Glucagon and glucose dynamics in sheep: evidence for glucagon resistance in the fetus

Devaskar, Sherin U.; Ganguli, Supriya; Styer, David J; Devaskar, Uday; Sperling, Mark A.

doi:10.1152/ajpendo.1984.246.3.e256

Cited by 23 publications

(21 citation statements)

References 22 publications

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“…The absence of an increase in norepinephrine in our model suggests a lesser role for catecholamines in mediating the activation of glucose production in response to hypoglycemia. Experimental fetal glucagon administration in fetal sheep induces endogenous hepatic glucose production and decreased glutamate output (4,35,42). Thus our results support a role for increased cortisol and glucagon in activating fetal hepatic glucose production.…”

Section: E310supporting

confidence: 76%

Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia

Houin

Rozance

Brown

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Houin SS, Rozance PJ, Brown LD, Hay WW Jr, Wilkening RB, Thorn SR. Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia. Am J Physiol Endocrinol Metab 308: E306 -E314, 2015. First published December 17, 2014 doi:10.1152/ajpendo.00396.2014.-Reduced fetal glucose supply, induced experimentally or as a result of placental insufficiency, produces an early activation of fetal glucose production. The mechanisms and substrates used to fuel this increased glucose production rate remain unknown. We hypothesized that in response to hypoglycemia, induced experimentally with maternal insulin infusion, the fetal liver would increase uptake of lactate and amino acids (AA), which would combine with hormonal signals to support hepatic glucose production. To test this hypothesis, metabolic studies were done in six late gestation fetal sheep to measure hepatic glucose and substrate flux before (basal) and after [days (d)1 and 4] the start of hypoglycemia. Maternal and fetal glucose concentrations decreased by 50% on d1 and d4 (P Ͻ 0.05). The liver transitioned from net glucose uptake (basal, 5.1 Ϯ 1.5 mol/min) to output by d4 (2.8 Ϯ 1.4 mol/min; P Ͻ 0.05 vs. basal). The [U-13 C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 Ϯ 0.01, vs. d4: 0.89 Ϯ 0.01, P Ͻ 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 (P Ͻ 0.05) and remained elevated throughout the study. This AA uptake was driven largely by decreased glutamate output and increased glycine uptake. Fetal plasma concentrations of insulin were 50% lower, while cortisol and glucagon concentrations increased 56 and 86% during hypoglycemia (P Ͻ 0.05 for basal vs. d4). Thus increased hepatic AA uptake, rather than pyruvate or lactate uptake, and decreased fetal plasma insulin and increased cortisol and glucagon concentrations occur simultaneously with increased fetal hepatic glucose output in response to fetal hypoglycemia.

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Section: E310supporting

confidence: 76%

Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia

Houin

Rozance

Brown

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…Fetal glucagon concentrations increased in the anemic group and correlated with both PCK1 and G6PC mRNA. Glucagon has been previously shown to activate fetal HGP, but the concentrations of glucagon required were greater than 1,000 pg/ml, suggesting fetal hepatic resistance to glucagon relative to adults (10,45). In our study, physiological concentrations of glucagon, 20 -80 pg/ml, correlated with higher PCK1 and G6PC mRNA levels.…”

Section: Discussionsupporting

confidence: 38%

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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“…It was not surprising that the blood glucose concentration tended to increase with supplementing cornstarch, but the differences between treatments were not significant, indicating that there exist mechanisms to regulate the blood glucose concentration within a normal physiological range (Devaskar et al, 1984;Apatu and Barnes, 1991). Serum insulin is highly sensitive to blood glucose, and was increased by supplemental cornstarch in the present study (Figure 1).…”

Section: Blood Metabolites and Insulinmentioning

confidence: 53%

Effects of protein-free energy supplementation on blood metabolites, insulin and hepatic PEPCK gene expression in growing lambs offered rice straw-based diet

Zhang¹,

Chen²,

Li³

et al. 2009

CZECH J ANIM SCI

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Energy supplementation is important for ruminants consuming low quality forage-based diets to achieve a desired rate of gain (Bowman and Sanson, 1996). Most of the studies concerning energy supplementation to forage-based diet were focused on the associative effects in digestive tracts (Caton and Dhuyvetter, 1997;Bodine and Purvis, 2003;Lardy et al., 2004), while little attention has been paid to the effect of supplemental energy on glucose metabolism and protein status in body tissues. It is well known that the fermentation of readily fermentable energy in the rumen will result in enhanced production of volatile fatty acids and lactate ). These changes in end products of rumen fermentation would consequently influence blood glucose metabolism and endocrine (Sowinska et al., 2001;Sano and Fujita, 2006) ABSTRACT: This study was conducted to investigate the effects of increasing levels of protein-free energy supplementation on blood glucose, urea nitrogen, insulin and gene expression of hepatic phosphoenolpyruvate carboxykinase (PEPCK) in growing lambs offered rice straw-based diet. Thirty-six male Hu lambs (3.5 months old) were divided into four equal groups according to body weight. All animals were fed rice straw ad libitum and supplemented with cornstarch at levels of 0 (control), 60, 120, and 180 g/day, respectively, along with 160 g/day of rapeseed meal. The trial lasted for 60 days with the first 15 days for adaptation. Body weight change and feed intake were recorded. Blood samples were taken at different time points after feeding at the end of the trial, and analyzed for blood glucose, total protein, urea nitrogen and insulin. Liver samples were collected and analysed for the mRNA abundance of hepatic PEPCK. Increasing cornstarch showed a low effect on rice straw intake, but increased average daily gain of lambs significantly (P < 0.05). Blood glucose tended to increase with starch supplementation, but altered within a narrow range. Blood urea nitrogen was decreased significantly (P < 0.05) with increment in supplemental starch. Supplementation of starch at 120 or 180 g/day significantly increased the insulin concentration (P < 0.05) compared with the control. The abundance of cytosolic PEPCK (PEPCK-C) mRNA increased 2.47 times and 3.98 times with 60 and 120 g per day of starch supplementation compared with the control, respectively, while the supplementation of 180 g per day of starch showed a low effect on PEPCK-C gene expression (P > 0.05). Amounts of mitochondrial PEPCK (PEPCK-M) mRNA were not affected by the supplementation of starch at any level (P > 0.05). These results indicate that proper energy supplementation increases the expression of PEPCK-C, and consequently gluconeogenesis and blood glucose increase, while excessive energy may have an inhibitory effect on gluconeogenesis through insulin-involved mechanisms.

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Glucagon and glucose dynamics in sheep: evidence for glucagon resistance in the fetus

Cited by 23 publications

References 22 publications

Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia

Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia

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

Effects of protein-free energy supplementation on blood metabolites, insulin and hepatic PEPCK gene expression in growing lambs offered rice straw-based diet

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