Intrauterine growth restriction (IUGR) increases the relative risk for perinatal morbidity and mortality, and epidemiological evidence suggests a predisposition for adult onset diseases related to fetal metabolic abnormalities. Perturbations in pancreatic development due to IUGR may lead to an inappropriate beta cell ontogeny resulting in a population of beta cells that are unable to cope with metabolic stress. The long-term goal of this project is to understand mechanisms underlying abnormal pancreatic development and/or function leading to reduced insulin production/secretion in IUGR infants. The specific aims are designed to define critical periods of pancreatic endocrine development and growth and determine the effects on islet function in a sheep model of IUGR resulting from environmentally induced (by moderate hyperthermia) placental insufficiency (PI). The onset of fetal hypoglycemia and hypoaminoacidemia will be determined and pancreatic development and function examined. Metabolic studies will be conducted during gestation in the PI-IUGR fetus using in vivo and in vitro physiological techniques to assess beta cell function. Additionally, morphology of developing pancreas (islets) will be examined to identify changes occurring in cellular composition and to identify specific developmental mechanisms involved in insulin secretion. These studies are crucial for determining how IUGR leads to abnormal pancreatic development and decreased insulin secretion capacity that may potentially contribute to pathology in later life.