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Biomedical subjects

W W Hay

Publications and source records attributed to W W Hay.

At least 19 recordsLinked to original sources
PubMed2006

Nutritional modulation of adolescent pregnancy outcome -- a review.

The risks of miscarriage, prematurity and low birth weight are particularly acute in adolescent girls who are still growing at the time of conception. The role of maternal nutrition in mediating pregnancy outcome in this vulnerable group has been examined in sheep models. When singleton bearing adolescent dams are overnourished to promote rapid maternal growth throughout pregnancy, growth of both the placenta and fetus is impaired, and birth occurs prematurely relative to control adolescents of equivalent age. Studies at mid-gestation, prior to alterations in placental mass, suggest that reduced proliferation of the fetal trophectoderm, impaired angiogenesis, and attenuated uteroplacental blood flows are early defects in placental development. By late pregnancy, relative placental mass is reduced by 45% but uteroplacental metabolism and placental glucose transfer capacity remain normal when expressed on a placental weight specific basis. The asymmetrically growth-restricted fetuses are hypoxic, hypoglycemic and have reduced insulin and IGF-1 concentrations. Absolute umbilical nutrient uptakes are attenuated but fetal utilisation of glucose, oxygen and amino acids remains normal on a fetal weight basis. This suggests altered sensitivities to metabolic signals and may have implications for subsequent metabolic health. At the other end of the nutritional spectrum, many girls who become pregnant have inadequate or marginal nutritional status during pregnancy. This situation is replicated in a second model whereby dams are prevented from growing during pregnancy by relatively underfeeding. Limiting maternal intake in this way gradually depletes maternal body reserves leading to a lower transplacental glucose gradient and a modest slowing of fetal growth in late pregnancy. These changes appear to be independent of alterations in placental growth per se. Thus, while the underlying mechanisms differ, maternal intake at both ends of the nutritional spectrum is a powerful determinant of fetal growth in pregnant adolescents.

Adolescent↗
PubMed2006

Early postnatal nutritional requirements of the very preterm infant based on a presentation at the NICHD-AAP workshop on research in neonatology.

Normal fetal nutrition is a useful guide for understanding postnatal nutrition of infants born very preterm. Fetal lipid uptake gradually increases towards term and is primarily used to produce fat in adipose tissue, with essential fatty acid uptake providing necessary structural and functional elements in membranes of cells in the central nervous system. Fetal glucose uptake and utilization rates are nearly twice as high at 23-26 weeks gestation as they are at term, contributing primarily to energy production and glycogen formation. Amino-acid uptake by the fetus is two-to threefold greater at 23-26 weeks gestation than at term and is required to meet the very high fractional protein synthesis and growth rates at this gestational period; amino acids also contribute significantly to fetal energy production. In contrast, after birth most of the very preterm infants are fed more lipid and glucose and less amino acids and protein than they need. Not surprisingly, therefore, very preterm infants accumulate fat but remain relatively growth restricted at term gestational age compared to those infants who grew normally in utero, and this postnatal growth restriction has long-term adverse growth, development, and health consequences. More thorough understanding of the unique nutritional, metabolic, and growth requirements of the normally growing fetus and the very preterm infant, once born, are needed to determine optimal nutritional strategies to improve the outcome of preterm infants.

Amino Acids↗
PubMed2005

Investigating the causes of low birth weight in contrasting ovine paradigms.

Intrauterine growth restriction (IUGR) still accounts for a large incidence of infant mortality and morbidity worldwide. Many of the circulatory and transport properties of the sheep placenta are similar to those of the human placenta and as such, the pregnant sheep offers an excellent model in which to study the development of IUGR. Two natural models of ovine IUGR are those of hyperthermic exposure during pregnancy, and adolescent overfeeding, also during pregnancy. Both models yield significantly reduced placental weights and an asymmetrically growth-restricted fetus, and display altered maternal hormone concentrations, indicative of an impaired trophoblast capacity. Additionally, impaired placental angiogenesis and uteroplacental blood flow appears to be an early defect in both the hyperthermic and adolescent paradigms. The effects of these alterations in placental functional development appear to be irreversible. IUGR fetuses are both hypoxic and hypoglycaemic, and have reduced insulin and insulin-like growth factor-1 (IGF-1), and elevated concentrations of lactate. However, fetal utilization of oxygen and glucose, on a weight basis, remain constant compared with control pregnancies. Maintained utilization of these substrates, in a substrate-deficient environment, suggests increased sensitivities to metabolic signals, which may play a role in the development of metabolic diseases in later adult life.

Animals↗
PubMed2005

Fetoplacental transport and utilization of amino acids in IUGR--a review.

Amino acids have multiple functions in fetoplacental development. The supply of amino acids to the fetus involves active transport across and metabolism within the trophoblast. Transport occurs through various amino acid transport systems located on both the maternal and fetal facing membranes, many of which have now been documented to be present in rat, sheep and human placentas. The capacity of the placenta to supply amino acids to the fetus develops during pregnancy through alterations in such factors as surface area and specific time-dependent transport system expression. In intrauterine growth restriction (IUGR), placental surface area and amino acid uptakes are decreased in human and experimental animal models. In an ovine model of IUGR, produced by hyperthermia-induced placental insufficiency (PI-IUGR), umbilical oxygen and essential amino acid uptake rates are significantly reduced in the most severe cases in concert with decreased fetal growth. These changes indicate that severe IUGR is likely associated with a shift in amino acid transport capacity and metabolic pathways within the fetoplacental unit. After transport across the trophoblast in normal conditions, amino acids are actively incorporated into tissue proteins or oxidized. In the sheep IUGR fetus, however, which is hypoxic, hypoglycemic and hypoinsulinemic, there appear to be net effluxes of amino acids from the liver and skeletal muscle, suggesting changes in amino acid metabolism. Potential changes may be occurring in the insulin/IGF-I signaling pathway that includes decreased production and/or activation of specific signaling proteins leading to a reduced protein synthesis in fetal tissues. Such observations in the placental insufficiency model of IUGR indicate that the combination of decreased fetoplacental amino acid uptake and disrupted insulin/IGF signaling in liver and muscle account for decreased fetal growth in IUGR.

Amino Acids↗
PubMed2004

Localisation of glucose transport in the ruminant placenta: implications for sequential use of transporter isoforms.

The facilitative glucose transporters 1 and 3 are the major routes for glucose transport across placental membranes. Using light and electron microscope immunocytochemistry on acrylic sections this study shows a similar pattern of expression from mid to late pregnancy in all four ruminants examined [cow, deer, ewe and goat]. GT1 and GT3 are localised on different membrane layers of the synepitheliochorial placental barrier and glucose must utilise both isoforms sequentially to pass from the maternal to fetal circulations. It is suggested that this arrangement is designed to support the high glucose utilisation by the multilayered placenta in the ruminant.

Animals↗
PubMed2004

Characterization of glucose transporter 8 (GLUT8) in the ovine placenta of normal and growth restricted fetuses.

Facilitated glucose transporters (GLUTs) in the chorionic epithelium are primary conduits for glucose delivery to placental and fetal tissues. The objective of this study was to characterize GLUT8 in the ovine placenta and determine if differences in mRNA and protein concentrations occur in an ovine model of intrauterine growth restriction (IUGR). A GLUT8 partial mRNA was generated, which shares 95 per cent identity with bovine GLUT8 nucleotide sequence. Northern hybridization identified a 2.1 kilobase transcript. GLUT8 mRNA concentrations normalized to beta-actin mRNA concentrations increased during late gestation. Western immunoblots with an affinity-purified anti-mouse GLUT8 antiserum detected GLUT8 in late gestation ovine placenta plasma membranes. GLUT8 was immunolocalized to the chorionic epithelial layer and uterine epithelial cells from mid to late gestation. GLUT8 mRNA and protein concentrations at 135 days gestational age were decreased by 34.8 per cent and 21.8 per cent, respectively (P<0.05), in an ovine placental insufficiency model of IUGR. Identification of GLUT8 in the ovine placenta indicates a potential role for GLUT8 in mediating glucose uptake within the placenta and transport to the fetus. Further studies are necessary to confirm this hypothesis and whether the observed decreases in GLUT8 in the PI-IUGR model might contribute, at least in part, to the placental glucose transport deficit that occurs in this model.

Actins↗
PubMed2001

Early aggressive nutrition in preterm infants.

Increasingly, neonatologists are realizing that current feeding practices for preterm infants are insufficient to produce reasonable rates of growth, and earlier and larger quantities of both parenteral and enteral feeding should be provided to these infants. Unfortunately, there is very little outcome data to recommend any particular nutritional strategy to achieve better growth. Instead, the rationale for feeding regimens in many nurseries has been quite variably extrapolated from animal data and human studies conducted in gestationally more mature and/or stable neonates. Additionally, there are no well-controlled, prospective studies that validate any nutritional regimen for the very preterm and or sick, unstable neonate. The goal of this review is to present available data to help define the risks and benefits of early parenteral and enteral nutrition, particularly in very preterm neonates, concluding with a more aggressive approach to feeding these infants than has been customary practice.

Amino Acids↗
PubMed2001

Fetal hyperinsulinemia increases farnesylation of p21 Ras in fetal tissues.

Even though the role of fetal hyperinsulinemia in the pathogenesis of fetal macrosomia in patients with overt diabetes and gestational diabetes mellitus seems plausible, the molecular mechanisms of action of hyperinsulinemia remain largely enigmatic. Recent indications that hyperinsulinemia "primes" various tissues to the mitogenic influence of growth factors by increasing the pool of prenylated Ras proteins prompted us to investigate the effect of fetal hyperinsulinemia on the activitiy of farnesyltransferase (FTase) and the amounts of farnesylated p21 Ras in fetal tissues in the ovine experimental model. Induction of fetal hyperinsulinemia by direct infusion of insulin into the fetus and by either fetal or maternal infusions of glucose resulted in significant increases in the activity of FTase and the amounts of farnesylated p21 Ras in fetal liver, skeletal muscle, fat, and white blood cells. An additional infusion of somatostatin into hyperglycemic fetuses blocked fetal hyperinsulinemia and completely prevented these increases, specifying insulin as the causative factor. We conclude that the ability of fetal hyperinsulinemia to increase the size of the pool of farnesylated p21 Ras may prime fetal tissues to the action of other growth factors and thereby constitute one mechanism by which fetal hyperinsulinemia could induce macrosomia in diabetic pregnancies.

Adipose Tissue↗
PubMed2001

Effects of selective hyperglycemia and hyperinsulinemia on glucose transporters in fetal ovine skeletal muscle.

We measured net fetal glucose uptake rate from the placenta, shown previously to be equal to total fetal glucose utilization rate (GUR(f)) and proportional to fetal hindlimb skeletal muscle glucose utilization, under normal conditions and after 1, 2.5, and 24 h of selective hyperglycemia increasing G or selective hyperinsulinemia increasing I. We simultaneously measured the amount of Glut 1 and Glut 4 glucose transporter proteins in fetal sheep skeletal muscle. With increasing G , GUR(f) was increased approximately 40% at 1 and 2.5 h but returned to the control rate by 24 h. This transient increasing G -specific increasing GUR(f) was associated with increased plasma membrane-associated Glut 1 (4-fold) and intracellular Glut 4 (3-fold) protein beginning at 1 h. With increasing I, GUR(f) was increased approximately 70% at 1, 2.5, and 24 h. This more sustained increasing I-specific increasing GUR(f) was associated with a significant increase in Glut 4 protein (2-fold) at 2.5 h but no change in Glut 1 protein. These results show that increasing G and increasing I have independent effects on the amount of Glut 1 and Glut 4 glucose transporter proteins in ovine fetal skeletal muscle. These effects are time dependent and isoform specific and may contribute to increased glucose utilization in fetal skeletal muscle. The lack of a sustained temporal correlation between the increase in transporter proteins and glucose utilization rates indicates that subcellular localization and activity of a transporter or tissues other than the skeletal muscle contribute to net GUR(f).

Animals↗
PubMed2001

Glucose transporter protein responses to selective hyperglycemia or hyperinsulinemia in fetal sheep.

The acute effect of selective hyperglycemia or hyperinsulinemia on late gestation fetal ovine glucose transporter protein (GLUT-1, GLUT-3, and GLUT-4) concentrations was examined in insulin-insensitive (brain and liver) and insulin-sensitive (myocardium and fat) tissues at 1, 2.5, and 24 h. Hyperglycemia with euinsulinemia caused a two- to threefold increase in brain GLUT-3, liver GLUT-1, and myocardial GLUT-1 concentrations only at 1 h. There was no change in GLUT-4 protein amounts at any time during the selective hyperglycemia. In contrast, selective hyperinsulinemia with euglycemia led to an immediate and persistent twofold increase in liver GLUT-1, which lasted from 1 until 24 h with a concomitant decline in myocardial tissue GLUT-4 amounts, reaching statistical significance at 24 h. No other significant change in response to hyperinsulinemia was noted in any of the other isoforms in any of the other tissues. Simultaneous assessment of total fetal glucose utilization rate (GURf) during selective hyperglycemia demonstrated a transient 40% increase at 1 and 2.5 h, corresponding temporally with a transient increase in brain GLUT-3 and liver and myocardial GLUT-1 protein amounts. In contrast, selective hyperinsulinemia led to a sustained increase in GURf, corresponding temporally with the persistent increase in hepatic GLUT-1 concentrations. We conclude that excess substrate acutely increases GURf associated with an increase in various tissues of the transporter isoforms GLUT-1 and GLUT-3 that mediate fetal basal glucose transport without an effect on the GLUT-4 isoform that mediates insulin action. This contrasts with the tissue-specific effects of selective hyperinsulinemia with a sustained increase in GURf associated with a sustained increase in hepatic basal glucose transporter (GLUT-1) amounts and a myocardial-specific emergence of mild insulin resistance associated with a downregulation of GLUT-4.

Adipose Tissue↗
PubMed2000

Intravenous nutrition and postnatal growth of the micropremie.

There is a growing body of evidence that early nutritional practices may affect short-term growth and developmental outcome. In addition, they may play a role in determining adult health and disease. There is much that needs to be learned about safe and efficacious nutrient administration in the ELBW population; about techniques to assess the effect of different nutritional strategies; and about the long-term effects of these regimen or development outcome, growth, and disease.

Food, Formulated↗
PubMed2000

Effect of hyperinsulinemia on amino acid utilization in the ovine fetus.

We studied the effect of an acute 4-h period of hyperinsulinemia (H) on net utilization rates (AAUR(net)) of 21 amino acids (AA) in 17 studies performed in 13 late-gestation fetal sheep by use of a novel fetal hyperinsulinemic-euglycemic-euaminoacidemic clamp. During H [84 +/- 12 (SE) microU/ml H, 15 +/- 2 microU/ml control (C), P < 0. 00001], euglycemia was maintained by glucose clamp (19 +/- 0.05 micromol/ml H, 1.19 +/- 0.04 micromol/ml C), and euaminoacidemia (mean 4.1 +/- 3.3% increase for all amino acid concentrations [AA], nonsignificantly different from zero) was maintained with a mixed amino acid solution adjusted to keep lysine concentration constant and other [AA] near C values. H produced a 63.7% increase in AAUR(net) (3.29 +/- 0.66 micromol. min(-1). kg(-1) H, 2.01 +/- 0.55 micromol. min(-1). kg(-1) C, P < 0.001), accounting for a 60.1% increase in fetal nitrogen uptake rate (2,064 +/- 108 mg. day(-1). kg(-1) H, 1,289 +/- 73 mg. day(-1). kg(-1) C, P < 0.001). Mean AA clearance rate (AAUR(net)/[AA]) increased by 64.5 +/- 18.9% (P < 0. 001). Thus acute physiological H increases net amino acid and nitrogen utilization rates in the ovine fetus independent of plasma glucose and [AA].

Amino Acids↗
PubMed2000

Regulation of uterine and umbilical amino acid uptakes by maternal amino acid concentrations.

We tested the hypothesis that decreased fetal amino acid (AA) supply, produced by maternal hypoaminoacidemia (low AA) during hyperglycemia (HG), is reversible with maternal AA infusion and regulates fetal insulin concentration ([I]). We measured net uterine and umbilical AA uptakes during maternal HG/low AA concentration ([AA]) and after maternal intravenous infusion of a mixed AA solution. After 5 days HG, all maternal [AA] except glycine were decreased >50%, particularly essential [AA] (P < 0.00005). Most fetal [AA] also were decreased, especially branched-chain AA (P < 0.001). Maternal AA infusion increased net uterine uptakes of Val, Leu, Ile, Met, and Ser and net umbilical uptakes of Val, Leu, Ile, Met, Phe, and Arg but did not change net uteroplacental uptake of any AA. Fetal [I] increased 55 +/- 14%, P < 0.001, with correction of fetal [AA], despite the lack of change in fetal glucose concentration. Thus generalized maternal hypoaminoacidemia decreases uterine and umbilical uptakes of primarily the essential AA and decreases fetal branched-chain [AA]. These changes are reversed with correction of maternal [AA], which also increases fetal [I].

Amino Acids↗
PubMed2000

Time-dependent physiological regulation of ovine placental GLUT-3 glucose transporter protein.

We immunolocalized the GLUT-3 glucose transporter isoform versus GLUT-1 in the late-gestation epitheliochorial ovine placenta, and we examined the effect of chronic maternal hyperglycemia and hypoglycemia on placental GLUT-3 concentrations. GLUT-3 was limited to the apical surface of the trophoectoderm, whereas GLUT-1 was on the basolateral and apical surfaces of this cell layer and in the epithelial cells lining the placental uterine glands. GLUT-3 concentrations declined at 17-20 days of chronic hyperglycemia (P < 0.05), associated with increased uterine and uteroplacental net glucose uptake rate, but a normal fetal glucose uptake rate was observed. Chronic hypoglycemia did not change GLUT-3 concentrations, although uterine, uteroplacental, and fetal net glucose uptake rates were decreased. Thus maternal hyperglycemia causes a time-dependent decline in the entire placental glucose transporter pool (GLUT-1 and GLUT-3). In contrast, maternal hypoglycemia decreases GLUT-1 but not GLUT-3, resulting in a relatively increased GLUT-3 contribution to the placental glucose transporter pool, which could maintain glucose delivery to the placenta relative to the fetus when maternal glucose is low.

Animals↗
PubMed1999

Small for gestational age: a new insight?

Acidosis reduces the ability of nitric oxide synthase to generate nitric oxide (NO) from L-arginine (L-arg), even if dietary intake or circulating plasma levels of L-arg are normal. During systemic acidemia, therefore, vascular perfusion in one or more organs may be compromised. Arginine is also a powerful anabolic amino acid. If dietary sources of L-arg are lower than normal, or if the production of NO is reduced even without frank acidemia, then vascular perfusion, and growth, and tissue repair are likely to be compromised. Two conditions in which acidemia is reported to occur, namely slow fetal growth in utero (acidemia is severe) and loss of bone and muscle in microgravity (acidemia is modest), are compared with respect to the accompanying alteration in the balance between acidemia and NO production.

Acidosis↗