insulin resistance have not been extensively studied. For two major reasons therefore we propose to investigate this insulin resistant group. First, because they are at a higher risk for clinical disease than insulin sensitive subjects, it is important to clearly document that exercise is a beneficial intervention for them. Second, in this group, an analysis of their insulin resistance is not confounded (as in the usual T2D patient) by metabolic abnormalities resulting from obesity or hyperglycemia. Therefore, in these subjects, we plan to measure whole body insulin sensitivity by insulin clamp, and the major components of the insulin signaling system in muscle both before and after exercise training. The components to be studied are: the insulin receptor; IRS proteins; PI 3-kinase; PKB/AKT; and GLUT 4. In addition, we will study the major known regulators of the system: adiponectin; PTP 1B; PC-l; IKK; NF-KB; and PKC. Next these resistant individuals will undergo 14 weeks of exercise training to increase insulin sensitivity. After training they will be restudied and the results obtained compared to two control groups: non-exercised, insulin resistant subjects; and insulin sensitive subjects. We believe that these studies will: 1) document the beneficial improvements insulin sensitivity that occur with exercise training in insulin resistant, non diabetic subjects; 2) further our understanding of the biochemical defects that underlie insulin resistance; and 3) have the potential to reveal new cellular targets for therapeutic intervention.