scholarly journals Effects of raising muscle glycogen synthesis rate on skeletal muscle ATP turnover rate in type 2 diabetes

2011 ◽  
Vol 301 (6) ◽  
pp. E1155-E1162 ◽  
Author(s):  
Ee L. Lim ◽  
Kieren G. Hollingsworth ◽  
Fiona E. Smith ◽  
Peter E. Thelwall ◽  
Roy Taylor
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Muscle Glycogen ◽  
Glycogen Synthesis ◽  
Turnover Rates ◽  
Atp Turnover ◽  
Muscle Glycogen Synthesis ◽  
Type 2 Diabetic

Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes. We hypothesized that any impairment in insulin-stimulated muscle ATP production could merely reflect the lower rates of muscle glucose uptake and glycogen synthesis, rather than cause it. If this is correct, muscle ATP turnover rates in type 2 diabetes could be increased if glycogen synthesis rates were normalized by the mass-action effect of hyperglycemia. Isoglycemic- and hyperglycemic-hyperinsulinemic clamps were performed on type 2 diabetic subjects and matched controls, with muscle ATP turnover and glycogen synthesis rates measured using 31P- and 13C-magnetic resonance spectroscopy, respectively. In diabetic subjects, hyperglycemia increased muscle glycogen synthesis rates to the level observed in controls at isoglycemia [from 19 ± 9 to 41 ± 12 μmol·l−1·min−1 ( P = 0.012) vs. 40 ± 7 μmol·l−1·min−1 in controls]. This was accompanied by a modest increase in muscle ATP turnover rates (7.1 ± 0.5 vs. 8.6 ± 0.7 μmol·l−1·min−1, P = 0.04). In controls, hyperglycemia brought about a 2.5-fold increase in glycogen synthesis rates (100 ± 24 vs. 40 ± 7 μmol·l−1·min−1, P = 0.028) and a 23% increase in ATP turnover rates (8.1 ± 0.9 vs. 10.0 ± 0.9 μmol·l−1·min−1, P = 0.025) from basal state. Muscle ATP turnover rates correlated positively with glycogen synthesis rates ( rs = 0.46, P = 0.005). Changing the rate of muscle glucose metabolism in type 2 diabetic subjects alters demand for ATP synthesis at rest. In type 2 diabetes, skeletal muscle ATP turnover rates reflect the rate of glucose uptake and glycogen synthesis, rather than any primary mitochondrial defect.

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.

scholarly journals Inhibition of lipolysis in Type 2 diabetes normalizes glucose disposal without change in muscle glycogen synthesis rates

2011 ◽  
Vol 121 (4) ◽  
pp. 169-177 ◽  
Author(s):  
Ee L. Lim ◽  
Kieren G. Hollingsworth ◽  
Fiona E. Smith ◽  
Peter E. Thelwall ◽  
Roy Taylor
Keyword(s):  
Muscle Glycogen ◽  
Glycogen Synthesis ◽  
Diabetic Group ◽  
Whole Body ◽  
Glucose Disposal ◽  
Resonance Spectroscopy ◽  
Turnover Rates ◽  
Atp Turnover ◽  
Glucose Storage

Suppression of lipolysis by acipimox is known to improve insulin-stimulated glucose disposal, and this is an important phenomenon. The mechanism has been assumed to be an enhancement of glucose storage as glycogen, but no direct measurement has tested this concept or its possible relationship to the reported impairment in insulin-stimulated muscle ATP production. Isoglycaemic–hyperinsulinaemic clamps with [13C]glucose infusion were performed on Type 2 diabetic subjects and matched controls with measurement of glycogen synthesis by 13C MRS (magnetic resonance spectroscopy) of muscle. 31P saturation transfer MRS was used to quantify muscle ATP turnover rates. Glucose disposal rates were restored to near normal in diabetic subjects after acipimox (6.2±0.8 compared with 4.8±0.6 mg·kgffm−1·min−1; P<0.01; control 6.6±0.5 mg·kgffm−1·min−1; where ffm, is fat-free mass). The increment in muscle glycogen concentration was 2-fold higher in controls compared with the diabetic group, and acipimox administration to the diabetic group did not increase this (2.0±0.8 compared with 1.9±1.1 mmol/l; P<0.05; control, 4.0±0.8 mmol/l). ATP turnover rates did not increase during insulin stimulation in any group, but a modest decrease in the diabetes group was prevented by lowering plasma NEFAs (non-esterified fatty acids; 8.4±0.7 compared with 7.1±0.5 μmol·g−1·min−1; P<0.05; controls 8.6±0.8 μmol·g−1·min−1). Suppression of lipolysis increases whole-body glucose uptake with no increase in the rate of glucose storage as glycogen but with increase in whole-body glucose oxidation rate. ATP turnover rate in muscle exhibits no relationship to the acute metabolic effect of insulin.

AMPK activity and isoform protein expression are similar in muscle of obese subjects with and without type 2 diabetes

2004 ◽  
Vol 286 (2) ◽  
pp. E239-E244 ◽  
Author(s):  
Kurt Højlund ◽  
Kirsty J. Mustard ◽  
Peter Stæhr ◽  
D. Grahame Hardie ◽  
Henning Beck-Nielsen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Protein Expression ◽  
Glycogen Synthesis ◽  
Control Subjects ◽  
Subunit Isoforms ◽  
Impaired Insulin Action ◽  
Amp Activated Protein Kinase ◽  
Type 2 Diabetic

Acute or chronic activation of AMP-activated protein kinase (AMPK) increases insulin sensitivity. Conversely, reduced expression and/or function of AMPK might play a role in insulin resistance in type 2 diabetes. Thus protein expression of the seven subunit isoforms of AMPK and activities and/or phosphorylation of AMPK and acetyl-CoA carboxylase-β (ACCβ) was measured in skeletal muscle from obese type 2 diabetic and well-matched control subjects during euglycemic-hyperinsulinemic clamps. Protein expression of all AMPK subunit isoforms (α1, α2, β1, β2, γ1, γ2, and γ3) in muscle of obese type 2 diabetic subjects was similar to that of control subjects. In addition, α1- and α2-associated activities of AMPK, phosphorylation of α-AMPK subunits at Thr172, and phosphorylation of ACCβ at Ser221 showed no difference between the two groups and were not regulated by physiological concentrations of insulin. These data suggest that impaired insulin action on glycogen synthesis and lipid oxidation in skeletal muscle of obese type 2 diabetic subjects is unlikely to involve changes in AMPK expression and activity.

Effect of muscle glycogen content on glucose uptake following exercise

1982 ◽  
Vol 52 (2) ◽  
pp. 434-437 ◽  
Author(s):  
R. D. Fell ◽  
S. E. Terblanche ◽  
J. L. Ivy ◽  
J. C. Young ◽  
J. O. Holloszy
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Muscle Glycogen ◽  
Glycogen Content ◽  
Glycogen Synthesis ◽  
Carbohydrate Restriction ◽  
Exhausting Exercise ◽  
Carbohydrate Feeding ◽  
Muscle Glycogen Synthesis ◽  
Muscle Glycogen Concentration

This study examined the effects of raising muscle glycogen by carbohydrate feeding and of keeping muscle glycogen low by carbohydrate restriction following exhausting exercise on the ability of perfused skeletal muscle to take up glucose and to synthesize glycogen. Muscle glycogen concentration was more than twice as high in the rats fed carbohydrate as in those not given carbohydrate. Muscle glycogen synthesis during a 30-min perfusion with glucose and insulin was significantly greater in the animals with low muscle glycogen. Furthermore the muscles with low glycogen content converted a greater proportion of the glucose taken up to glycogen and less to lactate than did the muscles with high glycogen content. In rats subjected to exhausting exercise on the preceding day, the rate of glucose uptake by perfused skeletal muscle was significantly higher (60–80%) at the same insulin concentration in animals in which muscle glycogen was kept low than in those in which glycogen was raised by carbohydrate feeding.

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.

Impaired Glucose Transport as a Cause of Decreased Insulin-Stimulated Muscle Glycogen Synthesis in Type 2 Diabetes

1999 ◽  
Vol 341 (4) ◽  
pp. 240-246 ◽  
Author(s):  
Gary W. Cline ◽  
Kitt Falk Petersen ◽  
Martin Krssak ◽  
Jun Shen ◽  
Ripudaman S. Hundal ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Transport ◽  
Muscle Glycogen ◽  
Glycogen Synthesis ◽  
Muscle Glycogen Synthesis

scholarly journals Low-Dose Acrolein, an Endogenous and Exogenous Toxic Molecule, Inhibits Glucose Transport via an Inhibition of Akt-Regulated GLUT4 Signaling in Skeletal Muscle Cells

2021 ◽  
Vol 22 (13) ◽  
pp. 7228
Author(s):  
Ching-Chia Wang ◽  
Huang-Jen Chen ◽  
Ding-Cheng Chan ◽  
Chen-Yuan Chiu ◽  
Shing-Hwa Liu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Protein Expression ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Type 2 Diabetic

Urinary acrolein adduct levels have been reported to be increased in both habitual smokers and type-2 diabetic patients. The impairment of glucose transport in skeletal muscles is a major factor responsible for glucose uptake reduction in type-2 diabetic patients. The effect of acrolein on glucose metabolism in skeletal muscle remains unclear. Here, we investigated whether acrolein affects muscular glucose metabolism in vitro and glucose tolerance in vivo. Exposure of mice to acrolein (2.5 and 5 mg/kg/day) for 4 weeks substantially increased fasting blood glucose and impaired glucose tolerance. The glucose transporter-4 (GLUT4) protein expression was significantly decreased in soleus muscles of acrolein-treated mice. The glucose uptake was significantly decreased in differentiated C2C12 myotubes treated with a non-cytotoxic dose of acrolein (1 μM) for 24 and 72 h. Acrolein (0.5–2 μM) also significantly decreased the GLUT4 expression in myotubes. Acrolein suppressed the phosphorylation of glucose metabolic signals IRS1, Akt, mTOR, p70S6K, and GSK3α/β. Over-expression of constitutive activation of Akt reversed the inhibitory effects of acrolein on GLUT4 protein expression and glucose uptake in myotubes. These results suggest that acrolein at doses relevant to human exposure dysregulates glucose metabolism in skeletal muscle cells and impairs glucose tolerance in mice.

scholarly journals Dysfunction of muscle contraction with impaired intracellular Ca2+ handling in skeletal muscle and the effect of exercise training in male db/db mice

2019 ◽  
Vol 126 (1) ◽  
pp. 170-182 ◽  
Author(s):  
Hiroaki Eshima ◽  
Yoshifumi Tamura ◽  
Saori Kakehi ◽  
Kyoko Nakamura ◽  
Nagomi Kurebayashi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Exercise Training ◽  
Muscle Contraction ◽  
Contractile Function ◽  
Contractile Force ◽  
Contractile Dysfunction ◽  
Muscle Contractile ◽  
Type 2 Diabetic

Type 2 diabetes is characterized by reduced contractile force production and increased fatigability of skeletal muscle. While the maintenance of Ca2+ homeostasis during muscle contraction is a requisite for optimal contractile function, the mechanisms underlying muscle contractile dysfunction in type 2 diabetes are unclear. Here, we investigated skeletal muscle contractile force and Ca2+ flux during contraction and pharmacological stimulation in type 2 diabetic model mice ( db/db mice). Furthermore, we investigated the effect of treadmill exercise training on muscle contractile function. In male db/db mice, muscle contractile force and peak Ca2+ levels were both lower during tetanic stimulation of the fast-twitch muscles, while Ca2+ accumulation was higher after stimulation compared with control mice. While 6 wk of exercise training did not improve glucose tolerance, exercise did improve muscle contractile dysfunction, peak Ca2+ levels, and Ca2+ accumulation following stimulation in male db/db mice. These data suggest that dysfunctional Ca2+ flux may contribute to skeletal muscle contractile dysfunction in type 2 diabetes and that exercise training may be a promising therapeutic approach for dysfunctional skeletal muscle contraction. NEW & NOTEWORTHY The purpose of this study was to examine muscle contractile function and Ca2+ regulation as well as the effect of exercise training in skeletal muscle in obese diabetic mice ( db/db). We observed impairment of muscle contractile force and Ca2+ regulation in a male type 2 diabetic animal model. These dysfunctions in muscle were improved by 6 wk of exercise training.

Persistent increase in glucose uptake by rat skeletal muscle following exercise

1981 ◽  
Vol 241 (5) ◽  
pp. C200-C203 ◽  
Author(s):  
J. L. Ivy ◽  
J. O. Holloszy
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Muscle Glycogen ◽  
Glycogen Synthesis ◽  
Exercise Stress ◽  
Rat Skeletal Muscle ◽  
Major Pathway ◽  
Glycogen Accumulation ◽  
Hindlimb Muscles ◽  
Muscle Glycogen Concentration

The effect of a bout of exercise on glucose uptake and glycogen synthesis in skeletal muscle was examined using a perfused rat hindlimb preparation. Rats were subjected to a bout of swimming. The exercise stress was moderate as reflected in a reduction of muscle glycogen concentration of only 50%. Glucose uptake and glycogen synthesis were measured in perfused hindlimb muscles for a 30-min period beginning approximately 60 min following the exercise. The rate of glucose uptake in the absence of insulin was 10-fold higher in hindlimbs of exercised animals than in the controls. The rate of glucose uptake was also higher in exercised than in control muscles in the presence of 50 microunits/ml or 10 mU/ml of insulin, but these differences were smaller than that found in the absence of insulin. Conversion to glycogen was the major pathway for disposal of the glucose taken up by muscle. The rate of glycogen accumulation in the exercised plantaris muscles was greater than in the control muscles both in the absence and presence of insulin.

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