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 (IR) provides the 'common soil' for the developement of Type 2 Diabetes Mellitus and Cardiovascular Disease, which are responsible for extensive morbidity and mortality. To develop rational approaches to prevent this, it is imperative to elucidate invironmental and genetic determinants, together with molecular mechanisms causing IR. Epidemiological studies in multiple populations have linked low birth weight (LBW) to the development of IR. The mechanism by which LBV imprints metabolism to adopt an IR phenotype in adult life has not been extensively studied. However, it is known that in adults, IR involves defects in lipid metabolism and glucose metabolism in skeletal muscle. The working hypothesis is that LBW reduces muscle CP2 resulting-in impaired lipid oxidation and accumulation of intramyocellular fat which is then linked to the formation of defects in GLUT4 translocation and IR. The effects of LBW on glucose and lipid metabolism in adult humans wil1 be examined with the measurement of glucose tolerance via OGTT; body composition via DEXA or underwater weighing; blood pressure; DNA; circulating insulin and FFA; muscle and fat composition via biopsies using histological and biochemical methods; intramyocellular lipid quantification using proton NMR spectroscopy; substrate oxidation, fuel partitioning, energy expenditure and spontaneous physical activity via calorimetry and V02 MAX exercise testing; and insulin sensitivty measured via euglycemic hyperinsulinemic infusion study or intravenous glucose tolerance testing.
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