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W W Hay

Publications and source records attributed to W W Hay.

At least 55 records · Page 3Linked to original sources
PubMed1996

A generalized Michaelis-Menten response surface.

We describe an application of recently developed generalized Michaelis-Menten response surface and non-linear mixed model methodologies to model glucose utilization in foetal sheep. More specifically, we model the response surface of glucose utilization rate in the foetal sheep as a function of glucose and insulin concentrations using a three-dimensional analogue of the Michaelis-Menten pharmacokinetic model. To account for multiple measurements per sheep, we apply the non-linear mixed effects model proposed by Lindstrom and Bates using the EM algorithm computational scheme presented by Hirst et al.

Animals↗
PubMed1996

Assessing the effect of disease on nutrition of the preterm infant.

OBJECTIVE: To review existing data on nutritional requirements of extremely low birth weight (ELBW) and very low birth weight (VLBW) preterm infants (those who weigh < 1000 g and 1000-1500 g at birth, respectively), and the effects of diseases on these nutritional requirements. DATA SOURCES: A literature search was conducted on applicable articles related to nutritional requirements of preterm ELBW and VLBW infants and the effects of diseases in these infants on their nutritional and metabolic requirements. DATA SYNTHESIS: The literature was analyzed to determine nutritional requirements of preterm ELBW and VLBW infants, to select the most common diseases that have significant and important effects on nutrition and metabolism in these infants, and to make recommendations about diagnostic and therapeutic approaches to nutritional problems as affected by diseases in ELBW and VLBW infants. CONCLUSIONS: Many diseases unique to preterm infants, either directly or by enhancing the effects of stress on the metabolism of such infants, provide important changes in the nutrient requirements. The overriding observation from all studies, however, is that ELBW and VLBW preterm infants are underfed during the early postnatal period and that this condition, combined with additional stresses from various diseases, increases the risk of long-term neurological sequelae. The value of achieving a specific body composition and growth weight is less certain. There remains a critical need for determining the right quality as well as quantity of nutrients for these infants.

Amino Acids↗
PubMed1996

Effect of low-level basal plus marked "pulsatile" hyperglycemia on insulin secretion in fetal sheep.

We compared fetal glucose- and arginine-stimulated insulin secretion (delta I, pM) among four groups of pregnant sheep after 10-11 days of different maternal glycemic patterns: 1) control, euglycemic; 2) low-level basal plus "pulsatile" hyperglycemic (PHG group); 3) markedly hyperglycemic (HG) group); 4) markedly hypoglycemic (LG group). Mean delta I during a hyperglycemic clamp was greatest in the PHG group (190 +/- 28 pM, P < 0.01) and least in the HG (64 +/- 13 pM, P < 0.05) and LG groups (68 +/- 15 pM, P < 0.05) compared with the control group (126 +/- 18 pM). After an arginine bolus, insulin concentration was greater in the PHG group at two of four sampling times over 30 min compared with the control group and at all times compared with the HG and LG groups. The trend in mean delta I over the postarginine sampling period (PHG 1,092 +/- 114 pM; control 921 +/- 86 pM; HG897 +/- 117 pM; LG831 +/- 57 pM) was in the same direction as for glucose and was significant (P < 0.05). Thus glucose-stimulated fetal insulin secretion is regulated by the duration and pattern, as well as the magnitude, of maternal and fetal hyperglycemia; this regulation may also extend to insulin-secretion capacity.

Animals↗
PubMed1995

Metabolic interrelationships of placenta and fetus.

Placental-fetal metabolic relationships are complex and dynamic. For example, the placenta consumes glucose as well as transports it to the fetus, thus regulating fetal glucose supply and fetal plasma glucose concentration. In turn, fetal plasma glucose concentration, which is also regulated by the relative rates of fetal glucose utilization and production (both also regulated by glucose-induced insulin secretion), regulates placental glucose consumption and the partition of uterine glucose uptake into placental glucose consumption and glucose transfer to the fetus. For amino acids, unique placental transport and metabolic processes determine the quality as well as the quantity of amino acids that enter the fetal circulation. In turn, this unique qualitative and quantitative supply of amino acids provides a variety of regulatory controls over a diverse set of developmental metabolic processes as well as fetal protein turnover and growth. Similarly, complex placental lipid metabolism and transport affect the quality and quantity of lipids delivered to the fetus and thus the composition and amount of lipids in fetal tissues. Clearly, placental and fetal metabolic interrelationships represent vital and unique processes that control and determine many aspects of fetal development.

Amino Acids↗
PubMed1995

Regulation of placental metabolism by glucose supply.

Glucose is supplied to the placenta and fetus from the maternal plasma according to concentration-dependent mechanisms exhibiting saturation kinetics that are mediated by facilitative transporter proteins on both the maternal-facing microvillus and fetal-facing basal trophoblast membranes. Placental glucose transport to the fetus requires a net maternal-to-fetal plasma glucose concentration gradient that is determined by placental as well as fetal glucose consumption. Fetal plasma glucose concentration, independent of maternal glucose concentration, regulates the partition of placental glucose uptake into transfer to the fetus and consumption by the placenta. Placental transport capacity increases with advancing gestation, probably by an increased number of transporter proteins as surface area increases. Placental glucose consumption contributes to most or all of placental lactate and fructose production and other less well defined non-oxidative pathways of carbon metabolism. Placental glucose consumption accounts for at least 50% of placental oxygen consumption which remains independent of short-term or long-term changes in placental glucose supply, thus requiring varying amounts of other carbon substrates. Placental glucose supply, therefore, plays a key role in regulating placental glucose metabolism and placental carbon balance, and interacts reciprocally with other carbon substrates to maintain placental oxidative metabolism.

Animals↗
PubMed1995

Placental norepinephrine clearance: in vivo measurement and physiological role.

The intrauterine clearance rate of catecholamines is higher than in newborn animals or in adults. The separate contributions of the fetus and placenta to this clearance are not known. The placenta is a site of expression of the amine plasma membrane transporters that mediate this process. To determine the physiological role of this placental transporter in vivo, we studied fetal sheep at 123 days with common umbilical vein (UV), fetal arterial (AO), and venous catheters. Tritiated norepinephrine ([3H]NE) was infused to determine the kinetics of placental and fetal NE appearance and clearance rates. Umbilical flow was determined by [3H]NE infusion. Placental and total (fetal-placental) NE clearance rates were determined by measurement of [3H]NE from simultaneously drawn UV and AO samples. Total clearance was 99 +/- 8 ml.kg-1.min-1. Placental fractional [3H]NE extraction was 21% and accounted for 48% of total clearance. Fetal plasma NE production rate was 85 +/- 20 ng.kg-1.min-1. We conclude that placental catecholamine clearance is an important metabolic function of the placenta. This mechanism for clearance of the high fetal production rate of catecholamines is vital for fetal homeostasis. We speculate that derangements in placental catecholamine clearance may explain the exaggerated adverse effects on the fetus of drugs like cocaine, which block catecholamine transport.

Animals↗
PubMed1995

Uteroplacental carbon substrate metabolism and O2 consumption after long-term hypoglycemia in pregnant sheep.

Chronic maternal hypoglycemia leads to fetal growth restriction, but the effects on placental metabolism and its contribution to reduced fetal growth have not been determined. To study these factors, experiments were conducted in seven normal control (C) and six chronically insulin-infused hypoglycemic (H) pregnant sheep over the second half of gestation to measure effects of maternal and fetal hypoglycemia [maternal: 2.0 +/- 0.2 (H) vs. 3.6 +/- 0.1 mM (C); fetal: 0.7 +/- 0.1 (H) vs. 1.1 +/- 0.1 mM (C)] on placental metabolism of glucose, other carbon substrates, and O2. Placental and fetal weight were proportionately reduced in the H group [placental wt: 258 +/- 18 (H) vs. 376 +/- 18 g (C), -31%; fetal wt: 2,540 +/- 190 (H) vs. 3,558 +/- 230 g (C), -29%]. Glucose uptake by the uterus was reduced in the H group [0.10 +/- 0.01 (H) vs. 0.19 +/- 0.02 mmol/min (C)]; it was partitioned more to uteroplacental consumption (UPGC) and less to transfer to the fetus (PGT) [UPGC-to-PGT ratio: 20.0 +/- 2.1 (H) and 13.5 +/- 1.2 (C), P < 0.05 for both]. Metabolism of glucose by nonoxidative and oxidative pathways (as estimated by uteroplacental lactate production-to-UPGC ratio and normal rates of placental O2 consumption) was not significantly changed in the H group. Acetoacetate and beta-hydroxybutyrate net uptake and fructose production rates were significantly reduced in the H group, and there was no change in free fatty acid or amino acid uptake rates. With acute return of maternal and fetal glucose concentrations to normal, UPGC and PGT exceeded normal rates by approximately 25%. Thus chronic reduced glucose supply to the uteroplacenta produces a smaller placenta that uses glucose normally and in preference to transfer to the fetus, demonstrating placental metabolic autonomy at the expense of the fetus.

Animals↗
PubMed1995

Contribution of fructose and lactate produced in placenta to calculation of fetal glucose oxidation rate.

We examined the rate of production of [14C]fructose and [14C]lactate from [U-14C]glucose by the placenta and the contribution of 14CO2 from fetal oxidation of these metabolic products to the calculation of glucose oxidation rate in fetal sheep. During fetal tracer infusions (n = 16), oxidation of fructose contributed 16 +/- 3% of total fetal CO2 production; oxidation of lactate accounted for 3.3 +/- 0.1%. Thus 80% of total fetal CO2 production resulted from direct oxidation of carbon atoms in glucose; the "direct" glucose oxidation fraction was 0.46 +/- 0.04. During maternal tracer infusion (n = 15), CO2 production from fructose was 21 +/- 3, 20 +/- 3, and 30 +/- 4% and from lactate was 16 +/- 3, 13 +/- 3, and 11 +/- 4% in hypo-, normo-, and hyperglycemic animals, respectively; the direct glucose oxidation fraction was 0.40 +/- 0.04, not different from the fraction obtained with the fetal tracer infusion. Fetal oxidation of substrates derived from glucose metabolism in the placenta contributes significantly to fetal CO2 production. Fetal oxidation of placental products of a metabolic substrate tracer should be considered in studies of fetal oxidative metabolism.

Animals↗
PubMed1995

Cerebral lactate metabolism in near-term fetal sheep.

The present study was designed to see if lactate can cross the blood-brain barrier of the near-term fetal sheep and replace glucose as an oxidative substrate during normoglycemia and acute insulin-induced hypoglycemia. Cerebral uptake of glucose, oxygen, lactate, and [14C]lactate as well as cerebral production of 14CO2 were measured under three conditions: 1) normoglycemia-normolactemia, 2) acute hypoglycemia-normolactemia, and 3) hypoglycemia-steady-state hyperlactemia. Although uptake of tracer [14C]lactate was consistent, there was no net uptake of unlabeled lactate during either normoglycemia or hypoglycemia. When arterial lactate concentration was raised from 2.2 +/- 0.5 to 3.3 +/- 0.4 (SE) mM by sodium lactate infusion, however, lactate was taken up. Comparison of cerebral [14C]lactate uptake with 14CO2 production indicated that the principal metabolic fate of lactate is oxidation. At increased concentrations, exogenous lactate accounted for approximately 7% of cerebral oxygen consumption. This study demonstrates that lactate crosses the blood-brain barrier of the near-term fetal sheep, is oxidized, and at elevated concentrations can partially replace glucose as an oxidative substrate during acute hypoglycemia.

Animals↗
PubMed1995

Identification of a unique form of protein C in the ovine fetus: developmentally linked transition to the adult form.

To investigate fetal development of protein C, a pregnant ovine model was used. Protein C was isolated from ovine plasma, and a polyclonal antibody was raised. Citrated plasma was obtained from undisturbed chronically catheterized fetal lambs. On Western blot, nonreduced adult ovine protein C had a molecular mass of 70 kD. Fetal ovine protein C was determined to have a molecular mass of 4 to 6 kD larger than the adult molecule. Crossed immunoelectrophoresis demonstrated slightly increased anodal migration of the fetal form. Isoelectric focusing demonstrated a decreased pI of the fetal molecule (4.45 versus 4.6). The ovine protein C molecules were deglycosylated with N-glycanase. Deglycosylated fetal protein C migrated more similarly to the adult form, although a portion of the fetal form persisted. These experiments demonstrate the first example of a unique fetal form of a vitamin K-dependent protein and are compatible with increased glycosylation of fetal ovine protein C. It is speculated that altered posttranslational processing may exist as a general process by which certain coagulation proteins are modified during fetal development. mRNA was isolated from maternal and fetal hepatic tissue and analyzed by Northern hybridization. Fetal plasma concentration and hepatic mRNA for protein C were both 40% of normal maternal values from midgestation onward. At term, protein C mRNA increased to adult range (p < 0.025), although plasma protein C concentration decreased slightly (p < 0.001). A transition from fetal to adult protein C form was found beginning 6 d before term birth, with a doubling time of 24 h. These data are compatible with a gestationally determined maturation of ovine protein C.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1995

Glucose suppression of insulin secretion in chronically hyperglycemic fetal sheep.

Previous observations in fetal sheep indicate that glucose may inhibit as well as enhance insulin secretion. To study conditions involved in inhibition of insulin secretion, we compared changes in plasma insulin concentration in response to acute increases in glucose and arginine concentrations in a group of normal, late gestation fetal sheep (euglycemic controls, EC) and a comparable group made chronically hyperglycemic by constant maternal glucose infusion (hyperglycemics, HG). After 7-10 d of maternal and fetal hyperglycemia, fetal glucose concentrations (G) were significantly increased in the HG group (0.98 +/- 0.07 mM EC, 2.00 +/- 0.11 mM HG, p < 0.001) but fetal plasma insulin concentrations (I) were not significantly different (57 +/- 7 pM EC, 71 +/- 9 pM HG, p = 0.2). Furthermore, the I/G ratio was significantly decreased in the HG group (60 +/- 9 EC, 40 +/- 4 HG, p = 0.03) and during a hyperglycemic glucose clamp (delta G approximately equal to 1.4 mM), glucose-stimulated increase in steady state I was less in the HG than in the EC fetuses (mean delta I/delta G = 106 +/- 15 EC, 61 +/- 10 HG, p = 0.01). An arginine infusion at the end of the clamp produced similar increases in I in the EC and HG groups (delta I = 824 +/- 116 pM EC, 906 +/- 131 pM HG, p = 0.45). There were no differences between groups for blood oxygen saturation and content, pH, or lactate concentration. After 14-17 d of hyperglycemia, glucose-stimulated increase in I was even more reduced in the HG fetuses than observed at 7-10 d. Decreased insulin response to arginine also was present, although pancreatic insulin concentration was not decreased. Glucose-stimulated increase in I returned to normal after 7 d of no glucose infusion and euglycemia. These data indicate that glucose-stimulated insulin secretion is reversibly decreased by marked, chronic hyperglycemia. Because pharmacologic inhibitors of insulin secretion (e.g. streptozotocin or alloxan) were not used, and oxygenation, pH, and lactate values were similar between the two groups, this decrease of insulin secretion appears to be glucose-specific, although mechanisms involved can include both glucose and amino acid (arginine) stimulation processes. Such decrease in fetal insulin secretion may limit the rate of fetal glucose utilization during chronic hyperglycemia and thereby modulate the rate of fetal growth.

Animals↗
PubMed1995

Metabolic substrates for fetal energy metabolism and growth.

This article reviews the basic aspects of fetal nutrition with emphasis on recent developments. Growth and energy requirements are first described, followed by a discussion about the contributions of main metabolic substrates for the fetus including amino acids, carbohydrates, and lipids. While the placenta is not the primary focus of this review, fetal and placental metabolism are intimately related. Current understanding of placental transport and metabolism is included where relevant. Lastly, a current review about the effects of nutrient deprivation on fetal growth and metabolism is presented.

Amino Acids↗
PubMed1994

Ovine uteroplacental glucose and oxygen metabolism in relation to chronic changes in maternal and fetal glucose concentrations.

We tested whether uterine glucose uptake rate (UtGU), placental glucose transport rate to the fetus (PGT) and uteroplacental glucose consumption rate (UPGC) were altered in chronically catheterized pregnant sheep after 2-5 week intravenous infusions of glucose or insulin that produced sustained maternal and fetal hyper- or hypoglycemia. In the hyperglycemic animals, UtGU was greater than that of controls; the excess UtGU was partitioned into non-oxidative UPGC rather than PGT. The 'normal' rate of PGT observed in the hyperglycemic animals is probably related to suppression of fetal insulin concentration which would decrease fetal glucose clearance and thus the transplacental glucose concentration gradient. The increase in UPGC may help prevent an excessive supply of glucose to the fetus. In the hypoglycemic animals, weight-specific UPGC and uteroplacental oxygen uptake were not different from controls; placental weight also was reduced, an adaptation that maintained normal placental metabolism per unit tissue and did not disproportionately deprive the fetus of glucose supply.

Animals↗
PubMed1994

Birth size and risk of insulin-dependent diabetes mellitus (IDDM).

A case-control study was conducted to test the hypotheses that birth size is increased in infants who develop IDDM in childhood and that birth size differs by diagnosis age. Cases were non-Hispanic white (NHW) children randomly selected from the Colorado IDDM Registry (n = 221). Controls (n = 197) were NHW children frequency-matched to cases by age-group and gender. Self-administered questionnaires collected birth size and demographic data. There were no significant univariate differences in birth weight (cases 3303.0 g; controls, 3346.1 g; P = 0.40), birth length (cases, 50.8 cm; controls, 51.2 cm; P = 0.28), or ponderal index (cases, 2.52; controls, 2.49; P = 0.92). The case/control odds ratio (OR) controlling for gender, maternal education, and birth place was 1.0 (95% confidence interval (CI) 0.4, 2.5) for the highest category of birth weight compared to the lowest. There were no statistically significant case/control differences in ponderal index (highest to lowest category OR = 1.1; 95% CI 0.6, 2.0) or birth length (1 cm increase OR, 1.0; 95% CI 0.9, 1.2). Similarly, analysis by age-at-diagnosis groups revealed no significant differences, suggesting that birth size does not reveal prenatal diabetogenic influences.

Adolescent↗
PubMed1994

Nutritional requirements of extremely low birthweight infants.

Extremely low birthweight (ELBW) infants are unique in many developmental characteristics that determine nutritional requirements, including: low energy reserves (both carbohydrate and fat); higher metabolic rate (intrinsically, due to a higher body content of more metabolically active organs, e.g. brain, heart, liver); higher protein turnover rate (especially when growing); higher glucose needs for energy and brain metabolism; higher lipid needs to match the in utero rate of fat deposition, and for essential fatty acids for brain, neural and vascular development; excessive evaporative rates, and occasionally very high urinary water and solute losses; low rates of gastrointestinal peristalsis; limited production of gut digestive enzymes and growth factors; high incidence of stressful events (e.g. hypoxemia, respiratory distress, sepsis); and abnormal neurological outcome if not fed adequately. Postnatally, ELBW infants do not grow well, or at all, often for weeks. This leads to a virtual "growth deficit", which has unknown consequences (which for the most part are not good) and requires excessive feeding later on to catch up to normal growth rates and body composition. The major future challenge for the nutrition of these infants is to define more accurately their nutritional requirements, particularly in the early postnatal period, in order to feed them more appropriately, to reduce to a minimum the nutritional and growth deficits that they so commonly develop and to prevent neurodevelopmental handicaps that are the result of nutritional deficiencies.

Animals↗