Prenatal Hypoxia and Development of Insulin Resistance

描述（由申请人提供）：流行病学研究提供了令人信服的证据，证明由胎儿生长受限、早产或两者兼有引起的低出生体重与成人疾病（如冠心病、2型糖尿病、肥胖和中风）之间存在联系。在发育受限的妊娠期，胎儿经常经历低氧血症。我们已经开始研究缺氧对妊娠特定发育阶段的影响，并有初步数据表明，在妊娠第12天至第15天缺氧的30天大的产后大鼠表现出血浆胰岛素升高，血浆葡萄糖正常，肝糖原和糖原合成酶浓度降低。在妊娠15 - 18天和18 - 21天暴露于产前缺氧的产后大鼠，这些特征都没有改变。基于这些研究，我们的总体假设是：发育阶段特异性的产前缺氧是“胎儿编程”的关键调节因子，为胰岛素抵抗、肥胖和最终的2型糖尿病的发生奠定了基础。要验证的具体假设是：从胎儿第12天到第15天的产前缺氧会改变年轻青春期大鼠的产后代谢，从而导致胰岛素抵抗。为了验证这一假设，我们将确定在发育的离散窗口期缺氧是否会诱发出生后第30天的胰岛素抵抗。时间交配的大鼠将在第12-15天、第15-18天或第18-21天暴露于低压缺氧环境中。这些妊娠的后代将与自由喂养对照组的后代、缺氧窗口期间配对喂养的对照组的后代和缺氧窗口期间配对喂养的对照组的后代进行比较。来自低氧怀孕的幼崽，以及来自成对喂养的幼崽，以及持续成对喂养的对照组，将在出生时被培养到额外的自由喂养的坝上。在30日龄时，大鼠将接受静脉葡萄糖或胰岛素耐量试验，或接受正常血糖、高胰岛素钳夹来评估胰岛素抵抗。接受糖耐量或胰岛素抵抗试验的大鼠，在48小时恢复后，将被处死，收集肝脏、骨骼肌和内脏脂肪组织。如果外周胰岛素抵抗被授予，将检查胰岛素受体和GLUT 4 mRNA和蛋白浓度的变化。如果胰岛素抵抗是肝脏特异性的，我们将重点关注肝脏中的胰岛素信号级联（如胰岛素受体、IRS、PIS激酶、蛋白激酶B、糖原合成酶激酶和糖原合成酶）。这些研究将为胎儿缺氧在X综合征发展中可能发挥的作用提供见解。

DESCRIPTION (provided by applicant): Epidemiological studies provide compelling evidence for a link between low birth weight, arising either from fetal growth restriction, preterm birth, or both, and adult diseases such as coronary heart disease, Type 2 diabetes, obesity and stroke. In growth restricted pregancies the fetus often experiences periods of hypoxemia. We have begun examining the effects of hypoxia during specific develomental stages of pregnancy, and have preliminary data suggesting that 30 day old postnatal rats whose dams were hypoxic from day 12 to 15 of pregnancy, exhibit elevated plasma insulin, normal plasma glucose, reduced liver glycogen and glycogen synthase concentrations. These characteristics were not altered in postnatal rats exposed to prenatal hypoxia from either day 15 to 18 or day 18 to 21 of gestation. Based on these studies, our overall hypothesis is: Development stage-specific prenatal hypoxia is a key regulator of "fetal programming" setting the stage for the onset of insulin resistance, obesity and ultimately Type 2 diabetes. The specific hypothesis to be tested is: Prenatal hypoxia from fetal day 12 through 15 will alter postnatal metabolism resulting in insulin resistance in the young adolescent rat. To test this hypothesis we will determine if hypoxia during discrete windows of development induces insulin resistance at postnatal day 30. Time-mated rats will be exposed to hypobaric-hypoxia from day 12-15, day 15-18 or day 18-21. Offspring from these pregnancies will be compared to offspring from ad-lib fed controls, controls pair-fed during the window of hypoxia, and controls pair-fed during the window of hypoxia through parturition. Pups derived from hypoxic pregnancies, as well as those derived from the pair-fed, and continuously pair-fed controls will be fostered onto additional ad-lib fed dams at birth. At 30 days of age, rats will receive intravenous glucose or insulin tolerance tests, or will undergo euglycemic, hyperinsulinemic clamps to assess insulin resistance. Rats undergoing glucose tolerance or insulin resistance tests, following a 48 hr recovery, will be sacraficed for collection of liver, skeletal muscle and visceral adipose tissue. If peripheral insulin resistance is conferred, alterations in insulin receptor and GLUT 4 mRNA and protein concentrations will be examined. If insulin resistance is liver specific, we will focus on the insulin signalling cascade (e.g. insulin receptor, IRS's, PIS kinase, protein kinase B, glycogen synthase kinase and glycogen synthase), in liver. These studies will provide insight in to the role fetal hypoxia alone may play in the development of Syndrome X.