Role of ENPP1 in insulin resistance without obesity

ENPP1 在不肥胖的胰岛素抵抗中的作用

• 批准号: 7104294
• 负责人: Nicola Abate
• 金额: $ 30.66万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104294
• 关键词: SDS polyacrylamide gel electrophoresis; adipose tissue; biomarker; biopsy; clinical research; gene expression; genetic polymorphism; genetic screening; genotype; glucose clamp technique; glucose metabolism; glucose tolerance test; insulin receptor; insulin sensitivity /resistance; pathologic process; phosphodiesterases; protein quantitation /detection; pyrophosphatase; receptor expression; statistics /biometry; striated muscles

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.

描述（由申请人提供）：本研究的目的是评估 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对于美国人口中日益流行的代谢综合征、2 型糖尿病和心血管疾病至关重要。然而，人们认识到，即使没有明显肥胖，某些人群（通常是美国人口中的少数族裔）也存在过度的胰岛素抵抗和相关代谢并发症的风险。这些人更有可能不会被纳入预防糖尿病和心血管疾病的干预计划中。尽管 ENPP1 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这样的可能性：即使在缺乏胰岛素抵抗的情况下，ENPP1 也可能是胰岛素抵抗的决定因素。肥胖。 ENPP1 是一种糖蛋白，位于大多数细胞类型的质膜中，与胰岛素受体相互作用，从而确定当其过度表达时胰岛素信号传导的减少。 K121Q 是一种常见的多态性，与“功能获得”相关，因此 121Q 携带者似乎对胰岛素抵抗具有更高的敏感性。这项研究的总体假设是，即使在没有肥胖的情况下，ENPP1 过度表达和 K121Q 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发挥协同作用。为了检验这一假设，我们建议采取评估非糖尿病和非肥胖者脂肪组织和骨骼肌中 ENPP1 K121Q 多态性和基因/蛋白质表达的方法，这些人将仔细研究脂肪组织胰岛素抵抗和外周胰岛素敏感性。葡萄糖处置。