scholarly journals Peroxovanadates have full insulin-like effects on glycogen synthesis in normal and insulin-resistant skeletal muscle

1991 ◽  
Vol 276 (2) ◽  
pp. 289-292 ◽  
Author(s):  
B Leighton ◽  
G J S Cooper ◽  
C DaCosta ◽  
E A Foot
Keyword(s):  
Skeletal Muscle ◽  
Soleus Muscle ◽  
Wistar Rats ◽  
Glucose Oxidation ◽  
Glycogen Synthesis ◽  
Zucker Rats ◽  
Insulin Resistant ◽  
Lactate Formation ◽  
Total Glucose ◽  
Synergistic Increase

1. The insulin-like effects of orthovanadate (10 mM) and peroxides of vanadate (peroxovanadates, at 1 mM) on rates of lactate formation, glucose oxidation and glycogen synthesis were measured in incubated soleus-muscle preparations isolated from non-obese Wistar rats and lean (fa/?) or insulin-resistant obese Zucker (fa/fa) rats. 2. The stimulation of the rates of lactate formation and glucose oxidation by either orthovanadate or peroxovanadates was of similar magnitude to the stimulation by a maximally effective concentration of insulin (1000 microunits/ml). 3. Peroxovanadates, but not orthovanadate, maximally stimulated the rate of glycogen synthesis in incubated soleus muscles isolated from Wistar rats. 4. When soleus-muscle preparations were incubated in the presence of both insulin (1000 microunits/ml) and peroxovanadates (1 mM), this did not result in a synergistic increase in the rate of total glucose utilization as compared with either agent alone. 5. Soleus muscles isolated from obese (fa/fa) Zucker rats exhibited a decrease in response to a physiologically relevant concentration of insulin (100 microunits/ml). Peroxovanadates, at 1 mM, maximally stimulated the rate of glycogen synthesis in soleus muscles isolated from obese (fa/fa) Zucker rats. 6. The findings indicate that peroxovanadates are useful and important agents for investigating the mechanism of action of insulin in skeletal muscle.

scholarly journals Effects of glucocorticoid excess on the sensitivity of glucose transport and metabolism to insulin in rat skeletal muscle

1997 ◽  
Vol 321 (3) ◽  
pp. 707-712 ◽  
Author(s):  
George DIMITRIADIS ◽  
Brendan LEIGHTON ◽  
Mark PARRY-BILLINGS ◽  
Shlomo SASSON ◽  
Martin YOUNG ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Plasma Membrane ◽  
Glucose Transport ◽  
Soleus Muscle ◽  
Glucose Oxidation ◽  
Glycogen Synthesis ◽  
Total Content ◽  
Glucose Transporters ◽  
Lactate Formation

This study examines the mechanisms of glucocorticoid-induced insulin resistance in rat soleus muscle. Glucocorticoid excess was induced by administration of dexamethasone to rats for 5 days. Dexamethasone decreased the sensitivity of 3-O-methylglucose transport, 2-deoxyglucose phosphorylation, glycogen synthesis and glucose oxidation to insulin. The total content of GLUT4 glucose transporters was not decreased by dexamethasone; however, the increase in these transporters in the plasma membrane in response to insulin (100 m-units/litre) was lessened. In contrast, the sensitivity of lactate formation to insulin was normal. The content of 2-deoxyglucose in the dexamethasone-treated muscle was decreased at 100 m-units/litre insulin, while the contents of glucose 6-phosphate and fructose 2,6-bisphosphate were normal at all concentrations of insulin studied. The maximal activity of hexokinase in the soleus muscle was not affected by dexamethasone; however, inhibition of this enzyme by glucose 6-phosphate was decreased. These results suggest the following. (1) Glucocorticoid excess causes insulin resistance in skeletal muscle by directly inhibiting the translocation of the GLUT4 glucose transporters to the plasma membrane in response to insulin; since the activity of hexokinase is not affected, the changes in the sensitivity of glucose phosphorylation to insulin seen under these conditions are secondary to those in glucose transport. (2) The sensitivity of glycogen synthesis and glucose oxidation to insulin is decreased, but that of glycolysis is not affected: a redistribution of glucose away from the pathway of glycogen synthesis and glucose oxidation could maintain a normal rate of lactate formation although the rate of glucose transport is decreased.

Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle

1997 ◽  
Vol 273 (1) ◽  
pp. E185-E191 ◽  
Author(s):  
R. S. Streeper ◽  
E. J. Henriksen ◽  
S. Jacob ◽  
J. Y. Hokama ◽  
D. L. Fogt ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Glucose Transport ◽  
Lipoic Acid ◽  
Glucose Oxidation ◽  
Glucose Transporter ◽  
Glycogen Synthesis ◽  
Racemic Mixture ◽  
Insulin Resistant ◽  
The Individual

The racemic mixture of the antioxidant alpha-lipoic acid (ALA) enhances insulin-stimulated glucose metabolism in insulin-resistant humans and animals. We determined the individual effects of the pure R-(+) and S-(-) enantiomers of ALA on glucose metabolism in skeletal muscle of an animal model of insulin resistance, hyperinsulinemia, and dyslipidemia: the obese Zucker (fa/fa) rat. Obese rats were treated intraperitoneally acutely (100 mg/kg body wt for 1 h) or chronically [10 days with 30 mg/kg of R-(+)-ALA or 50 mg/kg of S-(-)-ALA]. Glucose transport [2-deoxyglucose (2-DG) uptake], glycogen synthesis, and glucose oxidation were determined in the epitrochlearis muscles in the absence or presence of insulin (13.3 nM). Acutely, R-(+)-ALA increased insulin-mediated 2-DG-uptake by 64% (P < 0.05), whereas S-(-)-ALA had no significant effect. Although chronic R-(+)-ALA treatment significantly reduced plasma insulin (17%) and free fatty acids (FFA; 35%) relative to vehicle-treated obese animals, S-(-)-ALA treatment further increased insulin (15%) and had no effect on FFA. Insulin-stimulated 2-DG uptake was increased by 65% by chronic R-(+)-ALA treatment, whereas S-(-)-ALA administration resulted in only a 29% improvement. Chronic R-(+)-ALA treatment elicited a 26% increase in insulin-stimulated glycogen synthesis and a 33% enhancement of insulin-stimulated glucose oxidation. No significant increase in these parameters was observed after S-(-)-ALA treatment. Glucose transporter (GLUT-4) protein was unchanged after chronic R-(+)-ALA treatment but was reduced to 81 +/- 6% of obese control with S-(-)-ALA treatment. Therefore, chronic parenteral treatment with the antioxidant ALA enhances insulin-stimulated glucose transport and non-oxidative and oxidative glucose metabolism in insulin-resistant rat skeletal muscle, with the R-(+) enantiomer being much more effective than the S-(-) enantiomer.

Effects of Insulin on Glucose Metabolism in Skeletal Muscle from Septic and Endotoxaemic Rats

1989 ◽  
Vol 77 (1) ◽  
pp. 61-67 ◽  
Author(s):  
Brendan Leighton ◽  
George D. Dimitriadis ◽  
Mark Parry-Billings ◽  
Jane Bond ◽  
Paulo R. L. de Vasconcelos ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Glucose Transport ◽  
Soleus Muscle ◽  
Glycogen Synthesis ◽  
Dependent Manner ◽  
H 26 ◽  
Lactate Formation ◽  
Dose Dependent

1. The effects of non-lethal bacteraemia or endotoxaemia on insulin-stimulated glucose metabolism were studied in isolated, incubated soleus muscle of rats after 24 and 48 h. 2. The insulin-stimulated rates of lactate formation and glycogen synthesis were similar in muscles isolated from control and bacteraemic rats. 3. Endotoxaemia increased the rates of lactate formation, at all levels of insulin, both at 24 h (∼ 32%) and 48 h (∼ 26%). Endotoxaemia did not alter the sensitivity of glycolysis to insulin. 4. Endotoxaemia decreased the rates of glycogen synthesis at all concentrations of insulin both at 24 h (∼ 39%) and 48 h (∼ 23%). 5. The increase in the rate of glycolysis was related in a dose-dependent manner to the amount of endotoxin given to the animals. 6. Endotoxaemia decreased plasma tri-iodothyronine levels (41%). However, the effects of endotoxaemia (48 h) on glucose metabolism in muscle are similar to those caused by hyperthyroidism. In hypothyroid rats, endotoxin administration increased the rates of glycolysis in muscle in vitro. 7. It is concluded that there are enhanced basal and insulin-stimulated rates of glycolysis in soleus muscle from endotoxaemic rats. This may be due to both increased glucose transport and decreased glycogen synthesis.

More marked stimulation by lithium than insulin of the glycogenic pathway in rat skeletal muscle.

1997 ◽  
Vol 273 (3) ◽  
pp. E514 ◽  
Author(s):  
C Fürnsinn ◽  
C Noe ◽  
R Herdlicka ◽  
M Roden ◽  
P Nowotny ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Zucker Rats ◽  
Kinase Activation ◽  
Insulin Resistant ◽  
Primary Deficit ◽  
Rat Soleus Muscle ◽  
Glycogen Synthase Activity

Lithium's impact on glucose metabolism was compared with that of insulin in isolated rat soleus muscle. Lithium chloride (20 mmol/l) induced a 4.8-fold more pronounced increment over basal glycogen synthase activity than insulin (10 nmol/l) (nmol UDP-glucose into glycogen in synthase activity assay.g-1.min-1: lithium, +22.1 +/- 1.8 vs. insulin, +4.6 +/- 3.9; P < 0.01). In parallel, lithium was less efficient than insulin in stimulating glucose transport (counts per minute 2-deoxy-D-[3H]glucose.mg-1.h-1: lithium, +211 +/- 19 vs. insulin, +311 +/- 57; P < 0.05) and lactate release (mumol.g-1.h-1: lithium, +1.0 +/- 0.5 vs. insulin, +3.9 +/- 0.5; P < 0.01), and similar increments were induced in glycogen synthesis (mumol glucose into glycogen.g-1.h-1: lithium, +3.32 +/- 0.43 vs. insulin, +3.46 +/- 0.47; not significant). Full additivity of glycogenic effects and divergent dependency on phosphatidylinositol 3-kinase activation provided further evidence for different mechanisms of action. In muscle from insulin-resistant obese Zucker rats (fa/fa), failure of lithium to reverse deficits in glucose metabolism suggested a primary deficit in muscle glucose uptake rather than glycogen synthesis. Hence lithium distinctly stimulates glycogen synthase activity in skeletal muscle and may therefore be regarded as a candidate for the treatment of disorders associated with primary deficits in the glycogenic pathway.

scholarly journals Sensitivity of the soleus muscle to insulin in resting and exercising rats with experimental hypo- and hyper-thyroidism

1989 ◽  
Vol 263 (1) ◽  
pp. 243-247 ◽  
Author(s):  
A Dubaniewicz ◽  
H Kaciuba-Usciłko ◽  
K Nazar ◽  
L Budohoski
Keyword(s):  
Skeletal Muscle ◽  
Glucose Tolerance ◽  
Soleus Muscle ◽  
Interactive Effect ◽  
Glycogen Synthesis ◽  
Subcutaneous Administration ◽  
Lactate Production ◽  
Glucose Injection ◽  
Lactate Formation

1. The effects of hypothyroidism (caused by surgical thyroidectomy followed by treatment for 1 month with propylthiouracil) and of hyperthyroidism [induced by subcutaneous administration of L-tri-iodothyronine (T3)] on glucose tolerance and skeletal-muscle sensitivity to insulin were examined in rats. Glucose tolerance was estimated during 2 h after subcutaneous glucose injection (1 g/kg body wt.). The sensitivity of the soleus muscle to insulin was studied in vitro in sedentary and acutely exercised animals. 2. Glucose tolerance was impaired in both hypothyroid and hyperthyroid rats in comparison with euthyroid controls. 3. In the soleus muscle, responsiveness of the rate of lactate formation to insulin was abolished in hypothyroid rats, whereas the sensitivity of the rate of glycogen synthesis to insulin was unchanged. In hyperthyroid animals, opposite changes were found, i.e. responsiveness of the rate of glycogen synthesis was inhibited and the sensitivity of the rate of lactate production did not differ from that in control sedentary rats. 4. A single bout of exercise for 30 min potentiated the stimulatory effect of insulin on lactate formation in hyperthyroid rats and on glycogen synthesis in hypothyroid animals. 5. The data suggest that thyroid hormones exert an interactive effect with insulin in skeletal muscle. This is likely to be at the post-receptor level, inhibiting the effect of insulin on glycogen synthesis and stimulating oxidative glucose utilization.

scholarly journals Evidence for altered sensitivity of the nitric oxide/cGMP signalling cascade in insulin-resistant skeletal muscle

1998 ◽  
Vol 329 (1) ◽  
pp. 73-79 ◽  
Author(s):  
E. Martin YOUNG ◽  
Brendan LEIGHTON
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Soleus Muscle ◽  
Glucose Utilization ◽  
Phosphodiesterase Inhibitor ◽  
Zucker Rats ◽  
Insulin Resistant ◽  
Cgmp Signalling ◽  
Rat Soleus Muscle ◽  
Obese Zucker Rats

Nitric oxide activates guanylate cyclase to form cGMP, comprising a signalling system that is believed to be a distinct mechanism for increasing glucose transport and metabolism in skeletal muscle. The effects of a selective cGMP phosphodiesterase inhibitor, zaprinast, on basal glucose utilization was investigated in incubated rat soleus muscle preparations isolated from both insulin-sensitive (lean Zucker; Fa/?) and insulin-resistant (obese Zucker; fa/fa) rats. Zaprinast at 27 μM significantly increased cGMP levels in incubated soleus muscle isolated from lean, but not obese, Zucker rats. Muscles were incubated with 14C-labelled glucose and various concentrations of zaprinast (3, 27 and 243 μM). Zaprinast (at 27 and 243 μM) significantly increased rates of net and 14C-labelled lactate release and of glycogen synthesis in lean Zucker rat soleus muscle; glucose oxidation was also increased by 27 μM zaprinast. In addition, regardless of concentration, the phosphodiesterase inhibitor failed to increase any aspect of 14C-labelled glucose utilization in soleus muscles isolated from obese Zucker rats. The maximal activity of nitric oxide synthase (NOS) was significantly decreased in insulin-resistant obese Zucker muscles. Thus the lack of effect of zaprinast in insulin-resistant skeletal muscle is consistent with decreased NOS activity. To test whether there is a defect in insulin-resistant skeletal muscle for endogenous activation of guanylate cyclase, soleus muscles were isolated from both insulin-sensitive and insulin-resistant Zucker rats and incubated with various concentrations of the NO donor sodium nitroprusside (SNP; 0.1, 1, 5 and 15 mM). SNP significantly increased rates of net and 14C-labelled lactate release, as well as glucose oxidation in muscles isolated from both insulin-sensitive and insulin-resistant rats. A decreased response to SNP was observed in the dose-dependent generation of cGMP within isolated soleus muscles from insulin-resistant rats. A possible link between impaired NO/cGMP signalling and abnormal glucose utilization by skeletal muscle is discussed.

scholarly journals Effects of aging on the responsiveness and sensitivity of glucose metabolism to insulin in the incubated soleus muscle isolated from Sprague-Dawley and Wistar rats

1989 ◽  
Vol 261 (2) ◽  
pp. 383-387 ◽  
Author(s):  
B Leighton ◽  
G D Dimitriadis ◽  
M Parry-Billings ◽  
F J Lozeman ◽  
E A Newsholme
Keyword(s):  
Glucose Transport ◽  
Soleus Muscle ◽  
Wistar Rats ◽  
Glycogen Synthesis ◽  
Sprague Dawley ◽  
Marked Contrast ◽  
Maximal Stimulation ◽  
Sprague Dawley Rats ◽  
Lactate Formation ◽  
Effects Of Aging

1. The effects of aging on the sensitivity and responsiveness of glucose transport, lactate formation and glycogen synthesis to insulin were studied in the incubated stripped soleus muscle isolated from aging Sprague-Dawley and Wistar rats. 2. As Sprague-Dawley rats aged from 5 to 13 weeks, there were marked increases in the concentrations of insulin that were required for half-maximal stimulation (i.e. EC50 value, which is a measure of sensitivity) of glucose transport, lactate formation and glycogen synthesis. 3. In marked contrast, there were no alterations in sensitivities of any of these processes to insulin in soleus muscle prepared from Wistar rats aged between 6 and 12 weeks. 4. However, in soleus muscles from 85-week-old Wistar rats the rates of glycogen synthesis in response to basal, sub-maximal and maximal concentrations of insulin were markedly decreased. The insulin EC50 value of glycogen synthesis was increased 4-fold, but was unchanged for lactate formation. 5. The insulin-stimulated rates of glucose transport in soleus muscles from 5- or 85-week-old Wistar rats were not significantly different.

Selective in vitro reversal of the insulin resistance of glucose transport in denervated rat skeletal muscle

1989 ◽  
Vol 257 (3) ◽  
pp. E418-E425 ◽  
Author(s):  
M. O. Sowell ◽  
S. L. Dutton ◽  
M. G. Buse
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Glycogen Synthesis ◽  
Insulin Response ◽  
Medium Composition ◽  
Insulin Resistant ◽  
Denervated Muscles

Denervation (24 h) of skeletal muscle causes severe postreceptor insulin resistance of glucose transport and glycogen synthesis that is demonstrable in isolated muscles after short (30 min) preincubations. After longer preincubations (2-4 h), the insulin response of glucose transport increased to normal, whereas glycogen synthesis remained insulin resistant. Basal and insulin-stimulated amino acid transport were significantly lower in denervated muscles than in controls after short or long incubations, although the percentage stimulation of transport by insulin was not significantly different. The development of glucose transport insulin resistance after denervation was not attributable to increased sensitivity to glucocorticoids or adenosine. The selective in vitro reversal of glucose transport insulin resistance was not dependent on medium composition, did not require protein or prostaglandin synthesis, and could not be attributed to release of a positive regulator into the medium. The data suggest 1) the insulin receptor in muscle stimulates glucose transport by a signaling pathway that is not shared by other insulin-sensitive effector systems, and 2) denervation may affect insulin receptor signal transduction at more than one site.

scholarly journals The effect of insulin and exercise on c-Cbl protein abundance and phosphorylation in insulin-resistant skeletal muscle in lean and obese Zucker rats

Diabetologia ◽  
2004 ◽  
Vol 47 (3) ◽  
pp. 412-419 ◽  
Author(s):  
G. D. Wadley ◽  
C. R. Bruce ◽  
N. Konstantopoulos ◽  
S. L. Macaulay ◽  
K. F. Howlett ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Zucker Rats ◽  
Protein Abundance ◽  
Insulin Resistant ◽  
Obese Zucker Rats ◽  
Cbl Protein
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