Attenuated Insulin Release and Storage in Fetal Sheep Pancreatic Islets with Intrauterine Growth Restriction

Abstract

We determined in vivo and in vitro pancreatic islet insulin secretion and glucose metabolism in fetuses with intrauterine growth restriction (IUGR) caused by chronic placental insufficiency to identify functional deficits in the fetal pancreas that might be caused by nutrient restriction. Plasma insulin concentrations in the IUGR fetuses were 69% lower at baseline and 76% lower after glucose-stimulated insulin secretion (GSIS). Similar deficits were observed with arginine-stimulated insulin secretion. Fetal islets, immunopositive for insulin and glucagon, secreted insulin in response to increasing glucose and KCl concentrations. Insulin release as a fraction of total insulin content was greater in glucose-stimulated IUGR islets, but the mass of insulin released per IUGR islet was lower because of their 82% lower insulin content. A deficiency in islet glucose metabolism was found in the rate of islet glucose oxidation at maximal stimulatory glucose concentrations (11 mmol/liter). Thus, pancreatic islets from nutritionally deprived IUGR fetuses caused by chronic placental insufficiency have impaired insulin secretion caused by reduced glucose-stimulated glucose oxidation rates, insulin biosynthesis, and insulin content. This impaired GSIS occurs despite an increased fractional rate of insulin release that results from a greater proportion of releasable insulin as a result of lower insulin stores. Because this animal model recapitulates the human pathology of chronic placental insufficiency and IUGR, the beta-cell GSIS dysfunction in this model might indicate mechanisms that are developmentally adaptive for fetal survival but in later life might predispose offspring to adult-onset diabetes that has been previously associated with IUGR.

Prolonged infusion of amino acids increases leucine oxidation in fetal sheep

“…Biochemical methods. Blood gas measurements, O 2 content, hematocrit, and insulin, plasma amino acid, glucose, lactate, cortisol, and glucagon concentrations were measured as previously described (25,34,35). IGF-I concentrations were measured by ELISA (ALPCO Immunoassays, Salem, NH; intra-and interassay coefficients of variation ϭ 5-7% and 2-7%, respectively).…”

“…Organ isolation and measurements were performed at the completion of the physiological studies, as previously described (25,34). Biopsies of the fetal biceps femoris muscle were taken under steady-state experimental conditions, snap-frozen in liquid nitrogen, and stored at Ϫ70°C until further analysis.…”

Prenatal undernutrition and postnatal overnutrition alter thyroid hormone axis function in sheep

“…It is therefore important to get deeper insight into the (molecular) biological mechanisms underlying fetal programing in order to develop targeted and efficient intervention strategies to prevent or reverse later adverse health outcomes. The major endocrine systems in focus in research relating to fetal programing have been the hypothalamic-pituitary-adrenal axis function and the glucose-insulin axis including pancreatic endocrine function and the development of insulin resistance (Bloomfield et al 2004, Ozanne et al 2005, Limesand et al 2006. Only a few studies have addressed the implication of fetal malnutrition for hypothalamicpituitary-thyroid function later in life and results have been contradictory as presented in the following.…”

Metabolic Syndrome Development in Relation to Low Birth Weight

“…Research on animals proves that nutrition restriction before birth effect birth weight and metabolism of insulin and glucose in adult or later age (Arantes et al, 2002;Holness, 1996;Hales et al, 1996). There is increased risk of onset of non-insulin dependent diabetes mellitus in humans and decreased secretion of insulin and abnormal glucose metabolism in rats and sheep ( Limesand et al, 2006;Hale and Ozanne, 2003). There is less β-cell mass, decreased pancreatic insulin content and reduced response of insulin to glucose in intrauterine growth retarded young adult's offspring of rats (Simmons, 2008).…”