scholarly journals Insulin Deficiency Alters the Metabolic and Endocrine Responses to Undernutrition in Fetal Sheep Near Term

Endocrinology ◽  
2012 ◽  
Vol 153 (8) ◽  
pp. 4008-4018 ◽  
Author(s):  
Abigail L. Fowden ◽  
Alison J. Forhead
Keyword(s):  
Oxygen Consumption ◽  
Metabolic Response ◽  
Plasma Concentrations ◽  
Late Gestation ◽  
Similar Degree ◽  
Hepatic Glycogen ◽  
Insulin Deficiency ◽  
Fetal Sheep ◽  
Maternal Undernutrition ◽  
Significant Fall

Insulin deficiency affects the adult metabolic response to undernutrition, but its effects on the fetal response to maternal undernutrition remain unknown. This study examined the effects of maternal fasting for 48 h in late gestation on the metabolism of fetal sheep made insulin deficient by pancreatectomy (PX). The endocrine and metabolic responses to maternal fasting differed between intact, sham-operated and PX fetuses, despite a similar degree of hypoglycemia. Compared with intact fetuses, there was no increase in the plasma concentrations of cortisol or norepinephrine in PX fetuses during maternal fasting. In contrast, there was a significant fasting-induced rise in plasma epinephrine concentrations in PX but not intact fetuses. Umbilical glucose uptake decreased to a similar extent in both groups of fasted animals but was associated with a significant fall in glucose carbon oxidation only in intact fetuses. Pancreatectomized but not intact fetuses lowered their oxygen consumption rate by 15–20% during maternal fasting in association with increased uteroplacental oxygen consumption. Distribution of uterine oxygen uptake between the uteroplacental and fetal tissues therefore differed with fasting only in PX fetuses. Both groups of fetuses produced glucose endogenously after maternal fasting for 48 h, which prevented any significant fall in the rate of fetal glucose utilization. In intact but not PX fetuses, fasting-induced glucogenesis was accompanied by a lower hepatic glycogen content. Chronic insulin deficiency in fetal sheep therefore leads to changes in the counterregulatory endocrine response to hypoglycemia and an altered metabolic strategy in dealing with nutrient restriction in utero.

scholarly journals Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia

2015 ◽  
Vol 308 (4) ◽  
pp. E306-E314 ◽  
Author(s):  
Satya S. Houin ◽  
Paul J. Rozance ◽  
Laura D. Brown ◽  
William W. Hay ◽  
Randall B. Wilkening ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Hepatic Glucose Production ◽  
Plasma Concentrations ◽  
Glucose Production ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Hepatic Glucose ◽  
Molar Percent ◽  
Glucose Output

Reduced fetal glucose supply, induced experimentally or as a result of placental insufficiency, produces an early activation of fetal glucose production. The mechanisms and substrates used to fuel this increased glucose production rate remain unknown. We hypothesized that in response to hypoglycemia, induced experimentally with maternal insulin infusion, the fetal liver would increase uptake of lactate and amino acids (AA), which would combine with hormonal signals to support hepatic glucose production. To test this hypothesis, metabolic studies were done in six late gestation fetal sheep to measure hepatic glucose and substrate flux before (basal) and after [days (d)1 and 4] the start of hypoglycemia. Maternal and fetal glucose concentrations decreased by 50% on d1 and d4 ( P < 0.05). The liver transitioned from net glucose uptake (basal, 5.1 ± 1.5 μmol/min) to output by d4 (2.8 ± 1.4 μmol/min; P < 0.05 vs. basal). The [U-13C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 ± 0.01, vs. d4: 0.89 ± 0.01, P < 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 ( P < 0.05) and remained elevated throughout the study. This AA uptake was driven largely by decreased glutamate output and increased glycine uptake. Fetal plasma concentrations of insulin were 50% lower, while cortisol and glucagon concentrations increased 56 and 86% during hypoglycemia ( P < 0.05 for basal vs. d4). Thus increased hepatic AA uptake, rather than pyruvate or lactate uptake, and decreased fetal plasma insulin and increased cortisol and glucagon concentrations occur simultaneously with increased fetal hepatic glucose output in response to fetal hypoglycemia.

Pituitary and gonadal responses to the long-term pulsatile administration of gonadotrophin-releasing hormone in fetal fetal sheep

1997 ◽  
Vol 153 (3) ◽  
pp. 385-391 ◽  
Author(s):  
G B Thomas ◽  
A N Brooks
Keyword(s):  
Plasma Concentrations ◽  
Reproductive Function ◽  
Inverse Correlation ◽  
Experimental Period ◽  
Immediate Release ◽  
Late Gestation ◽  
Plasma Testosterone ◽  
Fetal Sheep ◽  
Pulsatile Administration

Abstract The fetal hypothalamo–pituitary–gonadal axis reaches a peak in activity at mid-gestation and this is followed by a period of suppression which persists until the onset of puberty. The decline in gonadotrophic activity during late gestation is thought to reflect the maturation of central and peripheral feedback signals. In order to establish if sustained pituitary responsiveness is rate limiting to the reinstatement of reproductive function, we have examined the endocrine consequences of repeated pulsatile GnRH administration to male and fetal sheep during late gestation. Beginning on day 121 of gestation (term=145 days) chronically catheterized fetal sheep were given i.v. pulses of either 500 ng GnRH or saline every 2 h for 14 days. Pituitary and gonadal responses were assessed by measuring changes in plasma concentrations of LH, FSH, inhibin and testosterone (in male fetuses) in response to the first pulse of GnRH on day 1 and to the corresponding pulse on days 4, 7, 10 and 14. In response to the first pulse of GnRH there was an immediate release of LH, with the peak response being significantly (P<0·01) greater than on subsequent days. In male fetuses each pulse of LH was followed by a rise in plasma testosterone concentrations within 40–60 min. The amplitude of these testosterone responses increased significantly (P<0·01) after 9 days of treatment despite a decline in the plasma LH response. Basal FSH concentrations increased progressively (P<0·05) during pituitary stimulation with GnRH in both male and female fetuses. Immunoreactive inhibin concentrations were significantly (P<0·05) higher in males than in females, and there was a gradual increase throughout the experimental period irrespective of treatment. We observed no inverse correlation between inhibin and FSH concentrations. These data show that pulsatile administration of GnRH to fetal sheep during late gestation results in sustained re-activation of pituitary–gonadal function. The decline in fetal gonadotrophins, which is a characteristic feature of late gestation, is therefore likely to result from inadequate GnRH secretion from the fetal hypothalamus rather than an inhibition of pituitary function by peripheral feedback signals. Journal of Endocrinology (1997) 153, 385–391

Maternal undernutrition during the first week after conception results in decreased expression of glucocorticoid receptor mRNA in the absence of GR exon 17 hypermethylation in the fetal pituitary in late gestation

2013 ◽  
Vol 4 (5) ◽  
pp. 391-401 ◽  
Author(s):  
S. Zhang ◽  
O. Williams-Wyss ◽  
S. M. MacLaughlin ◽  
S. K. Walker ◽  
D. O. Kleemann ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Mrna Expression ◽  
Hpa Axis ◽  
Early Embryo ◽  
Late Gestation ◽  
Control Group ◽  
Fetal Sheep ◽  
Maternal Undernutrition ◽  
Stress Responsiveness ◽  
Periconceptional Period

Exposure to maternal undernutrition during the periconceptional period results in an earlier prepartum activation of the fetal hypothalamo–pituitary–adrenal (HPA) axis and altered stress responsiveness in the offspring. It is not known whether such changes are a consequence of exposure of the oocyte and/or the early embryo to maternal undernutrition in the periconceptional period. We have compared the effects of ‘periconceptional’ undernutrition (PCUN: maternal undernutrition imposed from at least 45 days before until 6 days after conception), and ‘early preimplantation’ undernutrition (PIUN: maternal undernutrition imposed for only 6 days after conception) on the expression of genes in the fetal anterior pituitary that regulate adrenal growth and steroidogenesis, proopiomelanorcortin (POMC), prohormone convertase 1 (PC1), 11β-hydroxysteroid dehydrogenase type 1 and 2 (11βHSD1 and 2) and the glucocorticoid receptor (GR) in fetal sheep at 136–138 days of gestation. Pituitary GR mRNA expression was significantly lower in the PCUN and PIUN groups in both singletons and twins compared with controls, although this suppression of GR expression was not associated with hypermethylation of the exon 17 region of the GR gene. In twin fetuses, the pituitary 11βHSD1 mRNA expression was significantly higher in the PIUN group compared with the PCUN but not the control group. Thus, exposure of the single or twin embryo to maternal undernutrition for only 1 week after conception is sufficient to cause a suppression of the pituitary GR expression in late gestation. These changes may contribute to the increased stress responsiveness of the HPA axis in the offspring after exposure to poor nutrition during the periconceptional period.

Effect of alteration of maternal plasma progesterone concentrations on fetal behavioural state during late gestation

1997 ◽  
Vol 152 (3) ◽  
pp. 379-386 ◽  
Author(s):  
M B Nicol ◽  
J J Hirst ◽  
D Walker ◽  
G D Thorburn
Keyword(s):  
Plasma Concentrations ◽  
Maternal Plasma ◽  
Late Gestation ◽  
Emg Activity ◽  
Fetal Sheep ◽  
Plasma Progesterone ◽  
Fetal Plasma ◽  
Progesterone Synthesis ◽  
Progesterone Metabolites ◽  
Vascular Catheters

Placental progesterone synthesis exposes the fetus to high levels of progesterone and progesterone metabolites during late gestation which may influence fetal behaviour. To determine the role of maternal progesterone synthesis in the control of fetal arousal state and fetal breathing movements (FBM), the effect of raising and lowering maternal progesterone concentrations was examined in chronically catheterised fetal sheep. Fetal and maternal vascular catheters, fetal tracheal and amniotic fluid catheters as well as electrodes for recording fetal electrocortical (ECoG), electro-ocular (EOG) and nuchal muscle electromyographic (EMG) activity were implanted between 118 and 122 days gestational age (GA). Progesterone, 100 mg, administered twice daily i.m. for 3 days (130–133 days GA) resulted in a marked elevation in maternal plasma progesterone concentrations (370 ± 121%, n=5, P<0·05), but had no effect on fetal plasma concentrations. Fetal EOG episodes and the duration of fetal behavioural arousal were significantly suppressed throughout the progesterone treatment period (74·4–81·1% and 58–65% respectively, P<0·05, n=5). Four ewes received Trilostane (25 mg i.v.), a 3β-hydroxysteroid dehydrogenase inhibitor, between 136 and 140 days GA. Maternal and fetal progesterone concentrations were significantly lowered by 60 min after treatment (19·8 ± 8·0% and 39·5 ± 24·3% respectively, P<0·05). The incidence of fetal EOG activity increased from a pretreatment level of 26·8 ± 1·5 min/h to 30·3 ± 2·8 min/h at 1–6 h and to 35·0 ± 1·7 min/h (P<0·05) during the 7–12 h after Trilostane treatment. The duration of FBM episodes was significantly higher at 1–6 h and 7–12 h after Trilostane treatment (19·5 ± 3·0 and 23·6 ± 5·5 min/h respectively, P<0·05) compared with pretreatment levels (11·2 ± 1·2 min/h). We conclude that increasing maternal progesterone levels suppresses fetal EOG activity and behavioural arousal, whereas reducing maternal progesterone synthesis leads to an elevation of EOG activity and FBM. Journal of Endocrinology (1997) 152, 379–386

Altered endothelium-dependent responses in lambs with pulmonary hypertension and increased pulmonary blood flow

1996 ◽  
Vol 271 (2) ◽  
pp. H562-H570 ◽  
Author(s):  
V. M. Reddy ◽  
J. Wong ◽  
J. R. Liddicoat ◽  
M. Johengen ◽  
R. Chang ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Endothelial Function ◽  
Pulmonary Blood Flow ◽  
Main Pulmonary Artery ◽  
Plasma Concentrations ◽  
Phosphodiesterase Inhibitor ◽  
No Synthase ◽  
Late Gestation ◽  
Fetal Sheep

To investigate early endothelial function associated with increased pulmonary blood flow, vascular shunts were placed between the ascending aorta and main pulmonary artery in 18 late-gestation fetal sheep. Four weeks after delivery, the lambs were instrumented to measure vascular pressures and blood flows, and blood was collected to measure plasma concentrations of guanosine 3',5'-cyclic monophosphate [cGMP, the second messenger to nitric oxide (NO)-mediated vasodilation] and L-arginine (the precursor for NO synthesis). The responses to the endothelium-dependent vasodilators acetylcholine (ACh, 1.0 microgram/kg) and ATP (0.1 mg.kg-1.min-1), the endothelium-independent vasodilators M & B-22948 (a cGMP-specific phosphodiesterase inhibitor, 2.5 mg/kg) and inhaled NO (40 ppm), and N omega-nitro-L-arginine (an inhibitor of NO synthase, 5 mg/kg) were then compared with responses in 12 age-matched controls. Vasodilator responses in control lambs were determined during pulmonary hypertension induced by U-46619 (a thromboxane A2 mimic). Shunted lambs displayed a selective impairment of endothelium-dependent pulmonary vasodilation, an augmented pulmonary vasoconstricting response to NO synthase inhibition, increased plasma cGMP concentrations, and decreased L-arginine concentrations. Taken together, these data suggest that lambs with pulmonary hypertension and increased pulmonary blood flow have early aberrations in endothelial function, as manifested by increased basal NO activity, that cannot be further increased by agonist-induced endothelium-dependent vasodilators.

Sympathoadrenal responses during hypoglycemia, hyperinsulinemia, and hypoxemia in the ovine fetus

1991 ◽  
Vol 261 (1) ◽  
pp. E95-E102 ◽  
Author(s):  
W. R. Cohen ◽  
G. J. Piasecki ◽  
H. E. Cohn ◽  
J. B. Susa ◽  
B. T. Jackson
Keyword(s):  
Insulin Infusion ◽  
Plasma Concentrations ◽  
Sympathetic Nerves ◽  
Significant Rise ◽  
Late Gestation ◽  
Plasma Catecholamine ◽  
Fetal Sheep ◽  
Ovine Fetus ◽  
Per Se ◽  
Adrenal Secretion

Interrelations of sympathoadrenal function and changes in glucose and insulin homeostasis were studied in chronically cannulated late gestation fetal sheep. Catecholamine secretory rates (based on direct adrenal sampling) and plasma concentrations were determined in the fetus during 2 h of insulin-induced hypoglycemia, during a period of hypoxemia, and during hyperinsulinemia per se (i.e., without hypoglycemia). Fetal insulin infusion (5–10 mU.kg-1.min-1) resulted in hypoglycemia and a significant rise in secretion of epinephrine but not of norepinephrine. By contrast, fetal hypoxemia caused a prompt and significant increase in adrenal secretion of both norepinephrine and epinephrine. Changes in peripheral plasma catecholamine levels were usually, but not always, qualitatively similar to those in adrenal secretion; the latter was a far more sensitive indicator of adrenal function. Hyperinsulinemia per se caused no change in adrenal secretory rates or plasma concentrations of catecholamines. Nevertheless, insulin infusion caused a fetal tachycardia even in the absence of hypoglycemia and hypoxemia, suggesting either a direct effect on the heart or stimulation of sympathetic nerves.

scholarly journals Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep

2016 ◽  
Vol 311 (1) ◽  
pp. R200-R208 ◽  
Author(s):  
Christine Culpepper ◽  
Stephanie R. Wesolowski ◽  
Joshua Benjamin ◽  
Jennifer L. Bruce ◽  
Laura D. Brown ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Late Gestation ◽  
Hepatic Glycogen ◽  
Plasma Glucagon ◽  
Low Oxygen ◽  
Fetal Sheep ◽  
Hepatic Glucose ◽  
Arterial Plasma

Hepatic glucose production (HGP) normally begins just prior to birth. Prolonged fetal hypoglycemia, intrauterine growth restriction, and acute hypoxemia produce an early activation of fetal HGP. To test the hypothesis that prolonged hypoxemia increases factors which regulate HGP, studies were performed in fetuses that were bled to anemic conditions (anemic: n = 11) for 8.9 ± 0.4 days and compared with control fetuses ( n = 7). Fetal arterial hematocrit and oxygen content were 32% and 50% lower, respectively, in anemic vs. controls ( P < 0.005). Arterial plasma glucose was 15% higher in the anemic group ( P < 0.05). Hepatic mRNA expression of phosphonenolpyruvate carboxykinase ( PCK1) was twofold higher in the anemic group ( P < 0.05). Arterial plasma glucagon concentrations were 70% higher in anemic fetuses compared with controls ( P < 0.05), and they were positively associated with hepatic PCK1 mRNA expression ( P < 0.05). Arterial plasma cortisol concentrations increased 90% in the anemic fetuses ( P < 0.05), but fetal cortisol concentrations were not correlated with hepatic PCK1 mRNA expression. Hepatic glycogen content was 30% lower in anemic vs. control fetuses ( P < 0.05) and was inversely correlated with fetal arterial plasma glucagon concentrations. In isolated primary fetal sheep hepatocytes, incubation in low oxygen (3%) increased PCK1 mRNA threefold compared with incubation in normal oxygen (21%). Together, these results demonstrate that glucagon and PCK1 may potentiate fetal HGP during chronic fetal anemic hypoxemia.

scholarly journals Adrenal glands are essential for activation of glucogenesis during undernutrition in fetal sheep near term

2011 ◽  
Vol 300 (1) ◽  
pp. E94-E102 ◽  
Author(s):  
A. L. Fowden ◽  
A. J. Forhead
Keyword(s):  
Adrenal Glands ◽  
Metabolic Response ◽  
Glucose Production ◽  
Oxygen Metabolism ◽  
In Utero ◽  
Endogenous Glucose Production ◽  
Hepatic Glycogen ◽  
Fetal Sheep ◽  
Glucose Levels ◽  
Near Term

In adults, the adrenal glands are essential for the metabolic response to stress, but little is known about their role in fetal metabolism. This study examined the effects of adrenalectomizing fetal sheep on glucose and oxygen metabolism in utero in fed conditions and after maternal fasting for 48 h near term. Fetal adrenalectomy (AX) had little effect on the rates of glucose and oxygen metabolism by the fetus or uteroplacental tissues in fed conditions. Endogenous glucose production was negligible in both AX and intact, sham-operated fetuses in fed conditions. Maternal fasting reduced fetal glucose levels and umbilical glucose uptake in both groups of fetuses to a similar extent but activated glucose production only in the intact fetuses. The lack of fasting-induced glucogenesis in AX fetuses was accompanied by falls in fetal glucose ultilization and oxygen consumption not seen in intact controls. The circulating concentrations of cortisol and total catecholamines, and the hepatic glycogen content and activities of key gluconeogenic enzymes, were also less in AX than intact fetuses in fasted animals. Insulin concentrations were also lower in AX than intact fetuses in both nutritional states. Maternal glucose utilization and its distribution between the fetal, uteroplacental, and nonuterine maternal tissues were unaffected by fetal AX in both nutritional states. Ovine fetal adrenal glands, therefore, have little effect on basal rates of fetal glucose and oxygen metabolism but are essential for activating fetal glucogenesis in response to maternal fasting. They may also be involved in regulating insulin sensitivity in utero.

Effect of maternal glucose infusion on brown adipose tissue and liver development in the neonatal lamb

1996 ◽  
Vol 8 (7) ◽  
pp. 1045 ◽  
Author(s):  
L Clarke ◽  
DC Andrews ◽  
MA Lomax ◽  
ME Symonds
Keyword(s):  
Adipose Tissue ◽  
Thyroid Hormones ◽  
Brown Adipose Tissue ◽  
Plasma Concentrations ◽  
Glucose Infusion ◽  
Late Gestation ◽  
Hepatic Glycogen ◽  
Liver Development ◽  
Brown Adipose ◽  
Maternal Glucose

The effect of maternal glucose infusion over the final 5-7 days of gestation in under-fed ewes on perirenal brown adipose tissue (BAT) and liver development in lambs over the first month of neonatal life was examined. During glucose infusion, higher maternal plasma concentrations of glucose and thyroid hormones, and lower plasma concentrations of non-esterified fatty acids and 3-hydroxybutyrate were observed, compared with saline-infused controls. These differences were not observed 1-1.5 h before parturition when plasma concentrations of glucose, lactate, cortisol and thyroid hormones all increased in control ewes. Lamb birthweight and liver and BAT weights were similar between groups, but lambs born to glucose-infused ewes had a higher hepatic glycogen content and greater iodothyronine 5'deiodinase activities in liver and BAT. The norepinephrine, epinephrine and dopamine contents were also greater in BAT sampled from lambs born to glucose infused ewes. Three lambs born to glucose-infused ewes failed to survive beyond the second week of life and exhibited abnormally low plasma triiodothyronine concentrations. It is concluded that maternal glucose infusion stimulates development of the fetal sympathetic nervous system during late gestation but this adaptation does not appear to improve postnatal survival.

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