In-utero metabolic programming of the offspring

宫内生长受限(IUGR)与出生后营养改变导致性别和年龄- 特异性代谢异常为2型糖尿病(T2 DM)的发展奠定了基础。T2 DM 已经达到流行的程度，造成了一场世界性的危机。在确定两者之间的机械联系时 子宫内和出生后的代谢事件和最终的成人表型，我们观察到了分子 改变骨骼肌葡萄糖转运速率限制步骤的变化。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移位中的异常 转运蛋白亚型(GLUT4)。基于这些初步观察，我们假设1)子宫内 事件过早地改变了骨骼肌GLUT4和GLUT4的转录和翻译后处理 为成人的胰岛素抵抗和2型糖尿病的发展奠定基础，2)这些事件为 妊娠期糖尿病的发生对胰岛素跨代繁殖有表观遗传影响 阻力，以及3)这些事件也为引入某些干预策略提供了基础 出现症状，从而预防T2 DM的发病。这些假设将在一只大鼠身上进行测试 具有三个特定目的的IUGR模型：1)探讨出生后热量对IUGR的影响 男性和女性SKM的修饰a)参与GLUT4表达的转录机制，以及b) 在基础状态和高胰岛素-正常血糖状态下定量体内葡萄糖利用评估功能 夹具条件。2)确定a)禁食对IUGR雄性和雌性后代的影响，以及b) IUGR雌性后代中是否存在妊娠期糖尿病，并评估其对SKM GLUT4的影响 表达、易位和功能。3)检查由a)5‘-AMP组成的干预效果 在IUGR雄性子代中，通过运动和b)PPARy激动剂(噻唑烷二酮)激活的激酶 靶向增加SKM GLUT4的表达、易位和功能。 我们提议的调查结果将为我们提供必要的洞察，以了解 T2 DM的宫内代谢异常。此外，这些研究将验证针对以下目标的干预措施 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 指导未来旨在预防T2 DM发病的治疗方法的发展。这些 努力将有助于控制世界范围的2型糖尿病危机，特别是在 暴露于宫内营养限制的人群在大多数发展中是常见的，在一定程度上 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.