METABOLIC AND GENETIC DETERMINANTS OF INSULIN RESISTANCE

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 胰岛素抵抗是一种以对外源性或内源性胰岛素的生物学反应受损为特征的病症，已被认为是代谢综合征（致动脉粥样硬化性血脂异常、高血压、葡萄糖耐受不良、凝血缺陷）和心血管疾病发展的主要因素。 胰岛素抵抗发生的机制还不完全清楚。 我们以前的研究一直致力于确定肥胖、体脂分布和胰岛素抵抗之间的关系。 我们的研究表明，对于任何给定程度或位置的肥胖，胰岛素敏感性存在相当大的差异，这表明内源性（遗传）因素也对胰岛素抵抗有重要作用。 为了更好地评估遗传易感性对肥胖相关胰岛素抵抗变异性的作用，我们现在建议研究来自印度次大陆的个体（亚洲印度人）。 这个种族的心血管疾病和糖尿病的发病率比高加索人高四倍，似乎与过度胰岛素抵抗密切相关。 几项研究表明，亚洲印度人即使没有肥胖，也有过度的胰岛素抵抗，这可能是“遗传倾向”的次要原因。 因此，在亚洲印度人的身体脂肪基因相互作用的评价似乎是一个理想的方法，挑选出的作用，基因在胰岛素抵抗的发病机制，独立于已知的混杂因素，如肥胖，年龄或身体活动不足。 本研究的重点是代谢/生化决定因素[体脂含量和血浆非酯化脂肪酸（NEFA）水平]与遗传易感性（调节胰岛素信号通路近端片段的基因多态性）之间的相互作用，作为胰岛素抵抗发生的机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Insulin resistance, a condition characterized by impaired biological response to either exogenous or endogenous insulin, has been implicated as a major factor in the development of the metabolic syndrome (atherogenic dyslipidemia, hypertension, glucose intolerance, coagulation defects) and cardiovascular disease. The mechanisms involved in the development of insulin resistance are not entirely understood. Our previous studies have been directed towards defining the relations among obesity, body fat distribution and insulin resistance. Our studies revealed that for any given degree or location of obesity, there is considerable variability in insulin sensitivity, suggesting that endogenous (genetic) factors also contribute importantly to insulin resistance. To better evaluate the role of genetic predisposition on the variability of obesity-related insulin resistance, we now propose to study individuals from the Indian Subcontinent (Asian Indians). This ethnic group has a fourfold higher incidence of cardiovascular disease and diabetes than Caucasians, seemingly closely associated with excessive insulin resistance. Several studies have indicated that Asian Indians are excessively insulin resistant even in the absence of obesity, and this is probably secondary to "genetic predisposition". Therefore, the evaluation of body fat-gene interaction in Asian Indians seems to be an ideal approach to single out the role of genes in the pathogenesis of insulin resistance, independently of known confounding factors, such as obesity, age or physical inactivity. The present study focuses on the interaction between metabolic/biochemical determinants [body fat content and plasma levels of non-esterified fatty acids (NEFA) and genetic predisposition (polymorphism of genes regulating the proximal segment of the insulin-signaling pathway) as a mechanism for the development of insulin resistance.