Perinatal Origins of Adult Disease describes the association between the adult disease Syndrome X characterized by insulin resistance, obesity, dyslipidemia, hypertension and coronary artery disease, and intrauterine growth restriction (IUGR). To decipher the mechanism behind this association we examined the skeletal muscle insulin responsive glucose transporter (GLUT 4), that mediates the critical rate-limiting step in the insulin signaling cascade. We used two in-utero extremes of metabolic perturbations (nutrient excess versus restriction) associated with IUGR, along with postnatal nutrient modifications (ad lib restricted access to milk intake) and observed a decline in the adult skeletal muscle GLUT 4 function. This change was mediated by divergent mechanisms, e.g., by suppression of insulin-induced GLUT 4 translocation to the sarcolemma in the case of in-utero nutrient excess and a transcriptional decrease in GLUT 4 expression in the case of in-utero nutrient restriction. Based on the available information and our preliminary results, we hypothesize that aberrations in the in-utero metabolic environment of the IUGR progeny along with postnatal nutritional modifications (ad lib versus restricted access to milk intake) and observed a decline in the adult skeletal muscle GLUT 4 function. This change was mediated by divergent mechanisms, e.g., by suppression of insulin- induced GLUT translocation to the Sarcolemma in the case of in-utero nutrient excess and transcriptional decrease in GLUT 4 expression in the case of in-utero nutrient restriction. Based on the available information and our preliminary results, we hypothesize that aberrations in the in-utero metabolic environment of the IUGR progeny alone with postnatal nutritional modifications regulate mechanisms responsible for aberrant skeletal muscle GLUT4 expression, translocation, and function which cause a maladaptation in the adult that leads to insulin resistance. We will test this hypothesis by the following specific aims in rat models of streptozotocin-induced maternal diabetes with IUGR and prenatal starvation with IUGR. In both cases the offsprings will have ad lib or restricted access to milk intake 1] to determine the mechanisms regulating skeletal muscle GLUT 4 expression, availability, and function in the adult IUGR progeny exposed in-utero to nutrient excess and postnatal nutritional modifications, we will assess: a] total GLUT 4 mRNA and protein concentrations; b] the insulin-induced translocation of GLUT 4 from the intracellular, low-density microsomes to the sarcolemmal compartment; c] the alteration(s) in GLUT 4 DNA-bindability by certain nuclear trans-activating factors; and, d] the insulin translocation of GLUT 4 from LDM to PM, and the basal and insulin-induced cytochalasin B inhibitable 14C- glucose transport at d2, d21, d60 and d180 developmental stages in the progeny of the prenatally starved or control mothers who are allowed either ad lib or restricted postnatal milk intake. The results of these investigations will test our hypothesis and characterize the divergent mechanisms involved that alter the adult IUGR skeletal muscle GLUT4 concentrations/availability and function due to an in-utero metabolic program modified by postnatal nutritional influences. Defining these aberrant mechanisms will provide insights into the etiology of NIDDM. These studies will ultimately server as an impetus for the future development of interventional strategies to implement in childhood to target and prevent adult disease.
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