Changes in fetal mannose and other carbohydrates induced by a maternal insulin infusion in pregnant sheep

BACKGROUND: The importance of non-glucose carbohydrates, especially mannose and inositol, for normal development is increasingly recognized. Whether pregnancies complicated by abnormal glucose transfer to the fetus also affect the regulation of non-glucose carbohydrates is unknown. In pregnant sheep, maternal insulin infusions were used to reduce glucose supply to the fetus for both short (2-wk) and long (8-wk) durations to test the hypothesis that a maternal insulin infusion would suppress fetal mannose and inositol concentrations. We also used direct fetal insulin infusions (1-wk hyperinsulinemic-isoglycemic clamp) to determine the relative importance of fetal glucose and insulin for regulating non-glucose carbohydrates. RESULTS: A maternal insulin infusion resulted in lower maternal (50%, P < 0.01) and fetal (35-45%, P < 0.01) mannose concentrations, which were highly correlated (r(2) = 0.69, P < 0.01). A fetal insulin infusion resulted in a 50% reduction of fetal mannose (P < 0.05). Neither maternal nor fetal plasma inositol changed with exogenous insulin infusions. Additionally, maternal insulin infusion resulted in lower fetal sorbitol and fructose (P < 0.01). CONCLUSIONS: Chronically decreased glucose supply to the fetus as well as fetal hyperinsulinemia both reduce fetal non-glucose carbohydrates. Given the role of these carbohydrates in protein glycosylation and lipid production, more research on their metabolism in pregnancies complicated by abnormal glucose metabolism is clearly warranted

Intrauterine growth restriction increases fetal hepatic gluconeogenic capacity and reduces messenger ribonucleic acid translation initiation and nutrient sensing in fetal liver and skeletal muscle.

Expression of key metabolic genes and proteins involved in mRNA translation, energy sensing, and glucose metabolism in liver and skeletal muscle were investigated in a late-gestation fetal sheep model of placental insufficiency intrauterine growth restriction (PI-IUGR). PI-IUGR fetuses weighed 55% less; had reduced oxygen, glucose, isoleucine, insulin, and IGF-I levels; and had 40% reduction in net branched chain amino acid uptake. In PI-IUGR skeletal muscle, levels of insulin receptor were increased 80%, whereas phosphoinositide-3 kinase (p85) and protein kinase B (AKT2) were reduced by 40%. Expression of eukaryotic initiation factor-4e was reduced 45% in liver, suggesting a unique mechanism limiting translation initiation in PI-IUGR liver. There was either no change (AMP activated kinase, mammalian target of rapamycin) or a paradoxical decrease (protein phosphatase 2A, eukaryotic initiation factor-2 alpha) in activation of major energy and cell stress sensors in PI-IUGR liver and skeletal muscle. A 13- to 20-fold increase in phosphoenolpyruvate carboxykinase and glucose 6 phosphatase mRNA expression in the PI-IUGR liver was-associated with a 3-fold increase in peroxisome proliferator-activated receptor-gamma coactivator-1 alpha mRNA and increased phosphorylation of cAMP response element binding protein. Thus PI-IUGR is-associated with reduced branched chain amino acid uptake and growth factors, yet up-regulation of proximal insulin signaling and a marked increase in the gluconeogenic pathway. Lack of activation of several energy and stress sensors in fetal liver and skeletal muscle, despite hypoxia and low energy status, suggests a novel strategy for survival in the PI-IUGR fetus but with potential maladaptive consequences for reduced nutrient sensing and insulin sensitivity in postnatal life

Chronic late-gestation hypoglycemia upregulates hepatic PEPCK associated with increased PGC1alpha mRNA and phosphorylated CREB in fetal sheep.

Hepatic glucose production is normally activated at birth but has been observed in response to experimental hypoglycemia in fetal sheep. The cellular basis for this process remains unknown. We determined the impact of 2 wk of fetal hypoglycemia during late gestation on enzymes responsible for hepatic gluconeogenesis, focusing on the insulin-signaling pathway, transcription factors, and coactivators that regulate gluconeogenesis. Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase mRNA increased 12-fold and 7-fold, respectively, following chronic hypoglycemia with no change in hepatic glycogen. Chronic hypoglycemia decreased fetal plasma insulin with no change in glucagon but increased plasma cortisol 3.5-fold. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha mRNA and phosphorylation of cAMP response element binding protein at Ser(133) were both increased, with no change in Akt, forkhead transcription factor FoxO1, hepatocyte nuclear factor-4alpha, or CCAAT enhancer binding protein-beta. These results demonstrate that chronic fetal hypoglycemia triggers signals that can activate gluconeogenesis in the fetal liver

Differential Effects of Chronic Pulsatile versus Chronic Constant Maternal Hyperglycemia on Fetal Pancreatic β-Cells

Constant maternal hyperglycemia limits, while pulsatile maternal hyperglycemia may enhance, fetal glucose-stimulated insulin secretion (GSIS) in sheep. However, the impact of such different patterns of hyperglycemia on the development of the fetal β-cell is unknown. We measured the impact of one week of chronic constant hyperglycemia (CHG, n=6) versus pulsatile hyperglycemia (PHG, n=5) versus controls (n=7) on the percentage of the fetal pancreas staining for insulin (β-cell area), mitotic and apoptotic indices and size of fetal β-cells, and fetal insulin secretion in sheep. Baseline insulin concentrations were higher in CHG fetuses (P<0.05) compared to controls and PHG. GSIS was lower in the CHG group (P<0.005) compared to controls and PHG. PHG β-cell area was increased 50% (P<0.05) compared to controls and CHG. CHG β-cell apoptosis was increased over 400% (P<0.05) compared to controls and PHG. These results indicate that late gestation constant maternal hyperglycemia leads to significant β-cell toxicity (increased apoptosis and decreased GSIS). Furthermore, pulsatile maternal hyperglycemia increases pancreatic β-cell area but did not increase GSIS, indicating decreased β-cell responsiveness. These findings demonstrate differential effects that the pattern of maternal hyperglycemia has on fetal pancreatic β-cell development, which might contribute to later life limitation in insulin secretion

Prolonged Prepregnant Maternal High-Fat Feeding Reduces Fetal and Neonatal Blood Glucose Concentrations by Enhancing Fetal β-Cell Development in C57BL/6 Mice.

The main objective of this study was to investigate the effect of maternal obesity on offspring's glucose metabolism during the perinatal period. Maternal obesity was established by feeding C57BL/6 mice with a high-fat (HF) diet before or during pregnancy. Our results showed that prolonged prepregnant HF feeding but not HF feeding during pregnancy significantly reduced fetal and neonatal blood glucose concentrations. Remarkably, elevated blood insulin concentrations and increased activation of insulin signaling were observed in fetuses and neonates from prepregnant HF-fed dams. In addition, significantly larger β-cell areas were observed in pancreases of fetuses and neonates from prepregnant HF-fed dams. Although there was no significant change in placental cross-sectional area or GLUT 1 expression, prepregnant HF feeding significantly enhanced the expression of genes that control placental fatty acid supply. Interestingly, reducing fatty acid supply to the placenta and fetus by placental-specific knockout of adipose triglyceride lipase not only reduced fetal β-cell area and blood insulin concentration but also attenuated prepregnant HF feeding-induced reduction in offspring blood glucose concentrations during the perinatal period. Together, these results indicate that placental and fetal fatty acid supply plays an important role in fetal β-cell development, insulin secretion, and glucose metabolism. Prolonged prepregnant maternal HF feeding resembles pregravid maternal obesity in mice, which reduces fetal and neonatal blood glucose concentrations by enhancing fetal β-cell development and insulin secretion

Prolonged Prepregnant Maternal High-Fat Feeding Reduces Fetal and Neonatal Blood Glucose Concentrations by Enhancing Fetal β-Cell Development in C57BL/6 Mice.

The main objective of this study was to investigate the effect of maternal obesity on offspring's glucose metabolism during the perinatal period. Maternal obesity was established by feeding C57BL/6 mice with a high-fat (HF) diet before or during pregnancy. Our results showed that prolonged prepregnant HF feeding but not HF feeding during pregnancy significantly reduced fetal and neonatal blood glucose concentrations. Remarkably, elevated blood insulin concentrations and increased activation of insulin signaling were observed in fetuses and neonates from prepregnant HF-fed dams. In addition, significantly larger β-cell areas were observed in pancreases of fetuses and neonates from prepregnant HF-fed dams. Although there was no significant change in placental cross-sectional area or GLUT 1 expression, prepregnant HF feeding significantly enhanced the expression of genes that control placental fatty acid supply. Interestingly, reducing fatty acid supply to the placenta and fetus by placental-specific knockout of adipose triglyceride lipase not only reduced fetal β-cell area and blood insulin concentration but also attenuated prepregnant HF feeding-induced reduction in offspring blood glucose concentrations during the perinatal period. Together, these results indicate that placental and fetal fatty acid supply plays an important role in fetal β-cell development, insulin secretion, and glucose metabolism. Prolonged prepregnant maternal HF feeding resembles pregravid maternal obesity in mice, which reduces fetal and neonatal blood glucose concentrations by enhancing fetal β-cell development and insulin secretion