Role of ENPP1 in insulin resistance without obesity

描述(申请人提供)：这项研究的目的是评估ENPP1(也称为PC-1)在非肥胖者胰岛素抵抗发病机制中的作用。肥胖对胰岛素抵抗的影响在代谢综合征、2型糖尿病和心血管疾病在美国人口中日益流行的过程中具有重要意义。然而，人们认识到，人群，通常是美国人口的少数族裔的一部分，有过度的胰岛素抵抗及其相关代谢并发症的风险，即使没有明显的肥胖。这些人更有可能不被纳入预防糖尿病和心血管疾病的干预计划。尽管ENPP1在胰岛素抵抗的发病机制和预测2型糖尿病中的作用仍然存在争议，但从文献中获得的数据和主要研究人员的初步数据都支持这样一种可能性，即即使没有肥胖，ENPP1也可能是胰岛素抵抗的决定因素。ENPP1是一种糖蛋白，位于大多数细胞类型的质膜上，并与胰岛素受体相互作用，以确定其过度表达时胰岛素信号的减少。一种常见的K121Q多态与“功能获得”有关，因此121Q携带者似乎对胰岛素抵抗有更高的易感性。这项研究的总体假设是，即使没有肥胖，ENPP1的过度表达和K121Q基因多态性在确定脂肪组织胰岛素抵抗和系统性胰岛素介导的葡萄糖利用缺陷方面也是协同作用的。为了验证这一假设，我们建议采用评估ENPP1K121Q多态和非糖尿病和非肥胖者脂肪组织和骨骼肌基因/蛋白表达的方法，这些人将被仔细研究脂肪组织的胰岛素抵抗和对外周葡萄糖处理的胰岛素敏感性。

DESCRIPTION (provided by applicant): The objective of this study is to evaluate the role of ENPP1 (also known as PC-1) in the pathogenesis of insulin resistance in non-obese persons. The effects of obesity on insulin resistance are of importance in the growing epidemic of the metabolic syndrome, type 2 diabetes and cardiovascular disease in the US population. However, it is recognized that groups of persons, often part of ethnic minorities of the US population, have excessive insulin resistance and risk for its associated metabolic complications, even without significant obesity. These individuals are more likely not to be captured in intervention programs to prevent diabetes and cardiovascular disease. Although the role of ENPP1 in the pathogenesis of insulin resistance and prediction of type 2 diabetes is still controversial, both data available from the literature and preliminary data by the principal investigator support the possibility that it could be a determinant of insulin resistance even in absence of obesity. ENPP1 is a glycoprotein that is located in the plasma membrane of most cell types and interacts with the insulin receptor so to determine a reduction in insulin signaling when it is over-expressed. A common polymorphism, the K121Q, associates with a "gain of function" so that higher susceptibility to insulin resistance appears to be present in the 121Q carriers. The overall hypothesis of this study is that ENPP1 over-expression and K121Q polymorphism act synergistically in determining adipose tissue insulin resistance and defective systemic insulin-mediated glucose utilization, even in absence of obesity. To test this hypothesis we propose to take the approach of evaluating ENPP1 K121Q polymorphism and gene/protein expression in adipose tissue and skeletal muscle of non-diabetic and non-obese persons who will be carefully studied for adipose tissue insulin resistance and insulin sensitivity to peripheral glucose disposal.