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Xiaochuan Chen, Amy C Kelly, Dustin T Yates, Antoni R Macko, Ronald M Lynch, and Sean W Limesand

Complications in pregnancy elevate fetal norepinephrine (NE) concentrations. Previous studies in NE-infused sheep fetuses revealed that sustained exposure to high NE resulted in lower expression of α2-adrenergic receptors in islets and increased insulin secretion responsiveness after acutely terminating the NE infusion. In this study, we determined if the compensatory increase in insulin secretion after chronic elevation of NE is independent of hyperglycemia in sheep fetuses and whether it is persistent in conjunction with islet desensitization to NE. After an initial assessment of glucose-stimulated insulin secretion (GSIS) at 129 ± 1 days of gestation, fetuses were continuously infused for seven days with NE and maintained at euglycemia with a maternal insulin infusion. Fetal GSIS studies were performed again on days 8 and 12. Adrenergic sensitivity was determined in pancreatic islets collected at day 12. NE infusion increased (P < 0.01) fetal plasma NE concentrations and lowered (P < 0.01) basal insulin concentrations compared to vehicle-infused controls. GSIS was 1.8-fold greater (P < 0.05) in NE-infused fetuses compared to controls at both one and five days after discontinuing the infusion. Glucose-potentiated arginine-induced insulin secretion was also enhanced (P < 0.01) in NE-infused fetuses. Maximum GSIS in islets isolated from NE-infused fetuses was 1.6-fold greater (P < 0.05) than controls, but islet insulin content and intracellular calcium signaling were not different between treatments. The half-maximal inhibitory concentration for NE was 2.6-fold greater (P < 0.05) in NE-infused islets compared to controls. These findings show that chronic NE exposure and not hyperglycemia produce persistent adaptations in pancreatic islets that augment β-cell responsiveness in part through decreased adrenergic sensitivity.

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Alice S Green, Xiaochuan Chen, Antoni R Macko, Miranda J Anderson, Amy C Kelly, Nathaniel J Hart, Ronald M Lynch, and Sean W Limesand

Children from diabetic pregnancies have a greater incidence of type 2 diabetes. Our objective was to determine if exposure to mild–moderate hyperglycemia, by modeling managed diabetic pregnancies, affects fetal β-cell function. In sheep fetuses, β-cell responsiveness was examined after 2 weeks of sustained hyperglycemia with 3 pulses/day, mimicking postprandial excursions, and compared to saline-infused controls (n=10). Two pulsatile hyperglycemia (PHG) treatments were studied: mild (mPHG, n=5) with +15% sustained and +55% pulse; and moderate (PHG, n=10) with +20% sustained and +100% pulse. Fetal glucose-stimulated insulin secretion and glucose-potentiated arginine insulin secretion were lower (P<0.05) in PHG (0.86±0.13 and 2.91±0.39 ng/ml plasma insulin) but not in mPHG fetuses (1.21±0.08 and 4.25±0.56 ng/ml) compared to controls (1.58±0.25 and 4.51±0.56 ng/ml). Islet insulin content was 35% lower in PHG and 35% higher in mPHG vs controls (P<0.01). Insulin secretion and maximally stimulated insulin release were also reduced (P<0.05) in PHG islets due to lower islet insulin content. Isolated PHG islets also had 63% greater (P<0.01) reactive oxygen species (ROS) accumulation at 11.1 mmol/l glucose than controls (P<0.01), but oxidative damage was not detected in islet proteins. PHG fetuses showed evidence of oxidative damage to skeletal muscle proteins (P<0.05) but not insulin resistance. Our findings show that PHG induced dysregulation of islet ROS handling and decreased islet insulin content, but these outcomes are independent. The β-cell outcomes were dependent on the severity of hyperglycemia because mPHG fetuses had no distinguishable impairments in ROS handling or insulin secretion but greater insulin content.

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Melissa A Davis, Leticia E Camacho, Alexander L Pendleton, Andrew T Antolic, Rosa I Luna-Ramirez, Amy C Kelly, Nathan R Steffens, Miranda J Anderson, and Sean W Limesand

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 0.65 of gestation. Euglycemic (EC) and hyperinsulinemic–euglycemic (HEC) clamps were performed in control, intact-IUGR, and IAD fetuses at 0.87 of gestation. Compared to controls, basal oxygen, glucose, and insulin concentrations were lower in IUGR groups. Norepinephrine concentrations were five-fold higher in IUGR fetuses than in IAD fetuses. During the EC, rates of glucose entry (GER, umbilical + exogenous), glucose utilization (GUR), and glucose oxidation (GOR) were greater in IUGR groups than in controls. In IUGR and IAD fetuses with euglycemia and euinsulinemia, glucose production rates (GPR) remained elevated. During the HEC, GER and GOR were not different among groups. In IUGR and IAD fetuses, GURs were 40% greater than in controls, which paralleled the sustained GPR despite hyperinsulinemia. Glucose-stimulated insulin concentrations were augmented in IAD fetuses compared to IUGR fetuses. Fetal weights were not different between IUGR groups but were less than controls. Regardless of norepinephrine concentrations, IUGR fetuses not only develop greater peripheral insulin sensitivity for glucose utilization but also develop hepatic insulin resistance because GPR was maintained and unaffected by euglycemia or hyperinsulinemia. These findings show that adaptation in glucose metabolism of IUGR fetuses are independent of catecholamines, which implicate that hypoxemia and hypoglycemia cause the metabolic responses.