Effect of Acute Umbilical Cord Compression on Hepatic Carbohydrate Metabolism in the Fetal Lamb

Rudolph, Colin D.; Roman, Christine; Rudolph, Abraham M.

doi:10.1203/00006450-198903000-00002

Cited by 20 publications

(17 citation statements)

References 20 publications

(26 reference statements)

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“…In acute fetal O 2 deprivation, hyperlactatemia arises from ␤-adrenergic stimulation of muscle glycogenolysis by catecholamines, as well as from direct effects of tissue hypoxia (22). Significant gluconeogenesis from lactate does not occur, although it may become a source of glucose upon depletion of hepatic glycogen stores (42).…”

Section: Lactatementioning

confidence: 99%

Adenosine A₁ and A_2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep

Maeda¹,

Koos²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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A 1 and A2A receptor subtypes modulate metabolism in adult mammals. This study was designed to determine the role of these receptors in regulating plasma levels of insulin, glucose, and lactate in 20 chronically catheterized fetal sheep (Ͼ0.8 term). In normoxic fetuses (Pa O 2 ϳ24 Torr), systemic blockade of A1 receptors with DPCPX (n ϭ 6) increased plasma concentrations of insulin, glucose, and lactate, but antagonism of A 2A receptors with ZM-241385 (n ϭ 5) had no significant effects. Intravascular administration of adenosine (n ϭ 9) reduced insulin concentrations and elevated glucose and lactate levels. DPCPX (n ϭ 6) augmented the glycemic and lactatemic responses of adenosine. In contrast, ZM241385 (n ϭ 5) virtually abolished adenosine-induced hyperglycemia and hyperlactatemia. Isocapnic hypoxia (Pa O 2 ϳ13 Torr) suppressed insulinemia and enhanced glycemia and lactatemia, but only the hyperglycemia was blunted by blockade of A1 (n ϭ 6) or A2A (n ϭ 6) receptors. We conclude that 1) endogenous adenosine via A1 receptors depresses plasma concentrations of insulin, glucose, and lactate; 2) exogenous adenosine via A2A receptors increases glucose and lactate levels, but these responses are dampened by stimulation of A1 receptors; and 3) hypoxia, which increases endogenous adenosine concentrations, induces hyperglycemia that is partly mediated by activation of A1 and A2A receptors. We predict that adenosine, via A1 receptors, facilitates at least 12% of glucose uptake and utilization in normoxic fetuses. fetus; hypoxia; metabolism; growth; placenta ADENOSINE REGULATES GLUCOSE metabolism in mammals through several mechanisms that include inhibiting insulin secretion by islet cells, altering insulin transduction, and facilitating intracellular glucose transport. Interstitial levels of adenosine increase substantially in hypoxia, hypoglycemia, or heightened cellular metabolism that can occur through intense neuronal activity or skeletal muscle contractions. The physiological effects of adenosine are mediated through activation of G protein-liganded cell surface receptors that are subdivided into four adenosine receptor subtypes: A 1 , A 2A , A 2B , and A 3 (45). These receptors are connected to classical second-messenger pathways that modulate intracellular cAMP production, phospholipase C pathway, and mitogen-activated protein kinases (45,46). With regard to cAMP, stimulation of A 1 receptors, via inhibition of adenylyl cyclase, generally inhibits intracellular cAMP synthesis, while activation of A 2A and A 2B receptors has the opposite effects.Glucose promotes A 1 and A 2A expression in rat cardiac fibroblasts, while insulin suppresses the expression of A 1 and A 2B receptors (11). Insulin also facilitates the equilibrative transcellular movement of adenosine through stimulation of nucleoside transporters in human umbilical vein endothelial cells (37). Adenosine, in turn, inhibits insulin release via activation of islet A 1 receptors (21, 51). Stimulation of A 1 receptors also enhances glucose uptake in tissues thr...

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Section: Lactatementioning

confidence: 99%

Adenosine A₁ and A_2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep

Maeda¹,

Koos²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Current estimates of mean fetal hepatic VO 2 are based on 4 studies, and range between 1.1 and 3.3 Ìmol/min/gm of tissue [4][5][6][7]. The hepatic to fetal VO 2 ratio was estimated in two of these studies to be 6% [6] and 19% [5].…”

Section: Introductionmentioning

confidence: 99%

Fetal Hepatic Oxygen Consumption under Normal Conditions in the Fetal Lamb

Holcomb

Wilkening²

1999

Neonatology

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Previous measurements of fetal hepatic blood flow have relied on microsphere methodology. Estimates of fetal hepatic oxygen consumption (VO₂), based on these measurements and the oxygen content difference across the fetal hepatic circulation, have been quite variable. To estimate hepatic VO₂ in the fetal lamb by a different methodology, we applied the Fick principle using the steady-state uptake of indocyanine green (ICG) by the fetal liver to measure left hepatic blood flow in 10 pregnant ewes. Sampling catheters were inserted into the fetal external iliac artery, left hepatic vein, and umbilical vein. ICG was infused to steady state (for approximately 60 min) through a fetal brachial vein. Four sets of ICG concentration differences across the circulation of the left hepatic lobe were determined for each animal, and left hepatic lobe blood flow calculated. The oxygen concentration difference was measured simultaneously and VO₂ of the left hepatic lobe calculated. In addition, we measured fetal VO₂ and calculated the ratio of hepatic to fetal VO₂. Left hepatic lobe blood flow was 382.30 ml/min/100 g tissue (COV = 0.32), a result statistically no different than in 4 animals with an independent measurement of hepatic blood flow using an ethanol equilibration method. Hepatic VO₂ was 1.74 μmol/min/g tissue (COV = 0.13), and hepatic to fetal VO₂ ratio was 18.23% (COV = 0.19). Our results indicate that normal fetal hepatic oxygen uptake per gram of tissue is less variable than previously suggested, and that ICG can be applied in the fetus for the purpose of hepatic blood flow measurement.

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“…One of these conditions is decreased fetal glucose supply and fetal plasma glucose concentrations produced during maternal fasting and maternal hypoglycemia (11,26,50). Other conditions that also increase these factors and fetal HGP include acute maternal hypoxia, bilateral uterine artery ligation, umbilical cord compression, and intrauterine growth restriction from placental insufficiency (PI-IUGR) (5,15,25,34,38,40,48). A characteristic that is common to these conditions is fetal hypoxemia or low fetal blood oxygen concentration.…”

mentioning

confidence: 99%

“…A characteristic that is common to these conditions is fetal hypoxemia or low fetal blood oxygen concentration. Studies specifically testing the impact of low blood oxygen concentration and/or low PO 2 on factors regulating fetal HGP are limited to acute hypoxemia, intermittent hypoxemia, or hypoxemia coupled with hypoglycemia such as PI-IUGR (5,15,40,44,48,50). The effect of chronic sustained fetal hypoxemia without hypoglycemia on the factors that regulate HGP has not been studied.…”

mentioning

confidence: 99%

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

Culpepper

Wesolowski

Benjamin

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Wilkening RB, Hay WW Jr, Rozance PJ. Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep. Am J Physiol Regul Integr Comp Physiol 311: R200 -R208, 2016. First published May 11, 2016; doi:10.1152/ajpregu.00037.2016.-Hepatic glucose production (HGP) normally begins just prior to birth. Prolonged fetal hypoglycemia, intrauterine growth restriction, and acute hypoxemia produce an early activation of fetal HGP. To test the hypothesis that prolonged hypoxemia increases factors which regulate HGP, studies were performed in fetuses that were bled to anemic conditions (anemic: n ϭ 11) for 8.9 Ϯ 0.4 days and compared with control fetuses (n ϭ 7). Fetal arterial hematocrit and oxygen content were 32% and 50% lower, respectively, in anemic vs. controls (P Ͻ 0.005). Arterial plasma glucose was 15% higher in the anemic group (P Ͻ 0.05). Hepatic mRNA expression of phosphonenolpyruvate carboxykinase (PCK1) was twofold higher in the anemic group (P Ͻ 0.05). Arterial plasma glucagon concentrations were 70% higher in anemic fetuses compared with controls (P Ͻ 0.05), and they were positively associated with hepatic PCK1 mRNA expression (P Ͻ 0.05). Arterial plasma cortisol concentrations increased 90% in the anemic fetuses (P Ͻ 0.05), but fetal cortisol concentrations were not correlated with hepatic PCK1 mRNA expression. Hepatic glycogen content was 30% lower in anemic vs. control fetuses (P Ͻ 0.05) and was inversely correlated with fetal arterial plasma glucagon concentrations. In isolated primary fetal sheep hepatocytes, incubation in low oxygen (3%) increased PCK1 mRNA threefold compared with incubation in normal oxygen (21%). Together, these results demonstrate that glucagon and PCK1 may potentiate fetal HGP during chronic fetal anemic hypoxemia.glucose; oxygen; PEPCK; glycogen; hepatocyte GLUCOSE IS THE PRINCIPAL ENERGY substrate for the fetus and is essential for normal fetal metabolism and growth. The transport of glucose from the mother to the fetus occurs by facilitated diffusion across the placenta. Therefore, the rate of fetal glucose uptake depends largely on the maternal arterial plasma glucose concentration (19). Normally, transported maternal arterial glucose is the sole source of fetal glucose, and there is no fetal hepatic glucose production (HGP) (20).As part of the transition to extrauterine life, fetal HGP is activated just prior to delivery (13). At birth, infants have a period of reduced glucose intake when they are removed from their placental glucose supply and their mother's milk is being established. Thus, to avoid hypoglycemia, the neonate must rely on endogenous HGP. Fetal sheep at 0.97 gestation have increased endogenous HGP, as well as higher hepatic levels of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK, encoded by PCK1) and glucose-6-phosphatase (G6Pase, encoded by G6PC) compared with 0.95 gestation (11, 13). PEPCK catalyzes the rate-limiting step, and G6Pase catalyzes the final step in gluconeogenesis. Increased perinatal trans...

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Effect of Acute Umbilical Cord Compression on Hepatic Carbohydrate Metabolism in the Fetal Lamb

Cited by 20 publications

References 20 publications

Adenosine A₁ and A_2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep

Adenosine A₁ and A_2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep

Fetal Hepatic Oxygen Consumption under Normal Conditions in the Fetal Lamb

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

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Effect of Acute Umbilical Cord Compression on Hepatic Carbohydrate Metabolism in the Fetal Lamb

Cited by 20 publications

References 20 publications

Adenosine A1 and A2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep

Adenosine A1 and A2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep

Fetal Hepatic Oxygen Consumption under Normal Conditions in the Fetal Lamb

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

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Product

Resources

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Adenosine A₁ and A_2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep

Adenosine A₁ and A_2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep