Prenatal Hypoxia and Development of Insulin Resistance

产前缺氧和胰岛素抵抗的发展

• 批准号: 6969930
• 负责人: RUSSELL V ANTHONY
• 金额: $ 7.25万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6969930
• 关键词: animal birth weight; congenital disorders; disease /disorder model; disease /disorder onset; disease /disorder proneness /risk; embryo /fetus hypoxia; epidemiology; glucose tolerance test; human subject; insulin receptor; insulin sensitivity /resistance; low birth weight infant human; noninsulin dependent diabetes mellitus; obesity

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.

描述（由申请人提供）：流行病学研究提供了令人信服的证据，证明胎儿生长受限、早产或两者兼而有之的低出生体重与冠心病、2 型糖尿病、肥胖和中风等成人疾病之间存在联系。在生长受限的妊娠中，胎儿经常经历低氧血症时期。我们已经开始研究缺氧对妊娠特定发育阶段的影响，初步数据表明，在妊娠第 12 至 15 天处于缺氧状态的 30 日龄产后大鼠中，血浆胰岛素升高，血浆葡萄糖正常，肝糖原和糖原合酶浓度降低。在妊娠第 15 至 18 天或第 18 至 21 天暴露于产前缺氧的产后大鼠中，这些特征没有改变。基于这些研究，我们的总体假设是：特定发育阶段的产前缺氧是“胎儿编程”的关键调节因素，为胰岛素抵抗、肥胖和最终 2 型糖尿病的发生奠定了基础。要测试的具体假设是：胎儿第 12 天到第 15 天的产前缺氧将改变产后代谢，导致年轻的青少年大鼠出现胰岛素抵抗。为了检验这一假设，我们将确定离散发育窗口期间的缺氧是否会在出生后第 30 天诱导胰岛素抵抗。定时交配的大鼠将从第 12-15 天、第 15-18 天或第 18-21 天暴露于低压缺氧。这些怀孕的后代将与自由喂养对照、缺氧窗口期间配对喂养的对照以及分娩期间缺氧窗口期间配对喂养的对照的后代进行比较。来自缺氧妊娠的幼崽，以及来自配对喂养和持续配对喂养对照的幼崽，将在出生时被培养到额外的自由喂养母鼠上。 30天龄时，大鼠将接受静脉内葡萄糖或胰岛素耐量测试，或者将接受正常血糖、高胰岛素钳夹以评估胰岛素抵抗。接受葡萄糖耐量或胰岛素抵抗测试的大鼠，在恢复48小时后，将被处死以收集肝脏、骨骼肌和内脏脂肪组织。如果存在外周胰岛素抵抗，将检查胰岛素受体和 GLUT 4 mRNA 和蛋白质浓度的变化。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（例如胰岛素受体、IRS、PIS 激酶、蛋白激酶 B、糖原合成酶激酶和糖原合成酶）。这些研究将深入了解胎儿缺氧单独在 X 综合征的发生中可能发挥的作用。