Prenatal Oxygen and Glucose Therapy Normalizes Insulin Secretion and Action in Growth-Restricted Fetal Sheep.

Placental insufficiency (PI) lowers fetal oxygen and glucose concentrations, which disrupts glucose-insulin homeostasis and promotes fetal growth restriction (FGR). To date, prenatal treatments for FGR have not attempted to correct the oxygen and glucose supply simultaneously. Therefore, we investigated whether a 5-day correction of oxygen and glucose concentrations in PI-FGR fetuses would normalize insulin secretion and glucose metabolism.

Augmented glucose production is not contingent on high catecholamines in fetal sheep with IUGR.

Fetuses with intrauterine growth restriction (IUGR) have high concentrations of catecholamines, which lowers the insulin secretion and glucose uptake. Here, we studied the effect of hypercatecholaminemia on glucose metabolism in sheep fetuses with placental insufficiency-induced IUGR. Norepinephrine concentrations are elevated throughout late gestation in IUGR fetuses but not in IUGR fetuses with a bilateral adrenal demedullation (IAD) at 0.

Discovery and validation of candidate SNP markers associated to heat stress response in pregnant ewes managed inside a climate-controlled chamber.

Sheep production in desert environments during summer is challenging due to heat stress which reduces feed intake, growth, and fertility. Despite warm conditions, some ewes are able to maintain a normal performance suggesting the existence of genetic bases underlying heat tolerance. Our objective was to discover and validate genetic markers associated with thermo-tolerance in pregnant ewes exposed to warm environmental conditions.

Chronically elevated norepinephrine concentrations lower glucose uptake in fetal sheep.

Fetal conditions associated with placental insufficiency and intrauterine growth restriction (IUGR) chronically elevate plasma norepinephrine (NE) concentrations. Our objective was to evaluate the effects of chronically elevated NE on insulin-stimulated glucose metabolism in normally grown, non-IUGR fetal sheep, which are independent of other IUGR-related reductions in nutrients and oxygen availability. After surgical placement of catheters, near-term fetuses received either a saline (control) or NE intravenous infusion with controlled euglycemia.

Lower oxygen consumption and Complex I activity in mitochondria isolated from skeletal muscle of fetal sheep with intrauterine growth restriction.

Fetal sheep with placental insufficiency-induced intrauterine growth restriction (IUGR) have lower hindlimb oxygen consumption rates (OCRs), indicating depressed mitochondrial oxidative phosphorylation capacity in their skeletal muscle. We hypothesized that OCRs are lower in skeletal muscle mitochondria from IUGR fetuses, due to reduced electron transport chain (ETC) activity and lower abundances of tricarboxylic acid (TCA) cycle enzymes. IUGR sheep fetuses ( = 12) were created with mid-gestation maternal hyperthermia and compared with control fetuses ( = 12).

Postnatal β2 adrenergic treatment improves insulin sensitivity in lambs with IUGR but not persistent defects in pancreatic islets or skeletal muscle.

Key Points: Previous studies in fetuses with intrauterine growth restriction (IUGR) have shown that adrenergic dysregulation was associated with low insulin concentrations and greater insulin sensitivity. Although whole-body glucose clearance is normal, 1-month-old lambs with IUGR at birth have higher rates of hindlimb glucose uptake, which may compensate for myocyte deficiencies in glucose oxidation. Impaired glucose-stimulated insulin secretion in IUGR lambs is due to lower intra-islet insulin availability and not from glucose sensing.

Increased pyruvate dehydrogenase activity in skeletal muscle of growth-restricted ovine fetuses.

Fetal sheep with placental insufficiency-induced intrauterine growth restriction (IUGR) have lower fractional rates of glucose oxidation and greater gluconeogenesis, indicating lactate shuttling between skeletal muscle and liver. Suppression of pyruvate dehydrogenase () activity was proposed because of greater pyruvate dehydrogenase kinase (PDK) 4 and PDK1 mRNA concentrations in IUGR muscle. Although PDK1 and PDK4 inhibit PDH activity to reduce pyruvate metabolism, PDH protein concentrations and activity have not been examined in skeletal muscle from IUGR fetuses.

Oxygen Perfusion (Persufflation) of Human Pancreata Enhances Insulin Secretion and Attenuates Islet Proinflammatory Signaling.

Background: All human islets used in research and for the clinical treatment of diabetes are subject to ischemic damage during pancreas procurement, preservation, and islet isolation. A major factor influencing islet function is exposure of pancreata to cold ischemia during unavoidable windows of preservation by static cold storage (SCS). Improved preservation methods may prevent this functional deterioration.

Impact of thermal stress on placental function and fetal physiology.

In ruminants, prolonged exposure to high ambient temperatures negatively affects placental development and function. The pursuing limitations in placental oxygen and nutrient supply between the mother and fetus slow fetal growth lowering birth weights and postnatal performance. The pregnant ewe is a long-standing animal model for the study of maternal- fetal interactions and is susceptible to naturally occurring heat stress, which causes fetal growth restriction.

Adrenergic receptor stimulation suppresses oxidative metabolism in isolated rat islets and Min6 cells.

Insulin secretion is stimulated by glucose metabolism and inhibited by catecholamines through adrenergic receptor stimulation. We determined whether catecholamines suppress oxidative metabolism in β-cells through adrenergic receptors. In Min6 cells and isolated rat islets, epinephrine decreased oxygen consumption rates compared to vehicle control or co-administration of epinephrine with α2-adrenergic receptor antagonist yohimbine.

Enhanced insulin secretion and insulin sensitivity in young lambs with placental insufficiency-induced intrauterine growth restriction.

Intrauterine growth restriction (IUGR) is associated with persistent metabolic complications, but information is limited for IUGR infants. We determined glucose-stimulated insulin secretion (GSIS) and insulin sensitivity in young lambs with placental insufficiency-induced IUGR. Lambs with hyperthermia-induced IUGR ( = 7) were compared with control lambs ( = 8).

RNA Sequencing Exposes Adaptive and Immune Responses to Intrauterine Growth Restriction in Fetal Sheep Islets.

The risk of type 2 diabetes is increased in children and adults who exhibited fetal growth restriction. Placental insufficiency and intrauterine growth restriction (IUGR) are common obstetrical complications associated with fetal hypoglycemia and hypoxia that reduce the β-cell mass and insulin secretion. In the present study, we have defined the underlying mechanisms of reduced growth and proliferation, impaired metabolism, and defective insulin secretion previously established as complications in islets from IUGR fetuses.

Intrauterine growth-restricted sheep fetuses exhibit smaller hindlimb muscle fibers and lower proportions of insulin-sensitive Type I fibers near term.

Intrauterine growth restriction (IUGR) reduces muscle mass and insulin sensitivity in offspring. Insulin sensitivity varies among muscle fiber types, with Type I fibers being most sensitive. Differences in fiber-type ratios are associated with insulin resistance in adults, and thus we hypothesized that near-term IUGR sheep fetuses exhibit reduced size and proportions of Type I fibers.

Adrenal Demedullation and Oxygen Supplementation Independently Increase Glucose-Stimulated Insulin Concentrations in Fetal Sheep With Intrauterine Growth Restriction.

In pregnancies complicated by placental insufficiency and intrauterine growth restriction (IUGR), fetal glucose and oxygen concentrations are reduced, whereas plasma norepinephrine and epinephrine concentrations are elevated throughout the final third of gestation. Here we study the effects of chronic hypoxemia and hypercatecholaminemia on β-cell function in fetal sheep with placental insufficiency-induced IUGR that is produced by maternal hyperthermia. IUGR and control fetuses underwent a sham (intact) or bilateral adrenal demedullation (AD) surgical procedure at 0.

Effect of melatonin or maternal nutrient restriction on vascularity and cell proliferation in the ovine placenta.

Previously we reported increased umbilical artery blood flow in ewes supplemented with melatonin from mid- to late-pregnancy, while maternal nutrient restriction decreased uterine artery blood flow. To further unravel these responses, this study was designed to assess placental cell proliferation and vascularity following supplementation with melatonin or maternal nutrient restriction. For the first experiment, 31 primiparous ewes were supplemented with 5mg of melatonin per day (MEL) or no melatonin (CON) and allocated to receive 100% (adequate fed; ADQ) or 60% (restricted; RES) of their nutrient requirements from day 50 to 130 of gestation.

Uterine infusion of melatonin or melatonin receptor antagonist alters ovine feto-placental hemodynamics during midgestation.

Dietary melatonin supplementation from mid- to late gestation increases umbilical artery blood flow and causes disproportionate fetal growth. Melatonin receptors have been described throughout the cardiovascular system; however, there is a paucity of data on the function of placental melatonin receptors. The objectives of the current experiment were to determine fetal descending aorta blood flow, umbilical artery blood flow, and placental and fetal development following a 4-wk uterine infusion of melatonin (MEL), melatonin receptor 1 and 2 antagonist (luzindole; LUZ), or vehicle (CON) from Day 62 to Day 90 of gestation.

Neonatal hormone changes and growth in lambs born to dams receiving differing nutritional intakes and selenium supplementation during gestation.

To investigate the effects of maternal selenium (Se) supplementation and nutritional intake during gestation on hormone changes, percentage body weight (BW) change, and organ mass in neonatal lambs, ewes were allocated to differing Se levels (adequate Se (ASe, 11.5 μg/kg BW) or high Se (HSe, 77.0 μg/kg BW)) initiated at breeding and nutritional intake (60% (RES), 100% (CON), or 140% (HIGH) of NRC requirements) initiated at day 40 of gestation.

Melatonin supplementation alters uteroplacental hemodynamics and fetal development in an ovine model of intrauterine growth restriction.

Using a mid- to late-gestation ovine model of intrauterine growth restriction (IUGR), we examined uteroplacental blood flow and fetal growth during melatonin supplementation as a 2 × 2 factorial design. At day 50 of gestation, 32 ewes were supplemented with 5 mg of melatonin (MEL) or no melatonin (CON) and were allocated to receive 100% [adequate; (ADQ)] or 60% [restricted (RES)] of nutrient requirements until day 130 of gestation. Umbilical artery blood flow was increased from day 60 to day 110 of gestation in MEL vs.