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.
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