In-utero metabolic programming of the offspring

子宫内生长受限（IUGR）与产后营养改变导致性别和年龄- 2型糖尿病（T2 DM）的发生发展阶段的特定代谢异常。T2DM 已经达到了流行病的程度，造成了全球性的危机。在确定机械联系之间 子宫内和产后代谢事件和最终的成人表型，我们已经观察到分子 改变骨骼肌葡萄糖转运限速步骤的变化。这些包括子宫内 胰岛素反应性葡萄糖的表观遗传调节和囊泡易位中的畸变 转运蛋白同种型（GLUT 4）。基于这些初步观察，我们假设：1）子宫内 事件过早地改变骨骼肌GLUT 4的转录和翻译后加工， 为成人胰岛素抵抗和T2 DM的发展奠定了基础，2）这些事件为 妊娠期糖尿病的发展，表观遗传学影响胰岛素的跨代传播 耐药性，3）这些事件也为在治疗前引入某些干预策略提供了基础。 症状的发作，从而预防T2 DM的发作。这些假设将在大鼠中进行测试 目的：1）探讨出生后热量对IUGR的影响 对雄性和雌性SkM的修饰a）参与GLUT 4表达的转录机制，和B） 通过在基础和高胰岛素血症-正常血糖下量化体内葡萄糖利用来评估功能 夹紧条件。2)为了确定a）禁食对IUGR雄性和雌性后代的影响，和B）禁食对IUGR雄性和雌性后代的影响， IUGR女性后代中存在妊娠期糖尿病，并评估对SkM GLUT 4的影响 表达、易位和功能。3)检查由a）5 '-AMP组成的干预的效果 通过运动的激酶活化，和B）IUGR雄性后代中的PPARY激动剂（噻唑烷二酮类 靶向增加SkM GLUT 4表达、易位和功能。 我们提出的调查结果将提供必要的见解， 子宫内代谢异常与T2 DM的关系。此外，这些研究将验证针对以下方面的干预措施： 一些分子事件从而预防疾病。这些见解将被证明是至关重要的， 指导旨在预防T2 DM发作的未来治疗方式的开发。这些 这些努力将有助于控制全球范围内的T2 DM危机，特别是在 在子宫内暴露于营养限制的人群，这在大多数发育中很常见，在某种程度上， 发达国家

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.