scholarly journals The impact of obesity, sex, and diet on hepatic glucose production in cats

2009 ◽  
Vol 296 (4) ◽  
pp. R936-R943 ◽  
Author(s):  
Saskia Kley ◽  
Margarethe Hoenig ◽  
John Glushka ◽  
Eunsook S. Jin ◽  
Shawn C. Burgess ◽  
...  
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Citrate Synthase ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Glucose Metabolism ◽  
Peripheral Insulin Resistance ◽  
Pyruvate Cycling ◽  
Hepatic Glucose ◽  
The Impact

Obesity is a risk factor for type 2 diabetes in cats. The risk of developing diabetes is severalfold greater for male cats than for females, even after having been neutered early in life. The purpose of this study was to investigate the role of different metabolic pathways in the regulation of endogenous glucose production (EGP) during the fasted state considering these risk factors. A triple tracer protocol using 2H2O, [U-13C3]propionate, and [3,4-13C2]glucose was applied in overnight-fasted cats (12 lean and 12 obese; equal sex distribution) fed three different diets. Compared with lean cats, obese cats had higher insulin ( P < 0.001) but similar blood glucose concentrations. EGP was lower in obese cats ( P < 0.001) due to lower glycogenolysis and gluconeogenesis (GNG; P < 0.03). Insulin, body mass index, and girth correlated negatively with EGP ( P < 0.003). Female obese cats had ∼1.5 times higher fluxes through phosphoenolpyruvate carboxykinase ( P < 0.02) and citrate synthase ( P < 0.05) than male obese cats. However, GNG was not higher because pyruvate cycling was increased 1.5-fold ( P < 0.03). These results support the notion that fasted obese cats have lower hepatic EGP compared with lean cats and are still capable of maintaining fasting euglycemia, despite the well-documented existence of peripheral insulin resistance in obese cats. Our data further suggest that sex-related differences exist in the regulation of hepatic glucose metabolism in obese cats, suggesting that pyruvate cycling acts as a controlling mechanism to modulate EGP. Increased pyruvate cycling could therefore be an important factor in modulating the diabetes risk in female cats.

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.

Involvement of the vagus nerves in the regulation of basal hepatic glucose production in conscious dogs

2002 ◽  
Vol 283 (5) ◽  
pp. E958-E964 ◽  
Author(s):  
Sylvain Cardin ◽  
Konstantin Walmsley ◽  
Doss W. Neal ◽  
Phillip E. Williams ◽  
Alan D. Cherrington
Keyword(s):  
Hepatic Glucose Production ◽  
Control Period ◽  
Glucose Production ◽  
Heart Rate Change ◽  
Vagus Nerves ◽  
Hepatic Glucose Metabolism ◽  
Vagal Blockade ◽  
Hepatic Glucose ◽  
Cooling Coils ◽  
Glucose Output

We determined if blocking transmission in the fibers of the vagus nerves would affect basal hepatic glucose metabolism in the 18-h-fasted conscious dog. A pancreatic clamp (somatostatin, basal portal insulin, and glucagon) was employed. A 40-min control period was followed by a 90-min test period. In one group, stainless steel cooling coils (Sham, n = 5) were perfused with a 37°C solution, while in the other (Cool, n = 6), the coils were perfused with −20°C solution. Vagal blockade was verified by heart rate change (80 ± 9 to 84 ± 14 beats/min in Sham; 98 ± 12 to 193 ± 22 beats/min in Cool). The arterial glucose level was kept euglycemic by glucose infusion. No change in tracer-determined glucose production occurred in Sham, whereas in Cool it dropped significantly (2.4 ± 0.4 to 1.9 ± 0.4 mg · kg−1· min−1). Net hepatic glucose output did not change in Sham but decreased from 1.9 ± 0.3 to 1.3 ± 0.3 mg · kg−1· min−1in the Cool group. Hepatic gluconeogenesis did not change in either group. These data suggest that vagal blockade acutely modulates hepatic glucose production by inhibiting glycogenolysis.

Increased hepatic glucose production response to glucagon in trained subjects

1998 ◽  
Vol 274 (1) ◽  
pp. E23-E28 ◽  
Author(s):  
Réjean Drouin ◽  
Carole Lavoie ◽  
Josée Bourque ◽  
Francine Ducros ◽  
Danielle Poisson ◽  
...  
Keyword(s):  
Endurance Training ◽  
Hepatic Glucose Production ◽  
Area Under The Curve ◽  
Glucose Production ◽  
Trained Subjects ◽  
Endogenous Insulin ◽  
Hepatic Glucose ◽  
Glucagon And Insulin ◽  
The Impact ◽  
Male Subjects

This study was designed to characterize the impact of endurance training on the hepatic response to glucagon. We measured the effect of glucagon on hepatic glucose production (HGP) in resting trained ( n = 8) and untrained ( n = 8) healthy male subjects (maximal rate of O2 consumption: 65.9 ± 1.6 vs. 46.8 ± 0.6 ml O2 ⋅ kg−1 ⋅ min−1, respectively, P < 0.001). Endogenous insulin and glucagon were suppressed by somatostatin (somatotropin release-inhibiting hormone) infusion (450 μg/h) over 4 h. Insulin (0.15 mU ⋅ kg−1 ⋅ min−1) was infused throughout the study, and glucagon (1.5 ng ⋅ kg−1 ⋅ min−1) was infused over the last 2 h. During the latter period, plasma glucagon and insulin remained constant at 138.2 ± 3.1 vs. 145.3 ± 2.1 ng/l and at 95.5 ± 4.5 vs. 96.2 ± 1.9 pmol/l in trained and untrained subjects, respectively. Plasma glucose increased and peaked at 11.4 ± 1.1 mmol/l in trained subjects and at 8.9 ± 0.8 mmol/l in untrained subjects ( P < 0.001). During glucagon stimulation, the mean increase in HGP area under the curve was 15.8 ± 2.8 mol ⋅ kg−1 ⋅ min−1in trained subjects compared with 7.4 ± 1.6 mol ⋅ kg−1 ⋅ min−1in untrained subjects ( P < 0.01) over the first hour and declined to 6.8 ± 2.8 and 4.9 ± 1.4 mol ⋅ kg−1 ⋅ min−1during the second hour. In conclusion, these observations indicate that endurance training is associated with an increase in HGP in response to physiological levels of glucagon, thus suggesting an increase in hepatic glucagon sensitivity.

Gluconeogenesis is associated with high rates of tricarboxylic acid and pyruvate cycling in fasting northern elephant seals

2012 ◽  
Vol 303 (3) ◽  
pp. R340-R352 ◽  
Author(s):  
Cory D. Champagne ◽  
Dorian S. Houser ◽  
Melinda A. Fowler ◽  
Daniel P. Costa ◽  
Daniel E. Crocker
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Glucose Production ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Endogenous Glucose Production ◽  
Large Contribution ◽  
Protein Loss ◽  
Elephant Seals ◽  
Pyruvate Cycling ◽  
Northern Elephant Seals

Animals that endure prolonged periods of food deprivation preserve vital organ function by sparing protein from catabolism. Much of this protein sparing is achieved by reducing metabolic rate and suppressing gluconeogenesis while fasting. Northern elephant seals ( Mirounga angustirostris) endure prolonged fasts of up to 3 mo at multiple life stages. During these fasts, elephant seals maintain high levels of activity and energy expenditure associated with breeding, reproduction, lactation, and development while maintaining rates of glucose production typical of a postabsorptive mammal. Therefore, we investigated how fasting elephant seals meet the requirements of glucose-dependent tissues while suppressing protein catabolism by measuring the contribution of glycogenolysis, glycerol, and phosphoenolpyruvate (PEP) to endogenous glucose production (EGP) during their natural 2-mo postweaning fast. Additionally, pathway flux rates associated with the tricarboxylic acid (TCA) cycle were measured specifically, flux through phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate cycling. The rate of glucose production decreased during the fast (F1,13= 5.7, P = 0.04) but remained similar to that of postabsorptive mammals. The fractional contributions of glycogen, glycerol, and PEP did not change with fasting; PEP was the primary gluconeogenic precursor and accounted for ∼95% of EGP. This large contribution of PEP to glucose production occurred without substantial protein loss. Fluxes through the TCA cycle, PEPCK, and pyruvate cycling were higher than reported in other species and were the most energetically costly component of hepatic carbohydrate metabolism. The active pyruvate recycling fluxes detected in elephant seals may serve to rectify gluconeogeneic PEP production during restricted anaplerotic inflow in these fasting-adapted animals.

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.

scholarly journals Effect of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glucose metabolism in the conscious dog

2010 ◽  
Vol 298 (5) ◽  
pp. E1019-E1026 ◽  
Author(s):  
Dale S. Edgerton ◽  
Rita Basu ◽  
Christopher J. Ramnanan ◽  
Tiffany D. Farmer ◽  
Doss Neal ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hydroxysteroid Dehydrogenase ◽  
Insulin Deficiency ◽  
Potential Therapeutic Target ◽  
Hepatic Glucose Metabolism ◽  
Hepatic Glucose ◽  
Healthy Dogs ◽  
Excess Glucose

Inactive cortisone is converted to active cortisol within the liver by 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), and impaired regulation of this process may be related to increased hepatic glucose production (HGP) in individuals with type 2 diabetes. The primary aim of this study was to investigate the effect of acute 11β-HSD1 inhibition on HGP and fat metabolism during insulin deficiency. Sixteen conscious, 42-h-fasted, lean, healthy dogs were studied. Somatostatin was infused to create insulin deficiency, and the animals were treated with a specific 11β-HSD1 inhibitor (compound 531) or placebo for 5 h. 11β-HSD1 inhibition completely suppressed hepatic cortisol production, and this attenuated the increase in HGP that occurred during insulin deficiency. PEPCK and glucose-6-phosphatase expression were decreased when 11β-HSD1 was inhibited, but gluconeogenic flux was unchanged, implying an effect on glycogenolysis. Since inhibition of hepatic cortisol production reduces HGP during insulin deficiency, 11β-HSD1 is a potential therapeutic target for the treatment of excess glucose production that occurs in diabetes.

Insulin Control of Hepatic Glucose Production

1975 ◽  
Vol 53 (1) ◽  
pp. 28-36 ◽  
Author(s):  
Nobuo Matsuura ◽  
Jose S. Cheng ◽  
Norman Kalant
Keyword(s):  
Phosphatase Activity ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Hepatic Glucose Production ◽  
Initial Period ◽  
Control Point ◽  
Glucose Production ◽  
Rapid Fall ◽  
Hepatic Glucose ◽  
Insulin Control ◽  
Glucose Output

Insulin injected intravenously caused a rapid, marked decrease in hepatic glucose secretion in the rabbit, as determined by an isotope-dilution procedure. This was associated with a decrease in the concentrations of gluconeogenic intermediates from phosphoenolpyruvate to triose phosphates, inclusive, compatible with inhibition of gluconeogenesis at phosphoenolpyruvate carboxykinase. The concentration of glucose 6-phosphate was unaltered but that of hepatic glucose was reduced. The specific activities of the hexose phosphates, relative to that of liver glucose, were the same in control and insulin-treated animals. These observations can be explained by a decrease in the activity of glucose-6-phosphatase. It is concluded that this enzyme is a control point for hepatic glucose production and is inhibited by insulin.In the rat, insulin produced a rapid fall in blood sugar. The hepatic glucose output remained normal despite a fall in hepatic glucose 6-phosphate concentration during the initial period of insulin action. This suggests that glucose-6-phosphatase activity was increased. Subsequently the concentration of glucose 6-phosphate returned to normal with no change in the rate of glucose production. The data suggest that in the rat, insulin produces a transient increase in glucose-6-phosphatase activity.

scholarly journals Mass spectrometry-based microassay of 2H and 13C plasma glucose labeling to quantify liver metabolic fluxes in vivo

2015 ◽  
Vol 309 (2) ◽  
pp. E191-E203 ◽  
Author(s):  
Clinton M. Hasenour ◽  
Martha L. Wall ◽  
D. Emerson Ridley ◽  
Curtis C. Hughey ◽  
Freyja D. James ◽  
...  
Keyword(s):  
Steady State ◽  
Plasma Glucose ◽  
Ad Hoc ◽  
Citrate Synthase ◽  
Physiological Stress ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Glucose

Mouse models designed to examine hepatic metabolism are critical to diabetes and obesity research. Thus, a microscale method to quantitatively assess hepatic glucose and intermediary metabolism in conscious, unrestrained mice was developed. [13C3]propionate, [2H2]water, and [6,6-2H2]glucose isotopes were delivered intravenously in short- (9 h) and long-term-fasted (19 h) C57BL/6J mice. GC-MS and mass isotopomer distribution (MID) analysis were performed on three 40-μl arterial plasma glucose samples obtained during the euglycemic isotopic steady state. Model-based regression of hepatic glucose and citric acid cycle (CAC)-related fluxes was performed using a comprehensive isotopomer model to track carbon and hydrogen atom transitions through the network and thereby simulate the MIDs of measured fragment ions. Glucose-6-phosphate production from glycogen diminished, and endogenous glucose production was exclusively gluconeogenic with prolonged fasting. Gluconeogenic flux from phospho enolpyruvate (PEP) remained stable, whereas that from glycerol modestly increased from short- to long-term fasting. CAC flux [i.e., citrate synthase ( V CS)] was reduced with long-term fasting. Interestingly, anaplerosis and cataplerosis increased with fast duration; accordingly, pyruvate carboxylation and the conversion of oxaloacetate to PEP were severalfold higher than V CS in long-term fasted mice. This method utilizes state-of-the-art in vivo methodology and comprehensive isotopomer modeling to quantify hepatic glucose and intermediary fluxes during physiological stress in mice. The small plasma requirements permit serial sampling without stress and the affirmation of steady-state glucose kinetics. Furthermore, the approach can accommodate a broad range of modeling assumptions, isotope tracers, and measurement inputs without the need to introduce ad hoc mathematical approximations.

Effects of fructose on hepatic glucose metabolism in humans

2000 ◽  
Vol 279 (4) ◽  
pp. E907-E911 ◽  
Author(s):  
Mirjam Dirlewanger ◽  
Philippe Schneiter ◽  
Eric Jéquier ◽  
Luc Tappy
Keyword(s):  
Glycogen Synthesis ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Glycogen ◽  
Healthy Humans ◽  
Hepatic Glucose Metabolism ◽  
Insulin Requirements ◽  
Hepatic Glucose ◽  
Total Glucose ◽  
Glucose Output

Hepatic and extrahepatic insulin sensitivity was assessed in six healthy humans from the insulin infusion required to maintain an 8 mmol/l glucose concentration during hyperglycemic pancreatic clamp with or without infusion of 16.7 μmol · kg−1 · min−1fructose. Glucose rate of disappearance (GRd), net endogenous glucose production (NEGP), total glucose output (TGO), and glucose cycling (GC) were measured with [6,6-2H2]- and [2-2H1]glucose. Hepatic glycogen synthesis was estimated from uridine diphosphoglucose (UDPG) kinetics as assessed with [1-13C]galactose and acetaminophen. Fructose infusion increased insulin requirements 2.3-fold to maintain blood glucose. Fructose infusion doubled UDPG turnover, but there was no effect on TGO, GC, NEGP, or GRd under hyperglycemic pancreatic clamp protocol conditions. When insulin concentrations were matched during a second hyperglycemic pancreatic clamp protocol, fructose administration was associated with an 11.1 μmol · kg−1 · min−1increase in TGO, a 7.8 μmol · kg−1 · min−1increase in NEGP, a 2.2 μmol · kg−1 · min−1increase in GC, and a 7.2 μmol · kg−1 · min−1decrease in GRd ( P < 0.05). These results indicate that fructose infusion induces hepatic and extrahepatic insulin resistance in humans.

scholarly journals Systemic bile acids induce insulin resistance in a TGR5-independent manner

2019 ◽  
Vol 316 (5) ◽  
pp. E782-E793 ◽  
Author(s):  
Kristen E. Syring ◽  
Travis J. Cyphert ◽  
Thomas C. Beck ◽  
Charles R. Flynn ◽  
Nicholas A. Mignemi ◽  
...  
Keyword(s):  
Bile Acid ◽  
Insulin Sensitivity ◽  
Bile Acids ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Farnesoid X Receptor ◽  
Serum Bile Acid ◽  
Hepatic Insulin Sensitivity ◽  
Hepatic Glucose ◽  
The Impact

Bile acids are involved in the emulsification and absorption of dietary fats, as well as acting as signaling molecules. Recently, bile acid signaling through farnesoid X receptor and G protein-coupled bile acid receptor (TGR5) has been reported to elicit changes in not only bile acid synthesis but also metabolic processes, including the alteration of gluconeogenic gene expression and energy expenditure. A role for bile acids in glucose metabolism is also supported by a correlation between changes in the metabolic state of patients (i.e., obesity or postbariatric surgery) and altered serum bile acid levels. However, despite evidence for a role for bile acids during metabolically challenging settings, the direct effect of elevated bile acids on insulin action in the absence of metabolic disease has yet to be investigated. The present study examines the impact of acutely elevated plasma bile acid levels on insulin sensitivity using hyperinsulinemic-euglycemic clamps. In wild-type mice, elevated bile acids impair hepatic insulin sensitivity by blunting the insulin suppression of hepatic glucose production. The impaired hepatic insulin sensitivity could not be attributed to TGR5 signaling, as TGR5 knockout mice exhibited a similar inhibition of insulin suppression of hepatic glucose production. Canonical insulin signaling pathways, such as hepatic PKB (or Akt) activation, were not perturbed in these animals. Interestingly, bile acid infusion directly into the portal vein did not result in an impairment in hepatic insulin sensitivity. Overall, the data indicate that acute increases in circulating bile acids in lean mice impair hepatic insulin sensitivity via an indirect mechanism.

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