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

Abstract 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 0.65 gestation. As expected, AD-IUGR fetuses had lower norepinephrine concentrations than intact-IUGR fetuses despite being hypoxemic and hypoglycemic. Placental insufficiency reduced fetal weights, but the severity of IUGR was less with AD. Although basal plasma insulin concentrations were lower in intact-IUGR and AD-IUGR fetuses compared with intact-controls, glucose-stimulated insulin concentrations were greater in AD-IUGR fetuses compared with intact-IUGR fetuses. Interestingly, AD-controls had lower glucose- and arginine-stimulated insulin concentrations than intact-controls, but AD-IUGR and AD-control insulin responses were not different. To investigate chronic hypoxemia in the IUGR fetus, arterial oxygen tension was increased to normal levels by increasing the maternal inspired oxygen fraction. Oxygenation of IUGR fetuses enhanced glucose-stimulated insulin concentrations 3.3-fold in intact-IUGR and 1.7-fold in AD-IUGR fetuses but did not lower norepinephrine and epinephrine concentrations. Together these findings show that chronic hypoxemia and hypercatecholaminemia have distinct but complementary roles in the suppression of β-cell responsiveness in IUGR fetuses.

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Chronic exposure to elevated norepinephrine suppresses insulin secretion in fetal sheep with placental insufficiency and intrauterine growth restriction

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00494.2009 ◽

2010 ◽

Vol 298 (4) ◽

pp. E770-E778 ◽

Cited By ~ 53

Author(s):

Rafael A. Leos ◽

Miranda J. Anderson ◽

Xiaochuan Chen ◽

Juliana Pugmire ◽

K. Arbor Anderson ◽

...

Keyword(s):

Insulin Secretion ◽

Intrauterine Growth Restriction ◽

Adrenergic Receptor ◽

Plasma Insulin ◽

Placental Insufficiency ◽

Growth Restriction ◽

Receptor Expression ◽

Plasma Norepinephrine ◽

Fetal Sheep ◽

Intrauterine Growth

In this study, we examined chronic norepinephrine suppression of insulin secretion in sheep fetuses with placental insufficiency-induced intrauterine growth restriction (IUGR). Glucose-stimulated insulin secretion (GSIS) was measured with a square-wave hyperglycemic clamp in the presence or absence of adrenergic receptor antagonists phentolamine (α) and propranolol (β). IUGR fetuses were hypoglycemic and hypoxemic and had lower GSIS responsiveness ( P ≤ 0.05) than control fetuses. IUGR fetuses also had elevated plasma norepinephrine (3,264 ± 614 vs. 570 ± 86 pg/ml; P ≤ 0.05) and epinephrine (164 ± 32 vs. 60 ± 12 pg/ml; P ≤ 0.05) concentrations. In control fetuses, adrenergic inhibition increased baseline plasma insulin concentrations (1.7-fold, P ≤ 0.05), whereas during hyperglycemia insulin was not different. A greater ( P ≤ 0.05) response to adrenergic inhibition was found in IUGR fetuses, and the average plasma insulin concentrations increased 4.9-fold at baseline and 7.1-fold with hyperglycemia. Unlike controls, basal plasma glucose concentrations fell ( P ≤ 0.05) with adrenergic antagonists. GSIS responsiveness, measured by the change in insulin, was higher (8.9-fold, P ≤ 0.05) in IUGR fetuses with adrenergic inhibition than controls (1.8-fold, not significant), showing that norepinephrine suppresses insulin secretion in IUGR fetuses. Strikingly, in IUGR fetuses, adrenergic inhibition resulted in a greater GSIS responsiveness, because β-cell mass was 56% lower and the maximal stimulatory insulin response tended ( P < 0.1) to be higher than controls. This persistent norepinephrine suppression appears to be partially explained by higher mRNA concentrations of adrenergic receptors α1D, α2A, and α2B in a cohort of fetuses that were naïve to the antagonists. Therefore, norepinephrine suppression of insulin secretion was maintained, in part, by upregulating adrenergic receptor expression, but the β-cells also appeared to compensate with enhanced GSIS. These findings may begin to explain why IUGR infants have a propensity for increased glucose requirements if norepinephrine is suddenly decreased after birth.

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Diminished β-cell replication contributes to reduced β-cell mass in fetal sheep with intrauterine growth restriction

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00494.2004 ◽

2005 ◽

Vol 288 (5) ◽

pp. R1297-R1305 ◽

Cited By ~ 90

Author(s):

Sean W. Limesand ◽

Jan Jensen ◽

John C. Hutton ◽

William W. Hay

Keyword(s):

Intrauterine Growth Restriction ◽

Cell Mass ◽

Later Life ◽

Growth Restriction ◽

Pancreatic Β Cell ◽

Cell Replication ◽

Β Cells ◽

Β Cell ◽

Fetal Sheep ◽

Intrauterine Growth

Human fetuses with severe intrauterine growth restriction (IUGR) have less pancreatic endocrine tissue and exhibit β-cell dysfunction, which may limit β-cell function in later life and contribute to their increased incidence of noninsulin-dependent diabetes mellitus. Three factors, replication, apoptosis, and neoformation, contribute to fetal β-cell mass. We studied an ovine model of IUGR to understand whether nutrient deficits lead to decreased rates of fetal pancreatic β-cell replication, increased rates of apoptosis, or lower rates of differentiation. At 90% of term gestation, IUGR fetal and pancreatic weights were 58% and 59% less than pair-fed control, respectively. We identified a selective impairment of β-cell mass compared with other pancreatic cell types in IUGR fetuses. Insulin and insulin mRNA contents were less than other pancreatic endocrine hormones in IUGR fetuses, as were pancreatic insulin positive area (42%) and β-cell mass (76%). Pancreatic β-cell apoptosis was not different between treatments. β-cell capacity for cell cycling, determined by proliferating cell nuclear antigen (PCNA) immunostaining, was not different between treatment groups. However, the percentage of β-cells actually undergoing mitosis was 72% lower in IUGR fetuses. These results indicate that in utero nutrient deficits decrease the population of pancreatic β-cells by lengthening G1, S, and G2 stages of interphase and decreasing mitosis near term. Diminished β-cell mass in IUGR infants at birth, if not adequately compensated for after birth, may contribute to insufficient insulin production in later life and, thus, a predisposition to noninsulin-dependent diabetes.

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Intrauterine Growth Restriction: Cytokine Profiles of Trophoblast Antigen-Stimulated Maternal Lymphocytes

Clinical and Developmental Immunology ◽

10.1155/2012/734865 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 33

Author(s):

Raj Raghupathy ◽

Majedah Al-Azemi ◽

Fawaz Azizieh

Keyword(s):

Inflammatory Cytokines ◽

Peripheral Blood ◽

Intrauterine Growth Restriction ◽

Mononuclear Cells ◽

Normal Pregnancy ◽

Placental Insufficiency ◽

Growth Restriction ◽

Intrauterine Growth ◽

Anti Inflammatory ◽

Ifnγ And Tnfα

Intrauterine growth restriction (IUGR) is an important perinatal syndrome that poses several serious short- and long-term effects. We studied cytokine production by maternal peripheral blood lymphocytes stimulated by trophoblast antigens. 36 women with a diagnosis of IUGR and 22 healthy women with normal fetal growth were inducted. Peripheral blood mononuclear cells were stimulated with trophoblast antigens and levels of the proinflammatory cytokines IL-6, IL-8, IL-12, IL-23, IFNγ, and TNFα and the anti-inflammatory cytokines IL-4, IL-10, and IL-13 were measured in culture supernatants by ELISA. IL-8 was produced at higher levels by blood cells of the IUGR group than normal pregnant women, while IL-13 was produced at lower levels. IL-8, IFNγ, and TNFα were higher in IUGR with placental insufficiency than in normal pregnancy. IL-12 levels were higher and IL-10 levels were lower in IUGR with placental insufficiency than in IUGR without placental insufficiency. We suggest that a stronger pro-inflammatory bias exists in IUGR as compared to normal pregnancy and in IUGR with placental insufficiency when compared to IUGR without placental insufficiency. Several ratios of proinflammatory to anti-inflammatory cytokines also support the existence of an inflammatory bias in IUGR.

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Consequences in Infants That Were Intrauterine Growth Restricted

Journal of Pregnancy ◽

10.1155/2011/364381 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 44

Author(s):

Erich Cosmi ◽

Tiziana Fanelli ◽

Silvia Visentin ◽

Daniele Trevisanuto ◽

Vincenzo Zanardo

Keyword(s):

Intrauterine Growth Restriction ◽

Placental Insufficiency ◽

Growth Restriction ◽

Growth Potential ◽

Intrauterine Growth ◽

Cardiovascular Abnormalities ◽

Short And Long Term

Intrauterine growth restriction is a condition fetus does not reach its growth potential and associated with perinatal mobility and mortality. Intrauterine growth restriction is caused by placental insufficiency, which determines cardiovascular abnormalities in the fetus. This condition, moreover, should prompt intensive antenatal surveillance of the fetus as well as follow-up of infants that had intrauterine growth restriction as short and long-term sequele should be considered.

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Intrauterine growth restriction decreases NF-κB signaling in fetal pulmonary artery endothelial cells of fetal sheep

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00052.2018 ◽

2018 ◽

Vol 315 (3) ◽

pp. L348-L359 ◽

Cited By ~ 6

Author(s):

R. Blair Dodson ◽

Kyle N. Powers ◽

Jason Gien ◽

Paul J. Rozance ◽

Gregory Seedorf ◽

...

Keyword(s):

Pulmonary Artery ◽

Intrauterine Growth Restriction ◽

Lung Diseases ◽

Growth Restriction ◽

Mouse Lung ◽

Similar Degree ◽

Fetal Sheep ◽

Vascular Growth ◽

Intrauterine Growth ◽

Pulmonary Artery Endothelial Cell

Intrauterine growth restriction (IUGR) in premature newborns increases the risk for bronchopulmonary dysplasia, a chronic lung disease characterized by disrupted pulmonary angiogenesis and alveolarization. We previously showed that experimental IUGR impairs angiogenesis; however, mechanisms that impair pulmonary artery endothelial cell (PAEC) function are uncertain. The NF-κB pathway promotes vascular growth in the developing mouse lung, and we hypothesized that IUGR disrupts NF-κB-regulated proangiogenic targets in fetal PAEC. PAECs were isolated from the lungs of control fetal sheep and sheep with experimental IUGR from an established model of chronic placental insufficiency. Microarray analysis identified suppression of NF-κB signaling and significant alterations in extracellular matrix (ECM) pathways in IUGR PAEC, including decreases in collagen 4α1 and laminin α4, components of the basement membrane and putative NF-κB targets. In comparison with controls, immunostaining of active NF-κB complexes, NF-κB-DNA binding, baseline expression of NF-κB subunits p65 and p50, and LPS-mediated inducible activation of NF-κB signaling were decreased in IUGR PAEC. Although pharmacological NF-κB inhibition did not affect angiogenic function in IUGR PAEC, angiogenic function of control PAEC was reduced to a similar degree as that observed in IUGR PAEC. These data identify reductions in endothelial NF-κB signaling as central to the disrupted angiogenesis observed in IUGR, likely by impairing both intrinsic PAEC angiogenic function and NF-κB-mediated regulation of ECM components necessary for vascular development. These data further suggest that strategies that preserve endothelial NF-κB activation may be useful in lung diseases marked by disrupted angiogenesis such as IUGR.

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Catecholamines Mediate Multiple Fetal Adaptations during Placental Insufficiency That Contribute to Intrauterine Growth Restriction: Lessons from Hyperthermic Sheep

Journal of Pregnancy ◽

10.1155/2011/740408 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 28

Author(s):

D. T. Yates ◽

A. S. Green ◽

S. W. Limesand

Keyword(s):

Intrauterine Growth Restriction ◽

Somatic Growth ◽

Placental Insufficiency ◽

Growth Restriction ◽

Postnatal Life ◽

Adaptive Responses ◽

Hepatic Gluconeogenesis ◽

Intrauterine Growth ◽

Metabolic Adaptations ◽

Insulin Dependent

Placental insufficiency (PI) prevents adequate delivery of nutrients to the developing fetus and creates a chronic state of hypoxemia and hypoglycemia. In response, the malnourished fetus develops a series of stress hormone-mediated metabolic adaptations to preserve glucose for vital tissues at the expense of somatic growth. Catecholamines suppress insulin secretion to promote glucose sparing for insulin-independent tissues (brain, nerves) over insulin-dependent tissues (skeletal muscle, liver, and adipose). Likewise, premature induction of hepatic gluconeogenesis helps maintain fetal glucose and appears to be stimulated by both norepinephrine and glucagon. Reduced glucose oxidation rate in PI fetuses creates a surplus of glycolysis-derived lactate that serves as substrate for hepatic gluconeogenesis. These adrenergically influenced adaptive responses promotein uterosurvival but also cause asymmetric intrauterine growth restriction and small-for-gestational-age infants that are at greater risk for serious metabolic disorders throughout postnatal life, including obesity and type II diabetes.

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