Role of ENPP1 in insulin resistance without obesity

描述（由申请人提供）：本研究的目的是评价ENPP 1（也称为PC-1）在非肥胖人群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美国人群中代谢综合征、2型糖尿病和心血管疾病的日益流行中具有重要意义。然而，人们认识到，即使没有明显的肥胖，也有一些人群，通常是美国人口中少数民族的一部分，具有过度的胰岛素抵抗及其相关代谢并发症的风险。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ENPP 1在胰岛素抵抗发病机制和2型糖尿病预测中的作用仍存在争议，但文献数据和主要研究者的初步数据都支持其可能是胰岛素抵抗的决定因素，即使在没有肥胖的情况下。ENPP 1是一种糖蛋白，位于大多数细胞类型的质膜中，并与胰岛素受体相互作用，从而在其过表达时确定胰岛素信号传导的减少。一种常见的多态性，K121 Q，与“功能获得”相关，因此121 Q携带者似乎对胰岛素抵抗具有更高的易感性。本研究的总体假设是ENPP 1过表达和K121 Q多态性在确定脂肪组织胰岛素抵抗和有缺陷的全身胰岛素介导的葡萄糖利用方面协同作用，即使在没有肥胖的情况下。为了验证这一假设，我们建议采取的方法，评估ENPP 1 K121 Q多态性和基因/蛋白质表达的脂肪组织和骨骼肌的非糖尿病和非肥胖的人将仔细研究脂肪组织胰岛素抵抗和胰岛素敏感性外周葡萄糖处置。

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.