Prenatal Hypoxia and Development of Insulin Resistance

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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.