Role of cyclic AMP in regulation of hepatic glucose production during exercise

To investigate the role of sympathoadrenergic activity on glucose production (Ra) during exercise, eight healthy males bicycled 20 min at 41 +/- 2 and 74 +/- 4% maximal O2 uptake (VO2max; mean +/- SE) either without (control; Co) or with blockade of sympathetic nerve activity to liver and adrenal medulla by local anesthesia of the celiac ganglion (Bl). Epinephrine (Epi) was in some experiments infused during blockade to match (normal Epi) or exceed (high Epi) Epi levels during Co. A constant infusion of somatostatin and glucagon was given before and during exercise. At rest, insulin was infused at a rate maintaining euglycemia. During intense exercise, insulin infusion was halved to mimic physiological conditions. During exercise, Ra increased in Co from 14.4 +/- 1.0 to 27.8 +/- 3.0 mumol.min-1.kg-1 (41% VO2max) and to 42.3 +/- 5.2 (74% VO2max; P < 0.05). At 41% VO2max, plasma glucose decreased, whereas it increased during 74% VO2max. Ra was not influenced by Bl. In high Epi, Ra rose more markedly compared with control (P < 0.05), and plasma glucose did not fall during mild exercise and increased more during intense exercise (P < 0.05). Free fatty acid and glycerol concentrations were always lower during exercise with than without celiac blockade. We conclude that high physiological concentrations of Epi can enhance Ra in exercising humans, but normally Epi is not a major stimulus. The study suggests that neither sympathetic liver nerve activity is a major stimulus for Ra during exercise. The Ra response is enhanced by a decrease in insulin and probably by unknown stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

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Multiple metabolic effects of CGRP in conscious rats: role of glycogen synthase and phosphorylase

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.264.1.e1 ◽

1993 ◽

Vol 264 (1) ◽

pp. E1-E10 ◽

Cited By ~ 2

Author(s):

L. Rossetti ◽

S. Farrace ◽

S. B. Choi ◽

A. Giaccari ◽

L. Sloan ◽

...

Keyword(s):

Skeletal Muscle ◽

Glycogen Synthase ◽

Hepatic Glucose Production ◽

Glycogen Synthesis ◽

Plasma Concentrations ◽

Glucose Production ◽

Glucose Disposal ◽

Hepatic Glucose ◽

Intracellular Glucose

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is released at the neuromuscular junction in response to nerve excitation. To examine the relationship between plasma CGRP concentration and intracellular glucose metabolism in conscious rats, we performed insulin (22 pmol.kg-1.min-1) clamp studies combined with the infusion of 0, 20, 50, 100, 200, and 500 pmol.kg-1.min-1 CGRP (plasma concentrations ranging from 2 x 10(-11) to 5 x 10(-9) M). CGRP antagonized insulin's suppression of hepatic glucose production at plasma concentrations (approximately 10(-10) M) that are only two- to fivefold its basal portal concentration. Insulin-mediated glucose disposal was decreased by 20-32% when CGRP was infused at 50 pmol.kg-1.min-1 (plasma concentration 3 x 10(-10) M) or more. The impairment in insulin-stimulated glycogen synthesis in skeletal muscle accounted for all of the CGRP-induced decrease in glucose disposal, while whole body glycolysis was increased despite the reduction in total glucose uptake. The muscle glucose 6-phosphate concentration progressively increased during the CGRP infusions. CGRP inhibited insulin-stimulated glycogen synthase in skeletal muscle with a 50% effective dose of 1.9 +/- 0.36 x 10(-10) M. This effect on glycogen synthase was due to a reduction in enzyme affinity for UDP-glucose, with no changes in the maximal velocity. In vitro CGRP stimulated both hepatic and skeletal muscle adenylate cyclase in a dose-dependent manner. These data suggest that 1) CGRP is a potent antagonist of insulin at the level of muscle glycogen synthesis and hepatic glucose production; 2) inhibition of glycogen synthase is its major biochemical action in skeletal muscle; and 3) these effects are present at concentrations of the peptide that may be in the physiological range for portal vein and skeletal muscle. These data underscore the potential role of CGRP in the physiological modulation of intracellular glucose metabolism.

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Glucagon enhances the direct suppressive effect of insulin on hepatic glucose production in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.272.3.e371 ◽

1997 ◽

Vol 272 (3) ◽

pp. E371-E378 ◽

Cited By ~ 4

Author(s):

G. F. Lewis ◽

M. Vranic ◽

A. Giacca

Keyword(s):

Type I Diabetes ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Insulin Delivery ◽

Suppressive Effect ◽

Type I ◽

Constant Rate ◽

Hepatic Glucose ◽

Infusion Method

The present study examines the role of glucagon in modulating the hepatic and extrahepatic effects of insulin on hepatic glucose production (HGP). We infused glucagon at a constant rate (0.65 ng x kg(-1) x min(-1)) during equimolar portal and peripheral insulin delivery in seven healthy males by our previously published tolbutamide infusion method. In contrast to our previous study, in which glucagon fell by approximately 30% during hyperinsulinemia and suppression of HGP was significantly greater with equimolar peripheral than with portal insulin delivery, HGP was actually suppressed to a lesser extent with peripheral insulin delivery (69 +/- 10%) than when insulin was delivered portally (76 +/- 5%, P < 0.05). To further examine whether glucagon was enhancing the effect of portal insulin, in four additional individuals HGP was suppressed to a greater extent during a tolbutamide infusion when glucagon was administered continuously throughout the basal and hyperinsulinemic periods than when glucagon was infused during the basal period only; HGP suppressed by 63 +/- 3 vs. 52 +/- 3%, respectively, P = 0.02). Tolbutamide had no effect on HGP when infused into three C-peptide-negative individuals with type I diabetes during a low-dose insulin and glucagon infusion. These data suggest that glucagon levels are an important determinant of the balance between insulin's direct and indirect effects on HGP, with glucagon likely potentiating the direct hepatic effect of insulin.

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Predominant Role of Gluconeogenesis in Increased Hepatic Glucose Production in NIDDM

Diabetes ◽

10.2337/diab.38.5.550 ◽

1989 ◽

Vol 38 (5) ◽

pp. 550-557 ◽

Cited By ~ 186

Author(s):

A. Consoli ◽

N. Nurjhan ◽

F. Capani ◽

J. Gerich

Keyword(s):

Hepatic Glucose Production ◽

Glucose Production ◽

Predominant Role ◽

Hepatic Glucose

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THE ROLE OF iNOS FOR HEPATIC GLUCOSE PRODUCTION IN MURINE SEPTIC SHOCK

Shock ◽

10.1097/00024382-200610001-00010 ◽

2006 ◽

Vol 26 (Supplement 1) ◽

pp. 3-4

Author(s):

G. Albuszies ◽

J. Vogt ◽

P. Radermacher ◽

S. Weber ◽

U. Wachter ◽

...

Keyword(s):

Septic Shock ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Glucose

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Role of hepatic glucose production and glucose uptake in the pathogenesis of fasting hyperglycemia in type 2 diabetes: normalization of glucose kinetics by short-term fasting

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.78.3.536 ◽

1994 ◽

Vol 78 (3) ◽

pp. 536-542 ◽

Cited By ~ 16

Author(s):

F. Fery

Keyword(s):

Type 2 Diabetes ◽

Glucose Uptake ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Glucose Kinetics ◽

Short Term ◽

Hepatic Glucose

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Hepatocyte serine palmitoyl transferase 2 deficiency promotes liver C16:0-ceramide accumulation through sphingomyelin hydrolysis and leads to liver damage and dysfunction in mice

10.1101/2021.09.16.460588 ◽

2021 ◽

Author(s):

Justine Lallement ◽

Ilyès Raho ◽

Gregory Merlen ◽

Dominique Rainteau ◽

Mikael Croyal ◽

...

Keyword(s):

Bile Acid ◽

Glucose Tolerance ◽

Metabolic Disorders ◽

De Novo ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Lipid Absorption ◽

Compensatory Mechanism ◽

Hepatic Glucose

Objectives: Ceramides have been shown as lipotoxic inducers, which can trigger apoptosis, inflammation and disturb numerous cell signalling pathways leading to metabolic disorders such as type 2 diabetes (T2D). In this study, we aimed to determine the role of de novo hepatic ceramide synthesis on energy and liver homeostasis in mice. Methods: In order to investigate hepatic role of de novo ceramides synthesis, we generated mice lacking serine palmitoyltransferase 2 (Sptlc2) in hepatocytes using the cre-lox system. SPTLC2 allows condensation of serine and palmitoylCoA and is the rate limiting-enzyme necessary for ceramide de novo synthesis. Sptlc2ΔHep and their littermate controls were fed with high fat diet (HFD) to induce metabolic disorders. Liver ceramides content and metabolic parameters as glucose tolerance, insulin sensitivity, and hepatic glucose production were assessed. As ceramides may have impact on bile acids (BA), we investigated BA pool composition, synthesis and transport. Finally, inflammation and apoptosis were measured in the liver using western blot analysis, pro-inflammatory cytokines expression level and immunohistochemistry. Results: Despite lower expression of hepatic Sptlc2, we observed an increased concentration of hepatic ceramides, especially C16:0-ceramide. Hepatic deletion of Sptlc2 in mice was also associated with an increased neutral sphingomyelinase 2 (nSmase2) expression, and a decreased sphingomyelin content in the liver. We showed that Sptlc2ΔHep mice are protected against body mass gain normally induced by HFD and displayed a decreased body fat mass. BA hydrophobicity was drastically decreased in Sptlc2ΔHep mice, and was associated with a defect in lipid absorption. In addition, an important increase of tauro-murocholic acid T-MCA in BA pool composition of Sptlc2ΔHep mice was associated with a downregulation of the nuclear bile acid receptor FXR target genes in ileum and liver. Sptlc2 deficiency also enhanced glucose tolerance and attenuated hepatic glucose production in an insulin-independent manner. Finally, Sptlc2 disruption promoted progressive development of hepatic fibrosis, apoptosis and inflammation in an age-related manner. Conclusion: Our data demonstrate for the first time a potential compensatory mechanism to regulate hepatic ceramides content from sphingomyelin hydrolysis. In addition, our results highlight the role of hepatic sphingolipid modulation on hepatic glucose production through bile acid composition changes.

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Role of hepatic α- and β-adrenergic receptor stimulation on hepatic glucose production during heavy exercise

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.5.e831 ◽

1997 ◽

Vol 273 (5) ◽

pp. E831-E838 ◽

Cited By ~ 9

Author(s):

Robert H. Coker ◽

Mahesh G. Krishna ◽

D. Brooks Lacy ◽

Deanna P. Bracy ◽

David H. Wasserman

Keyword(s):

Portal Vein ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Test Period ◽

Saline Control ◽

Adrenergic Blockade ◽

Heavy Exercise ◽

Hepatic Glucose ◽

Glucose Output

The role of catecholamines in the control of hepatic glucose production was studied during heavy exercise in dogs, using a technique to selectively block hepatic α- and β-adrenergic receptors. Surgery was done >16 days before the study, at which time catheters were implanted in the carotid artery, portal vein, and hepatic vein for sampling and the portal vein and vena cava for infusions. In addition, flow probes were implanted on the portal vein and hepatic artery. Each study consisted of a 100-min equilibration, a 30-min basal, a 20-min heavy exercise (∼85% of maximum heart rate), a 30-min recovery, and a 30-min adrenergic blockade test period. Either saline (control; n= 7) or α (phentolamine)- and β (propranolol)-adrenergic blockers (Blk; n = 6) were infused in the portal vein. In both groups, epinephrine (Epi) and norepinephrine (NE) were infused in the portal vein during the blockade test period to create supraphysiological levels at the liver. Isotope ([3-3H]glucose) dilution and arteriovenous differences were used to assess hepatic function. Arterial Epi, NE, glucagon, and insulin levels were similar during exercise in both groups. Endogenous glucose production (Ra) rose similarly during exercise to 7.9 ± 1.2 and 7.5 ± 2.0 mg ⋅ kg−1⋅ min−1in control and Blk groups at time = 20 min. Net hepatic glucose output also rose to a similar rate in control and Blk groups with exercise. During the blockade test period, arterial plasma glucose and Rarose to 164 ± 5 mg/dl and 12.0 ± 1.4 mg ⋅ kg−1⋅ min−1, respectively, but were essentially unchanged in Blk. The attenuated response to catecholamine infusion in Blk substantiates the effectiveness of the hepatic adrenergic blockade. In conclusion, these results show that direct hepatic adrenergic stimulation does not participate in the increase in Ra, even during the exaggerated sympathetic response to heavy exercise.

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