Umbilical Glucose Uptake Research Articles

Increasing maternal glucose concentrations is insufficient to restore placental glucose transfer in chorionic somatomammotropin RNA interference pregnancies.

We previously demonstrated impaired placental nutrient transfer in chorionic somatomammotropin (CSH) RNA interference (RNAi) pregnancies, with glucose transfer being the most impacted. Thus, we hypothesized that despite experimentally elevating maternal glucose, diminished umbilical glucose uptake would persist in CSH RNAi pregnancies, demonstrating the necessity of CSH for adequate placental glucose transfer. Trophectoderm of sheep blastocysts (9 days of gestational age; dGA) were infected with a lentivirus expressing either nontargeting control (CON RNAi; n = 5) or CSH-specific shRNA (CSH RNAi; n = 7) before transfer into recipient sheep. At 126 dGA, pregnancies were fitted with vascular catheters and underwent steady-state metabolic studies (3H2O transplacental diffusion) at 137 ± 0 dGA, before and during a maternal hyperglycemic clamp. Umbilical glucose and oxygen uptakes, as well as insulin and IGF1 concentrations, were impaired (P ≤ 0.01) in CSH RNAi fetuses and were not rescued by elevated maternal glucose. This is partially due to impaired uterine and umbilical blood flow (P ≤ 0.01). However, uteroplacental oxygen utilization was greater (P ≤ 0.05) during the maternal hyperglycemic clamp, consistent with greater placental oxidation of substrates. The relationship between umbilical glucose uptake and the maternal-fetal glucose gradient was analyzed, and while the slope (CON RNAi, Y = 29.54X +74.15; CSH RNAi, Y = 19.05X + 52.40) was not different, the y-intercepts and elevation were (P = 0.003), indicating reduced maximal glucose transport during maternal hyperglycemia. Together, these data suggested that CSH plays a key role in modulating placental metabolism that ultimately promotes maximal placental glucose transfer.NEW & NOTEWORTHY The current study demonstrated a novel, critical autocrine role for chorionic somatomammotropin in augmenting placental glucose transfer and maintaining placental oxidative metabolism. In pregnancies with CSH deficiency, excess glucose in maternal circulation is insufficient to overcome fetal hypoglycemia due to impaired placental glucose transfer and elevated placental metabolic demands. This suggests that perturbations in glucose transfer in CSH RNAi pregnancies are due to compromised metabolic efficiency along with reduced placental mass.

Timing of maternal nutrient restriction during mid- to late-gestation influences net umbilical uptake of glucose and amino acids in adolescent sheep.

Previous research demonstrated that maternal nutrient restriction during mid- to late-gestation influenced net umbilical uptakes of glucose and amino acids in sheep. However, it is unclear how the timing and duration of nutrient restriction during mid- to late-gestation influences net uterine, uteroplacental, and fetal flux of glucose and amino acids. On day 50 of gestation, 41 adolescent ewe lambs carrying singletons were randomly assigned to one of six dietary treatments: 1) 100% of nutrient requirements from days 50 to 90 of gestation (CON; n = 7); 2) 60% of nutrient requirements (RES; n = 7) from days 50 to 90 of gestation; 3) 100% of nutrient requirements from days 50 to 130 of gestation (CON-CON; n = 6); 4) 100% of nutrient requirements from days 50 to 90 of gestation and 60% of nutrient requirements from days 90 to 130 of gestation (CON-RES; n = 7); 5) 60% of nutrient requirements from days 50 to 90 of gestation and 100% of nutrient requirements from days 90 to 130 of gestation (RES-CON; n = 7); or 6) 60% of nutrient requirements from days 50 to 130 of gestation (RES-RES; n = 7). On day 90 (n = 14) and day 130 (n = 27), intraoperative procedures were performed to evaluate uteroplacental blood flows, collect blood samples, and then ewes were euthanized. Net uterine, uteroplacental, and umbilical fluxes of glucose and amino acids were calculated by multiplying blood flow by the arterial-venous concentration difference. Data from days 90 and 130 were analyzed separately using ANOVA in SAS. Maternal nutrient restriction during mid-gestation increased (P = 0.04) net umbilical glucose uptake but, maternal nutrient restriction during late-gestation decreased (P = 0.02) net umbilical glucose uptake. Net umbilical essential amino acid uptake decreased (P = 0.03) with nutrient restriction during mid-gestation; however, net umbilical uptakes of Phe (P = 0.02), Thr (P = 0.05), Met (P = 0.09), and His (P = 0.08) increased or tended to increase after nutrient restriction during late-gestation. These data demonstrate that net umbilical glucose and amino acid uptakes were influenced by the timing of nutrient restriction during mid- to late-gestation. Elevated net umbilical glucose uptake after mid-gestational nutrient restriction was sustained throughout late-gestation, independent of late-gestational feeding level. Long-term adaptations in umbilical glucose uptake may have implications for prenatal and postnatal growth and development of the offspring.

152 Impact of chorionic somatomammotropin RNA interference on uterine blood flow and placental glucose uptake in the absence of intrauterine growth restriction

Abstract Chorionic somatomammotropin (CSH) is one of the most abundant hormones produced by the sheep placenta, yet the exact function of CSH has been elusive. Previously we reported the use of in vivo RNA interference (RNAi) to assess the impact of CSH deficiency on placental and fetal growth in sheep. Near-term (135 dGA), there are two distinct CSH RNAi phenotypes: 1) pregnancies with intrauterine growth restriction (IUGR), and 2) pregnancies with normal fetal and placental weights. This study describes physiological changes in the latter phenotype. To generate the CSH RNAi pregnancies, the trophectoderm of hatched blastocysts (9 dGA) were infected with lentiviral-constructs expressing either a scrambled control (NTS) or CSH-specific shRNA (CSH RNAi), prior to transfer into synchronized recipient ewes. At 120 dGA, 6 NTS and 6 CSH RNAi pregnancies were fitted with maternal and fetal catheters. Uterine and umbilical blood flows were measured utilizing the 3H2O transplacental diffusion technique at 132 dGA, and nutrient uptakes were calculated by the Fick principle. Resulting data were analyzed by Student’s t-test and significance was set at P ≤ 0.05. CSH RNAi tended (P ≤ 0.10) to reduce placentome weight with no effect on fetal weight. Absolute (ml/min) and relative (ml/min/kg fetus) uterine blood flows were reduced (P ≤ 0.05) in CSH RNAi pregnancies, but umbilical flows were not impacted. The uterine artery-to-vein glucose gradient (mmol/l) was significantly (P ≤ 0.05) increased, whereas the gradients for taurine and glycine were reduced (P ≤ 0.05). Uteroplacental glucose uptake (mmol/min/kg placenta) was increased 27% (P ≤ 0.05), whereas umbilical glucose uptake (mmol/min/kg fetus) was reduced 13%. This cohort demonstrates that even in the absence of IUGR, CSH deficiency has significant physiological ramifications, and the investigation of CSH RNAi pregnancies exhibiting both IUGR and non-IUGR phenotypes may help determine the direct effects of CSH and its potential impact on fetal programming. Supported by NIH R01 HD093701.

Impact of chorionic somatomammotropin RNA interference on uterine blood flow and placental glucose uptake in the absence of intrauterine growth restriction.

Chorionic somatomammotropin (CSH) is one of the most abundantly produced placental hormones, yet its exact function remains elusive. Near-term [135 days of gestational age (dGA)], CSH RNA interference (RNAi) results in two distinct phenotypes: 1) pregnancies with intrauterine growth restriction (IUGR), and 2) pregnancies with normal fetal and placental weights. Here, we report the physiological changes in CSH RNAi pregnancies without IUGR. The trophectoderm of hatched blastocysts (9 dGA) were infected with lentiviral-constructs expressing either a scrambled control (Control RNAi) or CSH-specific shRNA (CSH RNAi), prior to transfer into synchronized recipient ewes. At 126 dGA, Control RNAi (n = 6) and CSH RNAi (n = 6) pregnancies were fitted with maternal and fetal catheters. Uterine and umbilical blood flows were measured at 132 dGA and nutrient uptakes were calculated by the Fick's principle. Control RNAi and CSH RNAi pregnancies were compared by analysis of variance, and significance was set at P ≤ 0.05. Absolute (mL/min) and relative (mL/min/kg fetus) uterine blood flows were reduced (P ≤ 0.05) in CSH RNAi pregnancies, but umbilical flows were not impacted. The uterine artery-to-vein glucose gradient (mmol/L) was significantly (P ≤ 0.05) increased. The uteroplacental glucose uptake (μmoL/min/kg placenta) was increased (P ≤ 0.05), whereas umbilical glucose uptake (μmoL/min/kg fetus) was reduced. Our results demonstrate that CSH RNAi has significant physiological ramifications, even in the absence of IUGR, and comparing CSH RNAi pregnancies exhibiting both IUGR and non-IUGR phenotypes may help determine the direct effects of CSH and its potential impact on fetal development.

Fetal Oxygen and Glucose Consumption in Human Pregnancy Complicated by Fetal Growth Restriction.

In healthy pregnancy, glucose and oxygen availability are essential for fetal growth and well being. However, how substrate delivery and fetal uptake are affected in human pregnancy complicated by fetal growth restriction (FGR) is still unknown. Here, we show that the human FGR fetus has a strikingly reduced umbilical uptake of both oxygen and glucose. In 30 healthy term and 32 FGR human pregnancies, umbilical volume flow (Qumb) and parallel umbilical vein (uv) and artery (ua) blood samples were obtained at elective Cesarean section to calculate fetal glucose and oxygen uptake as Qumb · Δ (uv-ua) differences. Umbilical blood flow was significantly lower in FGR pregnancy (-63%; P<0.001) but not when normalized for fetal body weight. FGR pregnancy had significantly lower umbilical oxygen delivery and uptake, both as absolute values (delivery: -78%; uptake: -78%) and normalized (delivery: -50%; uptake: -48%) for fetal body weight (all P<0.001). Umbilical glucose absolute delivery and uptake were significantly reduced (delivery: -68%; uptake: -72%) but only glucose uptake was decreased when normalized for fetal body weight (-30%; P<0.05). The glucose/oxygen quotient was significantly increased (+100%; P<0.05) while glucose clearance was significantly decreased (71%; P<0.001) in FGR pregnancy (both P<0.05). The human fetus in FGR pregnancy triggers compensatory mechanisms to reduce its metabolic rate, matching the proportion of substrate consumption relative to oxygen delivery as a survival strategy during complicated pregnancy.

Sustained hypoxemia in late gestation potentiates hepatic gluconeogenic gene expression but does not activate glucose production in the ovine fetus.

Fetal hypoxemia is associated with pregnancy conditions that cause an early activation of fetal glucose production. However, the independent role of hypoxemia to activate this pathway is not well understood. We hypothesized that fetal hypoxemia would activate fetal glucose production by decreasing umbilical glucose uptake and increasing counter-regulatory hormone concentrations. We induced hypoxemia for 9 days with maternal tracheal N2 gas insufflation to reduce maternal and fetal arterial Po2 by ~20% (HOX) compared with fetuses from ewes receiving intratracheal compressed air (CON). At 0.9 of gestation, fetal metabolic studies were performed (n = 7 CON, 11 HOX). Umbilical blood flow rates, net fetal oxygen and glucose uptake rates, and fetal arterial plasma glucose concentrations were not different between the two groups. Fetal glucose utilization rates were lower in HOX versus CON fetuses but not different from umbilical glucose uptake rates, demonstrating the absence of endogenous glucose production. In liver tissue, mRNA expression of gluconeogenic genes G6PC (P < 0.01) and PCK1 (P = 0.06) were six- and threefold greater in HOX fetuses versus CON fetuses. Increased fetal norepinephrine and cortisol concentrations and hepatic G6PC and PCK1 expression were inversely related to fetal arterial Po2. These findings support a role for fetal hypoxemia to act with counter-regulatory hormones to potentiate fetal hepatic gluconeogenic gene expression. However, in the absence of decreased net fetal glucose uptake rates and plasma glucose concentrations, hypoxemia-induced gluconeogenic gene activation is not sufficient to activate fetal glucose production.

Prolonged amino acid infusion into intrauterine growth-restricted fetal sheep increases leucine oxidation rates.

Overcoming impaired growth in an intrauterine growth-restricted (IUGR) fetus has potential to improve neonatal morbidity, long-term growth, and metabolic health outcomes. The extent to which fetal anabolic capacity persists as the IUGR condition progresses is not known. We subjected fetal sheep to chronic placental insufficiency and tested whether prolonged amino acid infusion would increase protein accretion in these IUGR fetuses. IUGR fetal sheep were infused for 10 days with either mixed amino acids providing ~2 g·kg-1·day-1 (IUGR-AA) or saline (IUGR-Sal) during late gestation. At the end of the infusion, fetal plasma leucine, isoleucine, lysine, methionine, and arginine concentrations were higher in the IUGR-AA than IUGR-Sal group ( P < 0.05). Fetal plasma glucose, oxygen, insulin, IGF-1, cortisol, and norepinephrine concentrations were similar between IUGR groups, but glucagon concentrations were fourfold higher in the IUGR-AA group ( P < 0.05). Net umbilical amino acid uptake rate did not differ between IUGR groups; thus the total amino acid delivery rate (net umbilical amino acid uptake + infusion rate) was higher in the IUGR-AA than IUGR-Sal group (30 ± 4 vs. 19 ± 1 μmol·kg-1·min-1, P < 0.05). Net umbilical glucose, lactate, and oxygen uptake rates were similar between IUGR groups. Fetal leucine oxidation rate, measured using a leucine tracer, was higher in the IUGR-AA than IUGR-Sal group (2.5 ± 0.3 vs. 1.7 ± 0.3 μmol·kg-1·min-1, P < 0.05). Fetal protein accretion rate was not statistically different between the IUGR groups (1.6 ± 0.4 and 0.8 ± 0.3 μmol·kg-1·min-1 in IUGR-AA and IUGR-Sal, respectively) due to variability in response to amino acids. Prolonged amino acid infusion into IUGR fetal sheep increased leucine oxidation rates with variable anabolic response.

Ovine uteroplacental and fetal metabolism during and after fetal cortisol overexposure in late gestation.

Cortisol modifies fetal metabolism in preparation for delivery, but whether preterm cortisol exposure programs persisting changes in fetoplacental metabolism remains unknown. This study infused fetal sheep with saline (n = 36) or cortisol (n = 27) to raise fetal plasma cortisol to normal prepartum concentrations for 5 days from day 125 of gestation (term: ≈145 days). Fetal uptake and uteroplacental metabolism of glucose, oxygen, and lactate, together with fetal hepatic glucogenic capacity, were measured on the final day of infusion or 5 days later. Cortisol reduced adrenal weight and umbilical glucose uptake during infusion but increased fetal glucose concentrations, hepatic glycogen content, and hepatic glucogenic enzyme activity (fructose-1,6-bisphosphatase and glucose-6-phosphatase) and gene expression (PC and G6PC) compared with saline infusion. Postcortisol infusion, umbilical glucose uptake, and hepatic glucose-6-phosphatase activity remained low and high, respectively, whereas fetal glucose levels normalized and hepatic glycogen was lower with higher adrenal weights than in controls. Cortisol infusion increased the proportion of total uterine glucose uptake consumed by the uteroplacental tissues, irrespective of age. Placental tracer glucose transport capacity was also increased after, but not during, cortisol infusion, without changes in placental glucose transporter gene expression. Blood lactate concentration and Pco2 were higher, whereas pH and O2 content were lower in cortisol-infused than saline-infused fetuses, although uteroplacental metabolism and fetal uptake of oxygen and lactate were unaltered. The results suggest that preterm cortisol overexposure alters fetoplacental metabolism and adrenal function subsequently with persisting increases in uteroplacental glucose consumption at the expense of the fetal supply.

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

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.

Adrenal glands are essential for activation of glucogenesis during undernutrition in fetal sheep 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 utilization 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.

The hypoxia of high altitude causes restricted fetal growth in chick embryos with the extent of this effect depending on maternal altitudinal status

The hypoxia of high altitude causes restricted fetal growth in chick embryos with the extent of this effect depending on maternal altitudinal status

Increased insulin sensitivity and maintenance of glucose utilization rates in fetal sheep with placental insufficiency and intrauterine growth restriction

In this study we determined body weight-specific fetal (umbilical) glucose uptake (UGU), utilization (GUR), and production rates (GPR) and insulin action in intrauterine growth-restricted (IUGR) fetal sheep. During basal conditions, UGU from the placenta was 33% lower in IUGR fetuses, but GUR was not different between IUGR and control fetuses. The difference between glucose utilization and UGU rates in the IUGR fetuses demonstrated the presence and rate of fetal GPR (41% of GUR). The mRNA concentrations of the gluconeogenic enzymes glucose-6-phophatase and PEPCK were higher in the livers of IUGR fetuses, perhaps in response to CREB activation, as phosphorylated CREB/total CREB was increased 4.2-fold. A hyperglycemic clamp resulted in similar rates of glucose uptake and utilization in IUGR and control fetuses. The nearly identical GURs in IUGR and control fetuses at both basal and high glucose concentrations occurred at mean plasma insulin concentrations in the IUGR fetuses that were approximately 70% lower than controls, indicating increased insulin sensitivity. Furthermore, under basal conditions, hepatic glycogen content was similar, skeletal muscle glycogen was increased 2.2-fold, the fraction of fetal GUR that was oxidized was 32% lower, and GLUT1 and GLUT4 concentrations in liver and skeletal muscle were the same in IUGR fetuses compared with controls. These results indicate that insulin-responsive fetal tissues (liver and skeletal muscle) adapt to the hypoglycemic-hypoinsulinemic IUGR environment with mechanisms that promote glucose utilization, particularly for glucose storage, including increased insulin action, glucose production, shunting of glucose utilization to glycogen production, and maintenance of glucose transporter concentrations.

Effects of Pituitary Hormone Deficiency on Growth and Glucose Metabolism of the Sheep Fetus

Pituitary hormones are essential for normal growth and metabolic responsiveness after birth, but their role before birth remains unclear. This study examined the effects of hypophysectomizing fetal sheep on their growth and glucose metabolism during the late normal and extended periods of gestation, and on their metabolic response to maternal fasting for 48 h near term. Fetal hypophysectomy reduced crown rump length (CRL), limb lengths, and body weight but increased ponderal index relative to controls near normal term. It also lowered the daily rate of crown rump length increment uniformly from 35 d before, to 20 d after normal term. Hypophysectomized (HX) fetuses had normal weight-specific rates of umbilical uptake, utilization, and oxidation of glucose but lower rates of umbilical oxygen uptake than controls near term. All these metabolic rates were significantly less in HX fetuses during the extended period of gestation than in HX and intact fetuses near normal term. In contrast to controls, glucogenesis was negligible in HX fetuses during maternal fasting. Consequently, the rate of glucose utilization decreased significantly in fasted HX but not intact fetuses. Conversely, the rate of CO(2) production from glucose carbon decreased in fasted intact but not HX fetuses. Fetal hypophysectomy also prevented the fasting-induced increases in plasma cortisol and norepinephrine concentrations seen in controls. These findings demonstrate that the pituitary hormones are important in regulating the growth rate and adaptive responses of glucose metabolism to undernutrition in fetal sheep. They also suggest that fetal metabolism is altered when gestational length is extended.

Placental glucose transport in growth-restricted pregnancies induced by overnourishing adolescent sheep.

Glucose clamp procedures were used to determine whether the slowing of fetal growth during the final third of gestation in overnourished adolescent ewes is due to a reduction in placental glucose transport capacity. Singleton pregnancies to a single sire were established by embryo transfer and thereafter adolescent dams were offered a high (n = 11) or moderate (n = 7) nutrient intake. Studies were conducted at 130 +/- 0.5 days gestation. Uterine and umbilical blood flows were studied by the steady-state transplacental diffusion technique and glucose fluxes quantified by the Fick principle. To determine the relationship between the transplacental glucose gradient and umbilical (fetal) glucose uptake, studies were conducted with maternal arterial glucose clamped at 5 micromol ml(-1) and fetal glucose at spontaneously occurring and two additional higher levels. Maternal body weight gain during gestation averaged 282 and 57 g day(-1) for high- and moderate-intake dams, respectively. Total placentome weight (209 +/- 23 vs. 386 +/- 34 g) and fetal weight (3072 +/- 266 vs. 4670 +/- 196 g) were lower (P < 0.001) in high- than in moderate-intake groups. The growth-restricted pregnancies in the high-intake dams were associated with reduced uterine (P < 0.05) and umbilical (P < 0.02) blood flows and, in the non-perturbed state, the fetuses were relatively hypoxic (2.1 vs. 3.0 micromol ml(-1), P < 0.05) and hypoglycaemic (0.90 vs. 1.31 micromol ml(-1), P < 0.002). Linear regression analysis of umbilical glucose uptake at three steady-state uterine-umbilical arterial transplacental plasma glucose concentration gradients revealed that absolute placental glucose transport capacity was lower in high- than in moderate-intake dams (mean slope, 0.8 vs. 1.5 dl min(-1), P < 0.05; and mean intercept, 1.84 vs. 3.40 micromol ml(-1)). However, glucose transfer capacity was not different between the two groups when expressed on a placental weight-specific basis. This confirms that the small size of the placenta per se is the major limitation to placental glucose transfer in the overnourished adolescent pregnant sheep.

Fetal hepatic and umbilical uptakes of glucogenic substrates during a glucagon-somatostatin infusion.

To test the hypothesis that fetal hepatic glutamate output diverts the products of hepatic amino acid metabolism from hepatic gluconeogenesis, ovine fetal hepatic and umbilical uptakes of glucose and glucogenic substrates were measured before and during fetal glucagon-somatostatin (GS) infusion and during the combined infusion of GS, alanine, glutamine, and arginine. Before the infusions, hepatic uptake of lactate, alanine, glutamine, arginine, and other substrates was accompanied by hepatic output of pyruvate, aspartate, serine, glutamate, and ornithine. The GS infusion induced hepatic output of 1.00 +/- 0.07 mol glucose carbon/mol O(2) uptake, an equivalent reduction in hepatic output of pyruvate and glutamate carbon, a decrease in umbilical glucose uptake and placental uptake of fetal glutamate, an increase in hepatic alanine and arginine clearances, and a decrease in umbilical alanine, glutamine, and arginine uptakes. The latter result suggests that glucagon inhibits umbilical amino acid uptake. We conclude that fetal hepatic pyruvate and glutamate output is part of an adaptation to placental function that requires the fetal liver to maintain both a high rate of catabolism of glucogenic substrates and a low rate of gluconeogenesis.

Ontogenic and nutritionally induced changes in fetal metabolism in the horse.

1. Using the Fick principle and tracer methodology, the metabolic rates of chronically catheterized fetal foals (n = 24) were measured at different gestational ages during the second half of gestation and in response to maternal fasting for 36 h in late gestation (n = 4, term approximately 335 days). 2. Absolute rates of umbilical blood flow, fetal glucose utilization and umbilical uptake of oxygen (O2) and glucose increased from mid-gestation to 300 days and then plateauxed until term. The absolute rate of umbilical lactate uptake was significant after, but not before, 280 days of gestation. Weight specific rates of umbilical uptake and fetal utilization of glucose decreased progressively throughout the second half of gestation. 3. Weight specific rates of CO2 production from glucose carbon were also inversely correlated with gestational age. Umbilical lactate uptake per kilogram of fetus was lower after 320 days than between 281 and 300 days. In contrast, no gestational trends were observed in the weight specific rates of fetal O2 uptake and urea production. Glucose production by the fetal horse was negligible, even very close to term. 4. Maternal fasting for 36 h reduced the rate of umbilical uptake and utilization of glucose production but had no effect on the rates of endogenous glucose production and umbilical uptake of oxygen and lactate by the horse fetus. 5. The observations show that fetal metabolism is highly dependent on glucose in the horse compared to the sheep in mid- and late gestation. Different species therefore adopt different strategies in meeting the nutritional demands of the growing fetus during the second half of gestation.

Metabolic alterations in the fetal hepatic and umbilical circulations during glucocorticoid-induced parturition in sheep.

Fetal hepatic amino acid metabolism has unique features in comparison to postnatal life. Thus, it seemed likely that this metabolism might be changed by the endocrine changes which precede birth. To explore the changes in placental and fetal carbohydrate and amino acid metabolism that occur during parturition, labor was induced in six ewes at 131 +/- 1 d gestation with a fetal infusion of dexamethasone. For purpose of chemical analysis, blood was withdrawn before and approximately 3 and 25 h from the start of the infusion from maternal arterial, uterine venous, umbilical venous, fetal arterial, and left hepatic venous catheters. Fetal oxygenation remained normal. At 25 h, both fetal and maternal arterial plasma glucose concentrations increased (p < 0.01 and p < 0.02, respectively) and umbilical glucose uptake decreased (p < 0.05). Fetal glutamate showed a significant reduction in its hepatic output (p < 0.05) with a concomitant reduction in fetal arterial plasma concentration (p < 0.05) and placental uptake (p < 0.01). Fetal plasma concentrations of several other amino acids were markedly increased. The reduction in placental glutamate uptake was temporally associated with a decline in progesterone release by the pregnant uterus. These data suggest the hypothesis that glutamate plays a role in integrating the complex changes in placental and fetal hepatic metabolism that occur during parturition.

Glucose, lactate and oxygen metabolism in the fetal pig during late gestation.

Using [U-14C]glucose tracer, rates of umbilical uptake, utilization and production of glucose, and of CO2 production from glucose carbon, were measured in seven chronically catheterized fetal pigs, when the sow was in the fed state, between 100 and 113 days of gestation (term, 114 +/- 2 days). At the same time, rates of umbilical O2 and lactate uptake were determined in all seven fetuses by the Fick principle. The mean fetal rates of umbilical glucose uptake, glucose utilization and CO2 production from glucose carbon were 38.4 +/- 4.2, 41.3 +/- 5.2 and 126.9 +/- 12.6 mumol min-1 (kg fetal body weight)-1, respectively (n = 7), No glucose production was therefore detected in the fetuses. Production of CO2 from glucose carbon accounted for 37.3 +/- 3.4% (n = 7) of the umbilical O2 uptake, which averaged 340 +/- 13 mumol min-1 kg-1 (n = 7). There was also significant umbilical lactate uptake in the fetal piglets when the sow was in the fed state (32.6 +/- 10.4 mumol min-1 kg-1, n = 7, P < 0.05). No significant changes in fetal glucose, O2 or lactate metabolism were observed with increasing age towards term. The fetal rates of glucose metabolism and of umbilical uptake of O2 and lactate were not correlated with fetal blood glucose level. Hence, glucose is used for both oxidative and non-oxidative metabolism in utero and is an important, although not the sole, source of carbon for metabolic processes in the fetal pig during late gestation.

Effects of circulating IGF-I on glucose and amino acid kinetics in the ovine fetus.

To investigate the role of insulin-like growth factor I (IGF-I) in the regulation of fetal metabolism, the kinetics of leucine, phenylalanine, and glucose were assessed in the chronically catheterized ovine fetus (0.85 gestation) before and during infusion of recombinant human IGF-I (rhIGF-I). Substrate kinetics were determined by tracer dilution. rhIGF-I was infused at 6.7 nmol.kg fetus-1.h-1. Fetal insulin and growth hormone concentrations were significantly decreased by 50% during rhIGF-I infusion. Net umbilical glucose uptake was unchanged, and glucose rate of appearance increased in the fed state only. There were no changes in the net umbilical uptakes of leucine or phenylalanine, but the rates of appearance of both declined during rhIGF-I infusion, indicative of decreased fetal protein breakdown (Ra,Leu 45.4 +/- 1.40 to 40 +/- 1.4 mumol/min in the fed state, 43 +/- 1.5 to 37 +/- 1.5 mumol/min in the fasted state; Ra,Phe 10.7 +/- 0.3 to 10.4 +/- 0.3 mumol/min in the fed state and from 10.7 +/- 0.3 to 9.8 +/- 0.3 mumol/min in the fasted state). Leucine oxidation was also decreased (8.90 +/- 0.76 to 6.52 +/- 0.81 mumol/min, P = 0.025), more so in the fasted than the fed state. These results indicate a significant antiproteolytic endocrine effect for IGF-I in the late-gestation mammalian fetus.

Glucose and oxygen metabolism in the fetal foal during late gestation

With the use of [U-14C]glucose tracer methodology, the rates of umbilical uptake, utilization, oxidation, and production of glucose were determined in nine chronically catheterized fetal foals in the fed state between 268 and 325 days of gestation (term approximately 335 days). At the same time, the rates of umbilical O2 and lactate uptake were measured in all nine fetuses by Fick principle. The mean fetal rates of umbilical glucose uptake, glucose utilization, and CO2 production from glucose carbon were 36.9 +/- 2.5, 36.4 +/- 1.7, and 117.7 +/- 17.4 mumol.min-1.kg fetal body wt-1, respectively (n = 9). Endogenous glucose production was therefore negligible in the fetal foal in the fed state. Production of CO2 from glucose carbon accounted for 40.9 +/- 6.5% of the umbilical O2 uptake, which averaged 292 +/- 15 mumol.min-1.kg-1 (n = 9). No significant changes in fetal glucose or O2 metabolism were observed with increasing gestational age. The rates of umbilical glucose uptake, glucose utilization, and CO2 production from glucose carbon (P < 0.01), but not the rate of umbilical O2 uptake (P > 0.05), were positively correlated with the fetal blood glucose level. There was a significant umbilical lactate uptake in the fetuses older than 290 days (12.3 +/- 4.1 mumol.min-1.kg-1, n = 5, P < 0.05) but not in the younger animals (6.2 +/- 9.6 mumol.min-1.kg-1, n = 4, P > 0.05). Hence, glucose is used for both oxidative and nonoxidative metabolism in utero and is a major, although not the sole, oxidative substrate in the fetal foal during late gestation.