Effect of epinephrine on muscle glycogenolysis and insulin-stimulated muscle glycogen synthesis in humans

1998 ◽  
Vol 274 (1) ◽  
pp. E130-E138 ◽  
Author(s):  
Didier Laurent ◽  
Kitt Falk Petersen ◽  
Raymond R. Russell ◽  
Gary W. Cline ◽  
Gerald I. Shulman
Keyword(s):  
Muscle Glycogen ◽  
Glycogen Synthesis ◽  
Whole Body ◽  
Synthesis Rate ◽  
Initial Increase ◽  
Plasma Epinephrine ◽  
Epinephrine Infusion ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Muscle Glycogen Synthesis ◽  
Epinephrine Concentration

To examine the effects of a physiological increase in plasma epinephrine concentration (∼800 pg/ml) on muscle glycogenolysis and insulin-stimulated glycogenesis, we infused epinephrine [1.2 μg ⋅ (m2 body surface)−1 ⋅ min−1] for 2 h and monitored muscle glycogen and glucose 6-phosphate (G-6- P) concentrations with13C/31P nuclear magnetic resonance (NMR) spectroscopy. Epinephrine caused an increase in plasma glucose (Δ ∼50 mg/dl), lactate (Δ ∼1.4 mM), free fatty acids (Δ ∼1,200 μM at peak), and whole body glucose oxidation (Δ ∼0.85 mg ⋅ kg−1 ⋅ min−1) compared with levels in a group of control subjects ( n = 4) in the presence of slight hyperinsulinemia (∼13 μU/ml, n = 8) or basal insulin (∼7 μU/ml, n = 7). However, epinephrine did not induce any detectable changes in glycogen or G-6- P concentrations, whereas muscle inorganic phosphate (Pi) decreased by 35%. Epinephrine infusion during a euglycemic-hyperinsulinemic clamp ( n = 8) caused a 45% decrease in the glucose infusion rate that could be mostly attributed to a 73% decrease in muscle glycogen synthesis rate. After an initial increase to ∼160% of basal values, G-6- Plevels decreased by ∼30% with initiation of the epinephrine infusion. We conclude that a physiological increase in plasma epinephrine concentration 1) has a negligible effect on muscle glycogenolysis at rest, 2) decreases muscle Pi, which may maintain phosphorylase activity at a low level, and 3) causes a major impairment in insulin-stimulated muscle glycogen synthesis, possibly due to inhibition of glucose transport-phosphorylation activity.

Effects of FFA on insulin-stimulated glucose fluxes and muscle glycogen synthase activity in rats

1998 ◽  
Vol 275 (2) ◽  
pp. E338-E344 ◽  
Author(s):  
Joong-Yeol Park ◽  
Chul-Hee Kim ◽  
Sung K. Hong ◽  
Kyo I. Suh ◽  
Ki-Up Lee
Keyword(s):  
Skeletal Muscle ◽  
Muscle Glycogen ◽  
Infusion Rate ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Whole Body ◽  
Heparin Infusion ◽  
Muscle Glycogen Synthesis

To examine effects of free fatty acids (FFA) on insulin-stimulated glucose fluxes, euglycemic hyperinsulinemic (86 pmol ⋅ kg−1 ⋅ min−1) clamps were performed for 5 h in conscious rats with ( n = 8) or without ( n = 8) lipid-heparin infusion. Glucose infusion rate required to maintain euglycemia was not different between the two groups during the first 2 h of clamps but became significantly lower with lipid-heparin infusion in the 3rd h and thereafter. To investigate changes in intracellular glucose metabolism during lipid-heparin infusion, additional clamps ( n = 8 each) were performed for 1, 2, 3, or 5 h with an infusion of [3-3H]glucose. Insulin-stimulated whole body glucose utilization (Rd), glycolysis, and glycogen synthesis were estimated on the basis of tracer concentrations in plasma during the final 40 min of each clamp. Similar to changes in glucose infusion rate, Rd was not different between the two groups in the 1st and 2nd h but was significantly lower with lipid-heparin infusion in the 3rd h and thereafter. Whole body glycolysis was significantly lower with lipid-heparin infusion in all time periods, i.e., 1st, 2nd, 3rd, and 5th h of clamps. In contrast, whole body glycogen synthesis was higher with lipid-heparin infusion in the 1st and 2nd h but lower in the 5th h. Similarly, accumulation of [3H]glycogen radioactivity in muscle glycogen was significantly higher with lipid-heparin during the 1st and 2nd h but lower during the 3rd and 5th h. Glucose 6-phosphate (G-6- P) concentrations in gastrocnemius muscles were significantly higher with lipid-heparin infusion throughout the clamps. Muscle glycogen synthase (GS) activity was not altered with lipid-heparin infusion at 1, 2, and 3 h but was significantly lower at 5 h. Thus increased availability of FFA significantly reduced whole body glycolysis, but compensatory increase in skeletal muscle glycogen synthesis in association with accumulation of G-6- P masked this effect, and Rd was not affected in the early phase (within 2 h) of lipid-heparin infusion. Rd was reduced in the later phase (>2 h) of lipid-heparin infusion, when glycogen synthesis was reduced in association with reduced skeletal muscle GS activity.

scholarly journals Akt2 influences glycogen synthase activity in human skeletal muscle through regulation of NH2-terminal (sites 2 + 2a) phosphorylation

2013 ◽  
Vol 304 (6) ◽  
pp. E631-E639 ◽  
Author(s):  
Martin Friedrichsen ◽  
Jesper B. Birk ◽  
Erik A. Richter ◽  
Rasmus Ribel-Madsen ◽  
Christian Pehmøller ◽  
...  
Keyword(s):  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Fine Tuning ◽  
Whole Body ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Negatively Associated ◽  
Molecular Events ◽  
Muscle Glycogen Synthesis ◽  
Key Enzyme

Type 2 diabetes is characterized by reduced muscle glycogen synthesis. The key enzyme in this process, glycogen synthase (GS), is activated via proximal insulin signaling, but the exact molecular events remain unknown. Previously, we demonstrated that phosphorylation of Thr308 on Akt (p-Akt-Thr308), Akt2 activity, and GS activity in muscle were positively associated with insulin sensitivity. Here, in the same study population, we determined the influence of several upstream elements in the canonical PI3K signaling on muscle GS activation. One-hundred eighty-one nondiabetic twins were examined with the euglycemic hyperinsulinemic clamp combined with excision of muscle biopsies. Insulin signaling was evaluated at the levels of the insulin receptor, IRS-1-associated PI3K (IRS-1-PI3K), Akt, and GS employing activity assays and phosphospecific Western blotting. The insulin-stimulated GS activity was positively associated with p-Akt-Thr308 ( P = 0.01) and Akt2 activity ( P = 0.04) but not p-Akt-Ser473 or IRS-1-PI3K activity. Furthermore, p-Akt-Thr308 and Akt2 activity were negatively associated with NH2-terminal GS phosphorylation ( P = 0.001 for both), which in turn was negatively associated with insulin-stimulated GS activity ( P < 0.001). We found no association between COOH-terminal GS phosphorylation and Akt or GS activity. Employing whole body Akt2-knockout mice, we validated the necessity for Akt2 in insulin-mediated GS activation. However, since insulin did not affect NH2-terminal phosphorylation in mice, we could not use this model to validate the observed association between GS NH2-terminal phosphorylation and Akt activity in humans. In conclusion, our study suggests that although COOH-terminal dephosphorylation is likely necessary for GS activation, Akt2-dependent NH2-terminal dephosphorylation may be the site for “fine-tuning” insulin-mediated GS activation in humans.

Flux control in the rat gastrocnemius glycogen synthesis pathway by in vivo13C/31P NMR spectroscopy

2001 ◽  
Vol 280 (4) ◽  
pp. E598-E607 ◽  
Author(s):  
J. R. Chase ◽  
D. L. Rothman ◽  
R. G. Shulman
Keyword(s):  
Glucose Transport ◽  
Muscle Glycogen ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Synthesis Rate ◽  
31P Nmr Spectroscopy ◽  
Control Analysis ◽  
Control Coefficient ◽  
Flux Control ◽  
Muscle Glycogen Synthesis

To determine the relative contributions of glucose transport/hexokinase, glycogen synthase (GSase), and glycolysis to the control of insulin-stimulated muscle glycogen synthesis, we combined13C and 31P NMR to quantitate the glycogen synthesis rate and glucose 6-phosphate (G-6- P) levels in rat (Sprague-Dawley) gastrocnemius muscle during hyperinsulinemia at euglycemic (E) and hyperglycemic (H) glucose concentrations under thiopental anesthesia. Flux control was calculated using metabolic control analysis. The combined control coefficient of glucose transport/hexokinase (GT/Hk) for glycogen synthesis was 1.1 ± 0.03 (direct measure) and 1.14–1.16 (calculated for a range of glycolytic fluxes), whereas the control coefficient for GSase was much lower (0.011–0.448). We also observed that the increase in in vivo [G-6- P] from E to H (0.22 ± 0.03 to 0.40 ± 0.03 mM) effects a supralinear increase in the in vitro velocity of GSase, from 14.6 to 26.1 mU · kg−1 · min−1 (1.8-fold). All measurements suggest that the majority of the flux control of muscle glycogen synthesis is at the GT/Hk step.

scholarly journals Effect of epinephrine on muscle glycogenolysis during exercise in trained men

1998 ◽  
Vol 84 (2) ◽  
pp. 465-470 ◽  
Author(s):  
M. A. Febbraio ◽  
D. L. Lambert ◽  
R. L. Starkie ◽  
J. Proietto ◽  
M. Hargreaves
Keyword(s):  
Oxygen Uptake ◽  
Muscle Glycogen ◽  
Respiratory Exchange Ratio ◽  
Peak Oxygen Uptake ◽  
Plasma Epinephrine ◽  
Epinephrine Infusion ◽  
Glycogen Utilization ◽  
Muscle Glycogen Concentration ◽  
Epinephrine Concentration

Febbraio, M. A., D. L. Lambert, R. L. Starkie, J. Proietto, and M. Hargreaves. Effect of epinephrine on muscle glycogenolysis during exercise in trained men. J. Appl. Physiol. 84(2): 465–470, 1998.—To test the hypothesis that an elevation in circulating epinephrine increases intramuscular glycogen utilization, six endurance-trained men performed two 40-min cycling trials at 71 ± 2% of peak oxygen uptake in 20–22°C conditions. On the first occasion, subjects were infused with saline throughout exercise (Con). One week later, after determination of plasma epinephrine levels in Con, subjects performed the second trial (Epi) with an epinephrine infusion, which resulted in a twofold higher ( P < 0.01) plasma epinephrine concentration in Epi compared with Con. Although oxygen uptake was not different when the two trials were compared, respiratory exchange ratio was higher throughout exercise in Epi compared with Con (0.93 ± 0.01 vs. 0.89 ± 0.01; P < 0.05). Muscle glycogen concentration was not different when the trials were compared preexercise, but the postexercise value was lower ( P < 0.01) in Epi compared with Con. Thus net muscle glycogen utilization was greater during exercise with epinephrine infusion (224 ± 37 vs. 303 ± 30 mmol/kg for Con and Epi, respectively; P < 0.01). In addition, both muscle and plasma lactate and plasma glucose concentrations were higher ( P < 0.05) in Epi compared with Con. These data indicate that intramuscular glycogen utilization, glycolysis, and carbohydrate oxidation are augmented by elevated epinephrine during submaximal exercise in trained men.

scholarly journals Effects of plasma epinephrine on fat metabolism during exercise: interactions with exercise intensity

2000 ◽  
Vol 278 (4) ◽  
pp. E669-E676 ◽  
Author(s):  
Ricardo Mora-Rodriguez ◽  
Edward F. Coyle
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Exercise Intensity ◽  
Fat Metabolism ◽  
Peak Oxygen Consumption ◽  
Whole Body ◽  
Acid Oxidation ◽  
Plasma Epinephrine ◽  
Epinephrine Infusion ◽  
Epinephrine Concentration

This study determined the effects of elevated plasma epinephrine on fat metabolism during exercise. On four occasions, seven moderately trained subjects cycled at 25% of peak oxygen consumption (V˙o 2 peak) for 60 min. After 15 min of exercise, subjects were intravenously infused with low (0.96 ± 0.10 nM), moderate (1.92 ± 0.24 nM), or high (3.44 ± 0.50 nM) levels (all P < 0.05) of epinephrine to increase plasma epinephrine above control (Con; 0.59 ± 0.10 nM). During the interval between 35 and 55 min of exercise, lipolysis [i.e., rate of appearance of glycerol] increased above Con (4.9 ± 0.5 μmol ⋅ kg−1 ⋅ min−1) with low, moderate, and high (6.5 ± 0.5, 7.1 ± 0.8, and 10.6 ± 1.2 μmol ⋅ kg−1 ⋅ min−1, respectively; all P < 0.05) levels of epinephrine despite simultaneous increases in plasma insulin. The release of fatty acid into plasma also increased progressively with the graded epinephrine infusions. However, fatty acid oxidation was lower than Con (11.1 ± 0.8 μmol ⋅ kg−1 ⋅ min−1) during moderate and high levels (8.7 ± 0.7 and 8.1 ± 0.9 μmol ⋅ kg−1 ⋅ min−1, respectively; P < 0.05). In one additional trial, the same subjects exercised at 45%V˙o 2 peak without epinephrine infusion, which produced a plasma epinephrine concentration identical to low levels. However, lipolysis was lower (i.e., 5.5 ± 0.6 vs. 6.5 ± 0.5 μmol ⋅ kg−1 ⋅ min−1; P < 0.05). In conclusion, elevations in plasma epinephrine concentration during exercise at 25% ofV˙o 2 peak progressively increase whole body lipolysis but decrease fatty acid oxidation. Last, increasing exercise intensity from 25 to 45%V˙o 2 peak attenuates the lipolytic actions of epinephrine.

Effect of infusing epinephrine on liver and muscle glycogenolysis during exercise in rats

1986 ◽  
Vol 250 (6) ◽  
pp. E641-E649 ◽  
Author(s):  
D. A. Arnall ◽  
J. C. Marker ◽  
R. K. Conlee ◽  
W. W. Winder
Keyword(s):  
Muscle Glycogen ◽  
Vastus Lateralis ◽  
Plasma Concentrations ◽  
Physiological Saline ◽  
Threshold Concentration ◽  
Plasma Epinephrine ◽  
Glycogen Depletion ◽  
Epinephrine Infusion ◽  
Liver Glycogenolysis ◽  
Epinephrine Concentration

To determine the possibility of a threshold concentration of plasma epinephrine that stimulates liver glycogenolysis during exercise, adrenodemedullated (ADM) and sham-operated (SHAM) rats were infused with saline or epinephrine at rates that produced plasma concentrations ranging between 0.01 ng/ml (0.06 nM) and 4.3 ng/ml (23.7 nM). During the infusion rats were run on a rodent treadmill for 0, 30, or 60 min at 21 m/min up a 15% grade. Liver glycogen decreased at similar rates in all exercising rats regardless of plasma epinephrine concentration. Epinephrine infusion stimulated significant muscle glycogen depletion in the soleus and red and white vastus lateralis muscles. ADM saline-infused animals exhibited the least muscle glycogen depletion. Blood glucose and lactate in exercising ADM rats increased as the epinephrine infusion concentration increased. During exercise, there was no epinephrine concentration that stimulated liver glycogenolysis more effectively than physiological saline.

Quantitation of glycolysis and skeletal muscle glycogen synthesis in humans

1993 ◽  
Vol 265 (5) ◽  
pp. E761-E769 ◽  
Author(s):  
L. Rossetti ◽  
Y. T. Lee ◽  
J. Ruiz ◽  
S. C. Aldridge ◽  
H. Shamoon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Muscle Glycogen ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Whole Body ◽  
Skeletal Muscle Glycogen ◽  
Muscle Glycogen Synthesis ◽  
The Difference ◽  
Total Glucose

We measured the net rates of skeletal muscle glycogen synthesis and glycolysis (conversion of [3-3H]glucose to 3H2O) in healthy overnight-fasted volunteers. Two studies were performed. In study 1, seven subjects participated in two paired infusions under basal conditions of either [2-3H]glucose (H2) or [3-3H]glucose (H3). Total glucose uptake (Rd) and rates of whole body 3H2O formation (3H2O Ra) were measured. With H2, Rd and 3H2O Ra were similar. With H3, 3H2O Ra, equal to glycolysis, was 65% of Rd. In study 2, six different subjects underwent a 3-h, 40 mU.m-2 x min-1 euglycemic insulin clamp. [6,6-2H2]glucose was infused throughout and H3 was infused during the last hour of the study. Open muscle biopsies were obtained at 150 and 180 min. Glycogen synthesis was assessed by three independent means: 1) direct measurement, as 3H disintegrations per minute in isolated muscle glycogen per plasma H3 specific activity; 2) extrapolation from the activity of glycogen synthase assayed in the presence of the concentrations of glucose 6-phosphate and UDP-glucose measured in the biopsy; and 3) the difference between Rd and glycolysis. Despite a wide range in Rd [24.5-58.8 mumol.kg fat-free mass (FFM)-1 x min-1] and glycolysis (14.2-26.1), the three methods yielded similar results of 20.0 +/- 3.9, 22.5 +/- 3.7, and 20.6 +/- 3.7 mumol.kg FFM-1 x min-1 and correlated highly with each other (r2 = 0.92-0.96). Our results (study 1) indicate that the rate of plasma tritiated water formation reflects the intracellular detritiation of tritiated glucose. Under hyperinsulinemic conditions (study 2) the net rate of muscle glycogen synthesis can be accurately estimated from the glycogen synthase activity and from the difference between total glucose uptake and glycolysis. Thus, at high physiological plasma insulin concentrations resulting in submaximal stimulation of muscle glycogen synthesis, the latter can be accurately measured in humans.

scholarly journals Glycogen Synthesis in Human Gastrocnemius Muscle Is Not Representative of Whole-Body Muscle Glycogen Synthesis

Diabetes ◽  
2005 ◽  
Vol 54 (5) ◽  
pp. 1277-1282 ◽  
Author(s):  
M. J.M. Serlie ◽  
J. H. de Haan ◽  
C. J. Tack ◽  
H. J. Verberne ◽  
M. T. Ackermans ◽  
...  
Keyword(s):  
Muscle Glycogen ◽  
Gastrocnemius Muscle ◽  
Glycogen Synthesis ◽  
Whole Body ◽  
Body Muscle ◽  
Muscle Glycogen Synthesis

Insulin promotes glycogen synthesis in the absence of GSK3 phosphorylation in skeletal muscle

2008 ◽  
Vol 294 (1) ◽  
pp. E28-E35 ◽  
Author(s):  
Michale Bouskila ◽  
Michael F. Hirshman ◽  
Jørgen Jensen ◽  
Laurie J. Goodyear ◽  
Kei Sakamoto
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Muscle Glycogen ◽  
Glycogen Content ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Wild Type ◽  
Muscle Glycogen Synthesis ◽  
Mutant Forms

Insulin promotes dephosphorylation and activation of glycogen synthase (GS) by inactivating glycogen synthase kinase (GSK) 3 through phosphorylation. Insulin also promotes glucose uptake and glucose 6-phosphate (G-6- P) production, which allosterically activates GS. The relative importance of these two regulatory mechanisms in the activation of GS in vivo is unknown. The aim of this study was to investigate if dephosphorylation of GS mediated via GSK3 is required for normal glycogen synthesis in skeletal muscle with insulin. We employed GSK3 knockin mice in which wild-type GSK3α and -β genes are replaced with mutant forms (GSK3α/βS21A/S21A/S9A/S9A), which are nonresponsive to insulin. Although insulin failed to promote dephosphorylation and activation of GS in GSK3α/βS21A/S21A/S9A/S9Amice, glycogen content in different muscles from these mice was similar compared with wild-type mice. Basal and epinephrine-stimulated activity of muscle glycogen phosphorylase was comparable between wild-type and GSK3 knockin mice. Incubation of isolated soleus muscle in Krebs buffer containing 5.5 mM glucose in the presence or absence of insulin revealed that the levels of G-6- P, the rate of [14C]glucose incorporation into glycogen, and an increase in total glycogen content were similar between wild-type and GSK3 knockin mice. Injection of glucose containing 2-deoxy-[3H]glucose and [14C]glucose also resulted in similar rates of muscle glucose uptake and glycogen synthesis in vivo between wild-type and GSK3 knockin mice. These results suggest that insulin-mediated inhibition of GSK3 is not a rate-limiting step in muscle glycogen synthesis in mice. This suggests that allosteric regulation of GS by G-6- P may play a key role in insulin-stimulated muscle glycogen synthesis in vivo.

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