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

2016 ◽  
Vol 311 (1) ◽  
pp. R200-R208 ◽  
Author(s):  
Christine Culpepper ◽  
Stephanie R. Wesolowski ◽  
Joshua Benjamin ◽  
Jennifer L. Bruce ◽  
Laura D. Brown ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Late Gestation ◽  
Hepatic Glycogen ◽  
Plasma Glucagon ◽  
Low Oxygen ◽  
Fetal Sheep ◽  
Hepatic Glucose ◽  
Arterial Plasma

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 = 11) for 8.9 ± 0.4 days and compared with control fetuses ( n = 7). Fetal arterial hematocrit and oxygen content were 32% and 50% lower, respectively, in anemic vs. controls ( P < 0.005). Arterial plasma glucose was 15% higher in the anemic group ( P < 0.05). Hepatic mRNA expression of phosphonenolpyruvate carboxykinase ( PCK1) was twofold higher in the anemic group ( P < 0.05). Arterial plasma glucagon concentrations were 70% higher in anemic fetuses compared with controls ( P < 0.05), and they were positively associated with hepatic PCK1 mRNA expression ( P < 0.05). Arterial plasma cortisol concentrations increased 90% in the anemic fetuses ( P < 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 < 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.

scholarly journals Exogenous amino acids suppress glucose oxidation and potentiate hepatic glucose production in late gestation fetal sheep

2017 ◽  
Vol 312 (5) ◽  
pp. R654-R663 ◽  
Author(s):  
Laura D. Brown ◽  
Jaden R. Kohn ◽  
Paul J. Rozance ◽  
William W. Hay ◽  
Stephanie R. Wesolowski
Keyword(s):  
Glucose Oxidation ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Oxidation Rates ◽  
Carbon Supply ◽  
Hepatic Glucose ◽  
Arterial Plasma ◽  
Branched Chain

Acute amino acid (AA) infusion increases AA oxidation rates in normal late gestation fetal sheep. Because the fetal oxygen consumption rate does not change with increased AA oxidation, we hypothesized that AA infusion would suppress glucose oxidation pathways and that the additional carbon supply from AA would activate hepatic glucose production. To test this, late gestation fetal sheep were infused intravenously for 3 h with saline or exogenous AA (AA). Glucose tracer metabolic studies were performed and skeletal muscle and liver tissues samples were collected. AA infusion increased fetal arterial plasma branched chain AA, cortisol, and glucagon concentrations. Fetal glucose utilization rates were similar between basal and AA periods, yet the fraction of glucose oxidized and the glucose oxidation rate were decreased by 40% in the AA period. AA infusion increased expression of PDK4, an inhibitor of glucose oxidation, nearly twofold in muscle and liver. In liver, AA infusion tended to increase PCK1 gluconeogenic gene and PCK1 correlated with plasma cortisol concentrations. AA infusion also increased liver mRNA expression of the lactate transporter gene ( MCT1), protein expression of GLUT2 and LDHA, and phosphorylation of AMPK, 4EBP1, and S6 proteins. In isolated fetal hepatocytes, AA supplementation increased glucose production and PCK1, LDHA, and MCT1 gene expression. These results demonstrate that AA infusion into fetal sheep competitively suppresses glucose oxidation and potentiates hepatic glucose production. These metabolic patterns support flexibility in fetal metabolism in response to increased nutrient substrate supply while maintaining a relatively stable rate of oxidative metabolism.

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

2015 ◽  
Vol 308 (4) ◽  
pp. E306-E314 ◽  
Author(s):  
Satya S. Houin ◽  
Paul J. Rozance ◽  
Laura D. Brown ◽  
William W. Hay ◽  
Randall B. Wilkening ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Hepatic Glucose Production ◽  
Plasma Concentrations ◽  
Glucose Production ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Hepatic Glucose ◽  
Molar Percent ◽  
Glucose Output

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 < 0.05). The liver transitioned from net glucose uptake (basal, 5.1 ± 1.5 μmol/min) to output by d4 (2.8 ± 1.4 μmol/min; P < 0.05 vs. basal). The [U-13C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 ± 0.01, vs. d4: 0.89 ± 0.01, P < 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 ( P < 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 < 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.

scholarly journals Control of gluconeogenic genes during intense/prolonged exercise: hormone-independent effect of muscle-derived IL-6 on hepatic tissue and PEPCK mRNA

2009 ◽  
Vol 107 (6) ◽  
pp. 1830-1839 ◽  
Author(s):  
Sébastien Banzet ◽  
Nathalie Koulmann ◽  
Nadine Simler ◽  
Hervé Sanchez ◽  
Rachel Chapot ◽  
...  
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Independent Effect ◽  
Hepatic Tissue ◽  
Hepatic Glycogen ◽  
Mrna Levels ◽  
Hepatic Glucose ◽  
Responsive Gene ◽  
Gene Mrna

Prolonged intense exercise is challenging for the liver to maintain plasma glucose levels. Hormonal changes cannot fully account for exercise-induced hepatic glucose production (HGP). Contracting skeletal muscles release interleukin-6 (IL-6), a cytokine able to increase endogenous glucose production during exercise. However, whether this is attributable to a direct effect of IL-6 on liver remains unknown. Here, we studied hepatic glycogen, gluconeogenic genes, and IL-6 signaling in response to one bout of exhaustive running exercise in rats. To determine whether IL-6 can modulate gluconeogenic gene mRNA independently of exercise, we injected resting rats with recombinant IL-6. Exhaustive exercise resulted in a profound decrease in liver glycogen and an increase in gluconeogenic gene mRNA levels, phosphoenolpyruvate-carboxykinase (PEPCK), glucose-6-phosphatase (G6P), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), suggesting a key role for gluconeogenesis in hepatic glucose production. This was associated to an active IL-6 signaling in liver tissue, as shown by signal transducer and activator of transcription and CAAT/enhancer binding protein-β phosphorylation and IL-6-responsive gene mRNA levels at the end of exercise. Recombinant IL-6 injection resulted in an increase in IL-6-responsive gene mRNA levels in the liver. We found a dose-dependent increase in PEPCK gene mRNA strongly correlated with IL-6-induced gene mRNA levels. No changes in G6P and PGC-1α mRNA levels were found. Taken together, our results suggest that, during very demanding exercise, muscle-derived IL-6 could help increase HGP by directly upregulating PEPCK mRNA abundance.

scholarly journals Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver

2020 ◽  
Vol 117 (12) ◽  
pp. 6733-6740 ◽  
Author(s):  
Thiago M. Batista ◽  
Sezin Dagdeviren ◽  
Shannon H. Carroll ◽  
Weikang Cai ◽  
Veronika Y. Melnik ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Insulin Action ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Hepatic Glycogen ◽  
Glycogen Accumulation ◽  
Hepatic Glucose ◽  
Glucose Output

Insulin action in the liver is critical for glucose homeostasis through regulation of glycogen synthesis and glucose output. Arrestin domain-containing 3 (Arrdc3) is a member of the α-arrestin family previously linked to human obesity. Here, we show thatArrdc3is differentially regulated by insulin in vivo in mice undergoing euglycemic-hyperinsulinemic clamps, being highly up-regulated in liver and down-regulated in muscle and fat. Mice with liver-specific knockout (KO) of the insulin receptor (IR) have a 50% reduction inArrdc3messenger RNA, while, conversely, mice with liver-specific KO ofArrdc3(L-Arrdc3KO) have increased IR protein in plasma membrane. This leads to increased hepatic insulin sensitivity with increased phosphorylation of FOXO1, reduced expression of PEPCK, and increased glucokinase expression resulting in reduced hepatic glucose production and increased hepatic glycogen accumulation. These effects are due to interaction of ARRDC3 with IR resulting in phosphorylation of ARRDC3 on a conserved tyrosine (Y382) in the carboxyl-terminal domain. Thus,Arrdc3is an insulin target gene, and ARRDC3 protein directly interacts with IR to serve as a feedback regulator of insulin action in control of liver metabolism.

scholarly journals The Δ337T mutation on the TRβ causes alterations in growth, adiposity, and hepatic glucose homeostasis in mice

2011 ◽  
Vol 211 (1) ◽  
pp. 39-46 ◽  
Author(s):  
L A Santiago ◽  
D A Santiago ◽  
L C Faustino ◽  
A Cordeiro ◽  
P C Lisboa ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Thyroid Hormone Receptor ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Hepatic Glycogen ◽  
Dominant Negative Mutation ◽  
Hepatic Glucose

Mice bearing the genomic mutation Δ337T on the thyroid hormone receptor β (TRβ) gene present the classical signs of resistance to thyroid hormone (TH), with high serum TH and TSH. This mutant TR is unable to bind TH, remains constitutively bound to co-repressors, and has a dominant negative effect on normal TRs. In this study, we show that homozygous (TRβΔ337T) mice for this mutation have reduced body weight, length, and body fat content, despite augmented relative food intake and relative increase in serum leptin. TRβΔ337T mice exhibited normal glycemia and were more tolerant to an i.p. glucose load accompanied by reduced insulin secretion. Higher insulin sensitivity was observed after single insulin injection, when the TRβΔ337T mice developed a profound hypoglycemia. Impaired hepatic glucose production was confirmed by the reduction in glucose generation after pyruvate administration. In addition, hepatic glycogen content was lower in homozygous TRβΔ337T mice than in wild type. Collectively, the data suggest that TRβΔ337T mice have deficient hepatic glucose production, by reduced gluconeogenesis and lower glycogen deposits. Analysis of liver gluconeogenic gene expression showed a reduction in the mRNA of phosphoenolpyruvate carboxykinase, a rate-limiting enzyme, and of peroxisome proliferator-activated receptor-γ coactivator 1α, a key transcriptional factor essential to gluconeogenesis. Reduction in both gene expressions is consistent with resistance to TH action via TRβ, reproducing a hypothyroid phenotype. In conclusion, mice carrying the Δ337T-dominant negative mutation on the TRβ are leaner, exhibit impaired hepatic glucose production, and are more sensitive to hypoglycemic effects of insulin.

Interaction of free fatty acids and epinephrine in regulating hepatic glucose production in conscious dogs

2003 ◽  
Vol 284 (2) ◽  
pp. E291-E301 ◽  
Author(s):  
Chang An Chu ◽  
Pietro Galassetti ◽  
Kayano Igawa ◽  
Dana K. Sindelar ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Fatty Acids ◽  
High Glucose ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Conscious Dogs ◽  
Control Groups ◽  
Hepatic Glucose ◽  
Glycogenolytic Effect ◽  
Plasma Ffa ◽  
Arterial Plasma

To determine the effects of an increase in lipolysis on the glycogenolytic effect of epinephrine (EPI), the catecholamine was infused portally into 18-h-fasted conscious dogs maintained on a pancreatic clamp in the presence [portal (Po)-EPI+FFA, n = 6] and absence (Po-EPI+SAL, n = 6) of peripheral Intralipid infusion. Control groups with high glucose (70% increase) and free fatty acid (FFA; 200% increase; HG+FFA, n = 6) and high glucose alone (HG+SAL, n = 6) were also included. Hepatic sinusoidal EPI levels were elevated (Δ568 ± 77 and Δ527 ± 37 pg/ml, respectively) in Po-EPI+SAL and EPI+FFA but remained basal in HG+FFA and HG+SAL. Arterial plasma FFA increased from 613 ± 73 to 1,633 ± 101 and 746 ± 112 to 1,898 ± 237 μmol/l in Po-EPI+FFA and HG+FFA but did not change in EPI+SAL or HG+SAL. Net hepatic glycogenolysis increased from 1.5 ± 0.3 to 3.1 ± 0.4 mg · kg−1 · min−1( P < 0.05) by 30 min in response to portal EPI but did not rise (1.8 ± 0.2 to 2.1 ± 0.3 mg · kg−1 · min−1) in response to Po-EPI+FFA. Net hepatic glycogenolysis decreased from 1.7 ± 0.2 to 0.9 ± 0.2 and 1.6 ± 0.2 to 0.7 ± 0.2 mg · kg−1 · min−1by 30 min in HG+FFA and HG+SAL. Hepatic gluconeogenic flux to glucose 6-phosphate increased from 0.6 ± 0.1 to 1.2 ± 0.1 mg · kg−1 · min−1( P < 0.05; by 3 h) and 0.7 ± 0.1 to 1.6 ± 0.1 mg · kg−1 · min−1( P < 0.05; at 90 min) in HG+FFA and Po-EPI+FFA. The gluconeogenic parameters remained unchanged in the Po-EPI+SAL and HG+SAL groups. In conclusion, increased FFA markedly changed the mechanism by which EPI stimulated hepatic glucose production, suggesting that its overall lipolytic effect may be important in determining its effect on the liver.

Effect of somatostatin on plasma glucagon and insulin, and glucose turnover in exercising sheep

1979 ◽  
Vol 47 (2) ◽  
pp. 273-278 ◽  
Author(s):  
R. P. Brockman
Keyword(s):  
Insulin Secretion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Strenuous Exercise ◽  
Glucose Turnover ◽  
Moderate Exercise ◽  
Plasma Glucagon ◽  
Hepatic Glucose ◽  
Exercise Induced ◽  
Glucagon And Insulin

To examine the roles of glucagon and insulin in exercise, four sheep were run on a treadmill with and without simultaneous infusion of somatostatin (SRIF), a peptide that suppresses glucagon and insulin secretion. SRIF infusion suppressed the exercise-induced rise in plasma glucagon during both moderate (5--5.5 km/h) and strenuous exercise (7.0 km/h). In addition, SRIF prevented the rise insulin concentrations during moderate exercise. During strenuous exercise, insulin concentrations were depressed in both groups. The infusion of SRIF was associated with a reduction in exercise-induced glucose production, as determined by infusion of [6–3H]glucose, during the first 15 min of both moderate and strenuous exercise compared to controls. Beyond 15 min glucose production was not significantly altered by SRIF infusions. These data are consistent with glucagon having an immediate, but only transient, stimulatory effect on the exercise-induced hepatic glucose production.

scholarly journals Autoregulation of hepatic glucose production

1998 ◽  
pp. 240-248 ◽  
Author(s):  
MC Moore ◽  
CC Connolly ◽  
AD Cherrington
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Glycogen ◽  
Neural Pathways ◽  
Hepatic Glucose Output ◽  
Counterregulatory Hormones ◽  
Hepatic Glucose ◽  
Glucose Output

In vitro evidence indicates that the liver responds directly to changes in circulating glucose concentrations with reciprocal changes in glucose production and that this autoregulation plays a role in maintenance of normoglycemia. Under in vivo conditions it is difficult to separate the effects of glucose on neural regulation mediated by the central nervous system from its direct effect on the liver. Nevertheless, it is clear that nonhormonal mechanisms can cause significant changes in net hepatic glucose balance. In response to hyperglycemia, net hepatic glucose output can be decreased by as much as 60-90% by nonhormonal mechanisms. Under conditions in which hepatic glycogen stores are high (i.e. the overnight-fasted state), a decrease in the glycogenolytic rate and an increase in the rate of glucose cycling within the liver appear to be the explanation for the decrease in hepatic glucose output seen in response to hyperglycemia. During more prolonged fasting, when glycogen levels are reduced, a decrease in gluconeogenesis may occur as a part of the nonhormonal response to hyperglycemia. A substantial role for hepatic autoregulation in the response to insulin-induced hypoglycemia is most clearly evident in severe hypoglycemia (< or = 2.8 mmol/l). The nonhormonal response to hypoglycemia apparently involves enhancement of both gluconeogenesis and glycogenolysis and is capable of supplying enough glucose to meet at least half of the requirement of the brain. The nonhormonal response can include neural signaling, as well as autoregulation. However, even in the absence of the ability to secrete counterregulatory hormones (glucocorticoids, catecholamines, and glucagon), dogs with denervated livers (to interrupt neural pathways between the liver and brain) were able to respond to hypoglycemia with increases in net hepatic glucose output. Thus, even though the endocrine system provides the primary response to changes in glycemia, autoregulation plays an important adjunctive role.

scholarly journals Increased Hepatic Glucose Production in Fetal Sheep With Intrauterine Growth Restriction Is Not Suppressed by Insulin

Diabetes ◽  
2012 ◽  
Vol 62 (1) ◽  
pp. 65-73 ◽  
Author(s):  
Stephanie R. Thorn ◽  
Laura D. Brown ◽  
Paul J. Rozance ◽  
William W. Hay ◽  
Jacob E. Friedman
Keyword(s):  
Intrauterine Growth Restriction ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Growth Restriction ◽  
Fetal Sheep ◽  
Intrauterine Growth ◽  
Hepatic Glucose

Influence of prior exercise and liver glycogen content on the sensitivity of the liver to glucagon

2002 ◽  
Vol 92 (1) ◽  
pp. 188-194 ◽  
Author(s):  
Victoria Matas Bonjorn ◽  
Martin G. Latour ◽  
Patrice Bélanger ◽  
Jean-Marc Lavoie
Keyword(s):  
Glucose Utilization ◽  
Glycogen Content ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Liver Glycogen ◽  
Hepatic Glycogen ◽  
Prior Exercise ◽  
Hepatic Glucose ◽  
Increased Sensitivity ◽  
Glucagon And Insulin

The purpose of the present study was to test the hypothesis that a prior period of exercise is associated with an increase in hepatic glucagon sensitivity. Hepatic glucose production (HGP) was measured in four groups of anesthetized rats infused with glucagon (2 μg · kg−1 · min−1 iv) over a period of 60 min. Among these groups, two were normally fed and, therefore, had a normal level of liver glycogen (NG). One of these two groups was killed at rest (NG-Re) and the other after a period of exercise (NG-Ex; 60 min of running, 15–26 m/min, 0% grade). The two other groups of rats had a high hepatic glycogen level (HG), which had been increased by a fast-refed diet, and were also killed either at rest (HG-Re) or after exercise (HG-Ex). Plasma glucagon and insulin levels were increased similarly in all four conditions. Glucagon-induced hyperglycemia was higher ( P < 0.01) in the HG-Re group than in all other groups. HGP in the HG-Re group was not, however, on the whole more elevated than in the NG-Re group. Exercised rats (NG-Ex and HG-Ex) had higher hyperglycemia, HGP, and glucose utilization than rested rats in the first 10 min of the glucagon infusion. HG-Ex group had the highest HGP throughout the 60-min experiment. It is concluded that hyperglucagonemia-induced HGP is stimulated by a prior period of exercise, suggesting an increased sensitivity of the liver to glucagon during exercise.

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