Intra-Uterine Growth Restriction (IUGR) with postnatal nutritional modifications leads to sex- and age- specific metabolic aberrations setting the stage for development of type 2 diabetes mellitus (T2DM). T2DM has reached epidemic proportions creating a world-wide crisis. In determining the mechanistic link between intra-uterine and postnatal metabolic events and the ultimate adult phenotype, we have observed molecular changes that alter the skeletal muscle rate limiting step of glucose transport. These consist of intra-uterine aberrations in the epigenetic regulation and vesicular translocation of the insulin responsive glucose transporter isoform (GLUT4). Based on these preliminary observations, we hypothesize that 1) intra-uterine events prematurely alter the transcriptional and post-translational processing of skeletal muscle GLUT4 and set the stage for development of insulin resistance and T2DM in the adult, 2) these events set the stage for development of gestational diabetes that epigenetically influences trans-generational propagation of insulin resistance, and 3) these events also provide the basis for introducing certain interventional strategies prior to the onset of symptoms thereby preventing the onset of T2DM. These hypotheses will be tested in a rat model of IUGR with three specific aims: 1) To investigate the effect of IUGR with postnatal calorie modifications on male and female SkM a) transcriptional machinery involved in GLUT4 expression, and b) function assessed by quantifying glucose utilization in-vivo under basal and hyperinsulinemic-euglycemic clamp conditions. 2) To determine a) the effect of fasting in the IUGR male and female offspring, and b) the presence of gestational diabetes in the IUGR female offspring, and assess the impact on SkM GLUT4 expression, translocation and function. 3) To examine the effect of interventions consisting of a) 5'-AMP kinase activation via exercise, and b) PPARY agonists (thiazolidinediones) in the IUGR male offspring targeted at increasing SkM GLUT4 expression, translocation and function. The results of our proposed investigations will provide necessary insights into mechanisms that connect intra-uterine metabolic aberrations to T2DM. In addition, the studies will validate interventions targeted at some of the molecular events thereby preventing the disease. These insights will prove to be crucial in directing the development of future therapeutic modalities aimed at preventing the onset of T2DM. These efforts will contribute towards controlling the world-wide crisis of T2DM particularly in a subset of the population exposed to nutrient restriction in-utero as is common in most developing and to some extent in developed countries.
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