Exercise Training in Insulin Resistant Non-Diabetics

描述(由申请人提供)：本建议的目的是调查运动训练对有胰岛素抵抗但糖耐量正常的瘦削、非糖尿病患者的影响。胰岛素抵抗是大多数2型糖尿病(T2D)患者的主要特征。然而，人们没有意识到，类似性质和程度的胰岛素抵抗也发生在高达25%的瘦的、非糖尿病的、糖耐量正常的人中。在这组人中，胰岛素抵抗，在没有高血糖的情况下，容易发生：1)T2D；2)代谢综合征X(高血压、血脂异常和冠状动脉疾病)；以及3)癌症。然而，在这些非糖尿病患者中，干预策略还没有开发出来，胰岛素抵抗的生化机制也没有得到广泛的研究。因此，出于两个主要原因，我们建议对这一胰岛素抵抗人群进行研究。首先，因为他们比胰岛素敏感者有更高的临床疾病风险，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，对他们的胰岛素抵抗的分析不会(与通常的T2D患者一样)被肥胖或高血糖导致的代谢异常所混淆。因此，在这些受试者中，我们计划通过胰岛素钳夹检测全身胰岛素敏感性，以及运动训练前后肌肉中胰岛素信号系统的主要成分。要研究的成分包括：胰岛素受体、IRS蛋白、PI3-激酶、PKB/AKT和GLUT 4。此外，我们还将研究该系统的主要调节因子：脂联素、PTP 1B、PC-L、IKK、NF-KB和PKC。接下来，这些抵抗者将接受为期14周的运动训练，以提高胰岛素敏感性。训练结束后，他们将被重新研究，并将结果与两个对照组进行比较：不锻炼、胰岛素抵抗的受试者和胰岛素敏感的受试者。我们相信，这些研究将：1)证明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)加深我们对导致胰岛素抵抗的生化缺陷的理解；3)有可能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.