Influence of nutrients on islet development and function

DESCRIPTION (provided by applicant): 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.