Insulin Action on Glucose Transport in Isolated Skeletal Muscle from Patients with Liver Cirrhosis

1994 ◽  
Vol 29 (1) ◽  
pp. 71-76 ◽  
Author(s):  
U. Johansson ◽  
L. S. Eriksson ◽  
D. Galuska ◽  
J. R. Zierath ◽  
H. Wallberg-henriksson
Keyword(s):  
Skeletal Muscle ◽  
Liver Cirrhosis ◽  
Glucose Transport ◽  
Insulin Action

Acute selective glycogen synthase kinase-3 inhibition enhances insulin signaling in prediabetic insulin-resistant rat skeletal muscle

2005 ◽  
Vol 288 (6) ◽  
pp. E1188-E1194 ◽  
Author(s):  
Betsy B. Dokken ◽  
Julie A. Sloniger ◽  
Erik J. Henriksen
Keyword(s):  
Skeletal Muscle ◽  
Tyrosine Phosphorylation ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Glycogen Synthase ◽  
Serine Phosphorylation ◽  
Zucker Rats ◽  
Type I ◽  
Insulin Resistant

Glycogen synthase kinase-3 (GSK3) has been implicated in the multifactorial etiology of skeletal muscle insulin resistance in animal models and in human type 2 diabetic subjects. However, the potential molecular mechanisms involved are not yet fully understood. Therefore, we determined if selective GSK3 inhibition in vitro leads to an improvement in insulin action on glucose transport activity in isolated skeletal muscle of insulin-resistant, prediabetic obese Zucker rats and if these effects of GSK3 inhibition are associated with enhanced insulin signaling. Type I soleus and type IIb epitrochlearis muscles from female obese Zucker rats were incubated in the absence or presence of a selective, small organic GSK3 inhibitor (1 μM CT118637, Ki < 10 nM for GSK3α and GSK3β). Maximal insulin stimulation (5 mU/ml) of glucose transport activity, glycogen synthase activity, and selected insulin-signaling factors [tyrosine phosphorylation of insulin receptor (IR) and IRS-1, IRS-1 associated with p85 subunit of phosphatidylinositol 3-kinase, and serine phosphorylation of Akt and GSK3] were assessed. GSK3 inhibition enhanced ( P <0.05) basal glycogen synthase activity and insulin-stimulated glucose transport in obese epitrochlearis (81 and 24%) and soleus (108 and 20%) muscles. GSK3 inhibition did not modify insulin-stimulated tyrosine phosphorylation of IR β-subunit in either muscle type. However, in obese soleus, GSK3 inhibition enhanced (all P < 0.05) insulin-stimulated IRS-1 tyrosine phosphorylation (45%), IRS-1-associated p85 (72%), Akt1/2 serine phosphorylation (30%), and GSK3β serine phosphorylation (39%). Substantially smaller GSK3 inhibitor-mediated enhancements of insulin action on these insulin signaling factors were observed in obese epitrochlearis. These results indicate that selective GSK3 inhibition enhances insulin action in insulin-resistant skeletal muscle of the prediabetic obese Zucker rat, at least in part by relieving the deleterious effects of GSK3 action on post-IR insulin signaling. These effects of GSK3 inhibition on insulin action are greater in type I muscle than in type IIb muscle from these insulin-resistant animals.

Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM

Diabetologia ◽  
1996 ◽  
Vol 39 (10) ◽  
Author(s):  
J. R. Zierath ◽  
L. He ◽  
A. Gumà ◽  
E. Odegaard Wahlström ◽  
A. Klip ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Plasma Membrane ◽  
Glucose Transport ◽  
Insulin Action

scholarly journals Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake

1988 ◽  
Vol 252 (3) ◽  
pp. 733-737 ◽  
Author(s):  
E A Richter ◽  
B F Hansen ◽  
S A Hansen
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Muscle Glycogen ◽  
Insulin Action ◽  
Insulin Stimulation ◽  
Initial Values ◽  
Muscle Glucose Transport ◽  
Glycogen Stores ◽  
Effect Of Glucose

The ability of glucose and insulin to modify insulin-stimulated glucose transport and uptake was investigated in perfused skeletal muscle. Here we report that perfusion of isolated rat hindlimbs for 5 h with 12 mM-glucose and 20,000 microunits of insulin/ml leads to marked, rapidly developing, impairment of insulin action on muscle glucose transport and uptake. Thus maximal insulin-stimulated glucose uptake at 12 mM-glucose decreased from 34.8 +/- 1.9 to 11.5 +/- 1.1 mumol/h per g (mean +/- S.E.M., n = 10) during 5 h perfusion. This decrease in glucose uptake was accompanied by a similar change in muscle glucose transport as measured by uptake of 3-O-[14C]-methylglucose. Simultaneously, muscle glycogen stores increased to 2-3.5 times initial values, depending on fibre type. Perfusion for 5 h in the presence of glucose but in the absence of insulin decreased subsequent insulin action on glucose uptake by 80% of the effect of glucose with insulin, but without an increase in muscle glycogen concentration. Perfusion for 5 h with insulin but without glucose, and with subsequent addition of glucose back to the perfusate, revealed glucose uptake and transport similar to initial values obtained in the presence of glucose and insulin. The data indicate that exposure to a moderately increased glucose concentration (12 mM) leads to rapidly developing resistance of skeletal-muscle glucose transport and uptake to maximal insulin stimulation. The effect of glucose is enhanced by simultaneous insulin exposure, whereas exposure for 5 h to insulin itself does not cause measurable resistance to maximal insulin stimulation.

scholarly journals Chronic renin inhibition with aliskiren improves glucose tolerance, insulin sensitivity, and skeletal muscle glucose transport activity in obese Zucker rats

2012 ◽  
Vol 302 (1) ◽  
pp. R137-R142 ◽  
Author(s):  
Elizabeth M. Marchionne ◽  
Maggie K. Diamond-Stanic ◽  
Mujalin Prasonnarong ◽  
Erik J. Henriksen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Transport ◽  
Insulin Action ◽  
Whole Body ◽  
Zucker Rats ◽  
Obese Zucker Rats ◽  
Renin Inhibition

We have demonstrated previously that overactivity of the renin-angiotensin system (RAS) is associated with whole body and skeletal muscle insulin resistance in obese Zucker ( fa/fa) rats. Moreover, this obesity-associated insulin resistance is reduced by treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor (type 1) blockers. However, it is currently unknown whether specific inhibition of renin itself, the rate-limiting step in RAS functionality, improves insulin action in obesity-associated insulin resistance. Therefore, the present study assessed the effect of chronic, selective renin inhibition using aliskiren on glucose tolerance, whole body insulin sensitivity, and insulin action on the glucose transport system in skeletal muscle of obese Zucker rats. Obese Zucker rats were treated for 21 days with either vehicle or aliskiren (50 mg/kg body wt ip). Renin inhibition was associated with a significant lowering (10%, P < 0.05) of resting systolic blood pressure and induced reductions in fasting plasma glucose (11%) and free fatty acids (46%) and homeostatic model assessment for insulin resistance (13%). Glucose tolerance (glucose area under the curve) and whole body insulin sensitivity (inverse of the glucose-insulin index) during an oral glucose tolerance test were improved by 15% and 16%, respectively, following chronic renin inhibition. Moreover, insulin-stimulated glucose transport activity in isolated soleus muscle of renin inhibitor-treated animals was increased by 36% and was associated with a 2.2-fold greater Akt Ser473 phosphorylation. These data provide evidence that chronic selective inhibition of renin activity leads to improvements in glucose tolerance and whole body insulin sensitivity in the insulin-resistant obese Zucker rat. Importantly, chronic renin inhibition is associated with upregulation of insulin action on skeletal muscle glucose transport, and it may involve improved Akt signaling. These data support the strategy of targeting the RAS to improve both blood pressure regulation and insulin action in conditions of insulin resistance.

Phenylarsine oxide and denervation effects on hormone-stimulated glucose transport

1988 ◽  
Vol 255 (2) ◽  
pp. E159-E165 ◽  
Author(s):  
M. O. Sowell ◽  
K. A. Robinson ◽  
M. G. Buse
Keyword(s):  
Skeletal Muscle ◽  
Glucose Transport ◽  
Insulin Action ◽  
Denervated Muscle ◽  
Phenylarsine Oxide ◽  
Early Step ◽  
Factor I ◽  
Igf I ◽  
Receptor Number ◽  
Stimulation Of

Insulin and insulin-like growth factor I (IGF-I) stimulate glucose transport in skeletal muscle through separate receptors. The proximal postreceptor events in coupling insulin and IGF-I receptors to glucose transport have been suggested to differ. Denervation of skeletal muscle produces a postreceptor insulin resistance presumably at an early step in the signaling cascade. We examined the effects of denervation and phenylarsine oxide (PAO), an agent believed to block insulin action on transport at a postreceptor step, on insulin and IGF-I stimulated 2-deoxy-D-glucose transport in isolated solei. Denervation (24 h) produced severe IGF-I resistance without affecting IGF-I receptor number or affinity. PAO inhibited insulin and IGF-I stimulation of transport in control muscles by approximately 90 and approximately 70%, respectively. In denervated muscle PAO inhibited transport stimulation by both hormones less than in controls. Conclusions are that 1) skeletal muscle insulin and IGF-I receptors signal transport mainly through a PAO-sensitive mechanism, but IGF-I's action involves a larger PAO-resistant component; 2) the denervation-induced postreceptor resistance of glucose transport to both hormones involves primarily the PAO-sensitive pathway.

Effects of exercise training and antioxidant R-ALA on glucose transport in insulin-sensitive rat skeletal muscle

2002 ◽  
Vol 92 (1) ◽  
pp. 50-58 ◽  
Author(s):  
Vitoon Saengsirisuwan ◽  
Felipe R. Perez ◽  
Tyson R. Kinnick ◽  
Erik J. Henriksen
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Exercise Training ◽  
Glucose Transport ◽  
Insulin Action ◽  
Treadmill Running ◽  
Protein Carbonyls ◽  
Zucker Rats ◽  
Oral Glucose ◽  
Insulin Resistant

We have recently demonstrated (Saengsirisuwan V, Kinnick TR, Schmit MB, and Henriksen EJ, J Appl Physiol 91: 145–153, 2001) that exercise training (ET) and the antioxidant R-(+)-α-lipoic acid ( R-ALA) interact in an additive fashion to improve insulin action in insulin-resistant obese Zucker ( fa/fa) rats. The purpose of the present study was to assess the interactions of ET and R-ALA on insulin action and oxidative stress in a model of normal insulin sensitivity, the lean Zucker ( fa/−) rat. For 6 wk, animals either remained sedentary, received R-ALA (30 mg · kg body wt−1 · day−1), performed ET (treadmill running), or underwent both R-ALA treatment and ET. ET alone or in combination with R-ALA significantly increased ( P < 0.05) peak oxygen consumption (28–31%) and maximum run time (52–63%). During an oral glucose tolerance test, ET alone or in combination with R-ALA resulted in a significant lowering of the glucose response (17–36%) at 15 min relative to R-ALA alone and of the insulin response (19–36%) at 15 min compared with sedentary controls. Insulin-mediated glucose transport activity was increased by ET alone in isolated epitrochlearis (30%) and soleus (50%) muscles, and this was associated with increased GLUT-4 protein levels. Insulin action was not improved by R-ALA alone, and ET-associated improvements in these variables were not further enhanced with combined ET and R-ALA. Although ET and R-ALA caused reductions in soleus protein carbonyls (an index of oxidative stress), these alterations were not significantly correlated with insulin-mediated soleus glucose transport. These results indicate that the beneficial interactive effects of ET and R-ALA on skeletal muscle insulin action observed previously in insulin-resistant obese Zucker rats are not apparent in insulin-sensitive lean Zucker rats.

Interactions of exercise training and α-lipoic acid on insulin signaling in skeletal muscle of obese Zucker rats

2004 ◽  
Vol 287 (3) ◽  
pp. E529-E536 ◽  
Author(s):  
Vitoon Saengsirisuwan ◽  
Felipe R. Perez ◽  
Julie A. Sloniger ◽  
Thomas Maier ◽  
Erik J. Henriksen
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Protein Expression ◽  
Glucose Transport ◽  
Soleus Muscle ◽  
Lipoic Acid ◽  
Combination Treatment ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Insulin Resistant

We have shown previously (Saengsirisuwan V, Kinnick TR, Schmit MB, and Henriksen EJ. J Appl Physiol 91: 145–153, 2001) that the antioxidant R-(+)-α-lipoic acid (R-ALA), combined with endurance exercise training (ET), increases glucose transport in insulin-resistant skeletal muscle in an additive fashion. The purpose of the present study was to investigate possible cellular mechanisms responsible for this interactive effect. We evaluated the effects of R-ALA alone, ET alone, or R-ALA and ET in combination on insulin-stimulated glucose transport, protein expression, and functionality of specific insulin-signaling factors in soleus muscle of obese Zucker ( fa/fa) rats. Obese animals remained sedentary, received R-ALA (30 mg·kg body wt−1·day−1), performed ET (daily treadmill running for ≤60 min), or underwent both R-ALA treatment and ET for 15 days. R-ALA or ET individually increased ( P < 0.05) insulin-mediated (5 mU/ml) glucose transport (2-deoxyglucose uptake) in soleus muscle by 45 and 68%, respectively, and this value was increased to the greatest extent (124%) in the combined treatment group. Soleus insulin receptor substrate (IRS)-1 protein was significantly increased by R-ALA alone (30%) or ET alone (31%), and a further enhancement (55%) was observed after the combination treatment in the obese animals. Enhanced levels of IRS-1 protein expression after individual or combined interventions were significantly correlated with insulin action on glucose transport activity ( r = 0.597, P = 0.0055). Similarly, insulin-mediated IRS-1 associated with the p85 regulatory subunit of phosphatidylinositol 3-kinase was increased by R-ALA (317%) and ET (319%) and to the greatest extent (435%) (all P < 0.05) by the combination treatment. These results indicate that the improvements of insulin action in insulin-resistant skeletal muscle after R-ALA or ET, alone and in combination, were associated with increases in IRS-1 protein expression and IRS-1 associated with p85.

PPARδ activator GW-501516 has no acute effect on glucose transport in skeletal muscle

2006 ◽  
Vol 290 (4) ◽  
pp. E607-E611 ◽  
Author(s):  
Shin Terada ◽  
Scott Wicke ◽  
John O. Holloszy ◽  
Dong-Ho Han
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Transport ◽  
Insulin Action ◽  
Uncoupling Protein ◽  
Mitogen Activated Protein Kinase ◽  
Peroxisome Proliferator ◽  
Direct Stimulation ◽  
Cultured Myotubes ◽  
Stimulation Of

It has been reported that treatment of cultured human skeletal muscle myotubes with the peroxisome proliferator-activated receptor-δ (PPARδ) activator GW-501516 directly stimulates glucose transport and enhances insulin action. Cultured myotubes are minimally responsive to insulin stimulation of glucose transport and are not a good model for studying skeletal muscle glucose transport. The purpose of this study was to evaluate the effect of GW-501516 on glucose transport to determine whether the findings on cultured myotubes have relevance to skeletal muscle. Rat epitrochlearis and soleus muscles were treated for 6 h with 10, 100, or 500 nM GW-501516, followed by measurement of 2-deoxyglucose uptake. GW-501516 had no effect on glucose uptake. There was no effect on insulin sensitivity or responsiveness. Also, in contrast to findings on myotubes, treatment of muscles with GW-501516 did not result in increased phosphorylation or increased expression of AMP-activated protein kinase (AMPK) or p38 mitogen-activated protein kinase (MAPK). Treatment of epitrochlearis muscles with GW-501516 for 24 h induced a threefold increase in uncoupling protein-3 mRNA, providing evidence that the GW-501516 compound that we used gets into and is active in skeletal muscle. In conclusion, our results show that, in contrast to myotubes in culture, skeletal muscle does not respond to GW-501516 with 1) an increase in AMPK or p38 MAPK phosphorylation or expression or 2) direct stimulation of glucose transport or enhanced insulin action.

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