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.

Perfused rat hindlimb is suitable for skeletal muscle glucose transport measurements

1998 ◽  
Vol 274 (1) ◽  
pp. E184-E191 ◽  
Author(s):  
Jørgen F. P. Wojtaszewski ◽  
Allan B. Jakobsen ◽  
Thorkil Ploug ◽  
Erik A. Richter
Keyword(s):  
Electrical Stimulation ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Muscle Fiber Types ◽  
Fiber Types ◽  
Insulin Stimulation ◽  
Transport Measurements ◽  
Perfusate Flow ◽  
Muscle Glucose Transport ◽  
Fast Twitch

It has been postulated that the perfused rat hindlimb is unsuitable for measurements of muscle glucose transport [P. Hansen, E. Gulve, J. Gao, J. Schluter, M. Mueckler, and J. Holloszy. Am. J. Physiol. 268 ( Cell Physiol. 37): C30–C35, 1995]. The aim of the present study was therefore to critically evaluate the suitability of this preparation for glucose transport measurements using the extracellular marker mannitol and the glucose analogs 3- O-methyl-d-glucose or 2-deoxy-d-glucose. In all three muscle fiber types studied, the rate of 2-deoxy-d-glucose uptake during perfusion was linear from 1 to 40 min during maximal insulin stimulation and from 1 to 15 min during maximal electrical stimulation. Uptake of 2-deoxy-d-glucose was not increased by an increase in perfusate flow. Combined stimulation with a maximal insulin concentration and electrical stimulation elicited additive effects on 2-deoxy-d-glucose uptake in slow- and fast-twitch oxidative but not in fast-twitch glycolytic muscle fibers. Furthermore, in muscles having high glucose transport capacities 3- O-methyl-d-glucose is less suitable than 2-deoxy-d-glucose because of rapidly developing nonlinearity of accumulation. Our findings clearly demonstrate that the perfused hindlimb is suitable for measurements of muscle glucose transport and that the most feasible glucose analog for this purpose is 2-deoxy-d-glucose.

Prolonged increase in insulin-stimulated glucose transport in muscle after exercise

1989 ◽  
Vol 256 (4) ◽  
pp. E494-E499 ◽  
Author(s):  
G. D. Cartee ◽  
D. A. Young ◽  
M. D. Sleeper ◽  
J. Zierath ◽  
H. Wallberg-Henriksson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Transport ◽  
Muscle Glycogen ◽  
Caloric Intake ◽  
Carbohydrate Intake ◽  
Dietary Carbohydrate ◽  
Short Term ◽  
Insulin Responsiveness ◽  
Muscle Glucose Transport

Exercise can induce short-term increases in the sensitivity and responsiveness of skeletal muscle glucose transport to insulin. The purpose of this study was to determine the effect of carbohydrate deprivation on the persistence of increased insulin sensitivity and responsiveness after a bout of exercise. Three hours after a bout of exercise, epitrochlearis muscles from carbohydrate-deprived (fat fed) rats showed a 25% greater increase in 3-O-methylglucose (3-MG) transport in response to a maximal insulin stimulus compared with muscles of nonexercised rats; this increase in insulin responsiveness had reversed 18 h postexercise. Muscles of rats fed carbohydrate showed no increase in insulin responsiveness 3 h after exercise. The effect of 60 microU/ml of insulin on 3-MG transport was approximately twofold greater in muscles studied 3 h after exercise than in nonexercised controls regardless of dietary carbohydrate intake. This increase in insulin sensitivity was lost within 18 h in carbohydrate-fed rats but persisted for at least 48 h in carbohydrate-deprived rats. Muscle glycogen increased approximately 41 mumol/g in the rats fed carbohydrate for 18 h, and only approximately 14.5 mumol/g in the rats fed fat for 48 h, after exercise. The persistent increase in insulin sensitivity after exercise in carbohydrate-deprived rats was unrelated to caloric intake, as muscles of fasted and fat-fed rats behaved similarly.

scholarly journals Effect of chronic bradykinin administration on insulin action in an animal model of insulin resistance

1998 ◽  
Vol 275 (1) ◽  
pp. R40-R45 ◽  
Author(s):  
Erik J. Henriksen ◽  
Stephan Jacob ◽  
Donovan L. Fogt ◽  
Guenther J. Dietze
Keyword(s):  
Skeletal Muscle ◽  
Glucose Tolerance ◽  
Glucose Transport ◽  
Insulin Action ◽  
Obese Group ◽  
Whole Body ◽  
Transport Activity ◽  
Insulin Resistant ◽  
Muscle Glucose Transport

The nonapeptide bradykinin (BK) has been implicated as the mediator of the beneficial effect of angiotensin-converting enzyme inhibitors on insulin-stimulated glucose transport in insulin-resistant skeletal muscle. In the present study, the effects of chronic in vivo BK treatment of obese Zucker ( fa/ fa) rats, a model of glucose intolerance and severe insulin resistance, on whole body glucose tolerance and skeletal muscle glucose transport activity stimulated by insulin or contractions were investigated. BK was administered subcutaneously (twice daily at 40 μg/kg body wt) for 14 consecutive days. Compared with a saline-treated obese group, the BK-treated obese animals had significantly ( P < 0.05) lower fasting plasma levels of insulin (20%) and free fatty acids (26%), whereas plasma glucose was not different. During a 1 g/kg body wt oral glucose tolerance test, the glucose and insulin responses [incremental areas under the curve (AUC)] were 21 and 29% lower, respectively, in the BK-treated obese group. The glucose-insulin index, the product of the glucose and insulin AUCs and an indirect index of in vivo insulin action, was 52% lower in the BK-treated obese group compared with the obese control group. Moreover, 2-deoxyglucose uptake in the isolated epitrochlearis muscle stimulated by a maximally effective dose of insulin (2 mU/ml) was 52% greater in the BK-treated obese group. Contraction-stimulated (10 tetani) 2-deoxyglucose uptake was also enhanced by 35% as a result of the BK treatment. In conclusion, these findings indicate that in the severely insulin-resistant obese Zucker rat, chronic in vivo treatment with BK can significantly improve whole body glucose tolerance, possibly as a result of the enhanced insulin-stimulated skeletal muscle glucose transport activity observed in these animals.

Limitations to exercise- and maximal insulin-stimulated muscle glucose uptake

1998 ◽  
Vol 85 (6) ◽  
pp. 2305-2313 ◽  
Author(s):  
Amy E. Halseth ◽  
Deanna P. Bracy ◽  
David H. Wasserman
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Glucose Concentration ◽  
Treadmill Exercise ◽  
Concentration Difference ◽  
Isotopic Methods ◽  
Glucose Phosphorylation ◽  
Muscle Glucose Transport

The hypothesis of this investigation was that insulin and muscle contraction, by increasing the rate of skeletal muscle glucose transport, would bias control so that glucose delivery to the sarcolemma (and t tubule) and phosphorylation of glucose intracellularly would exert more influence over glucose uptake. Because of the substantial increases in blood flow (and hence glucose delivery) that accompany exercise, we predicted that glucose phosphorylation would become more rate determining during exercise. The transsarcolemmal glucose gradient (TSGG; the glucose concentration difference across the membrane) is inversely related to the degree to which glucose transport determines the rate of glucose uptake. The TSGG was determined by using isotopic methods in conscious rats during euglycemic hyperinsulinemia [Ins; 20 mU/(kg ⋅ min); n = 7], during treadmill exercise (Ex, n = 6), and in sedentary, saline-infused rats (Bas, n = 13). Rats received primed, constant intravenous infusions of trace 3- O-[3H] methyl-d-glucose and [U-14C]mannitol. Then 2-deoxy-[3H]glucose was infused for the calculation of a glucose metabolic index (Rg). At the end of experiments, rats were anesthetized, and soleus muscles were excised. Total soleus glucose concentration and the steady-state ratio of intracellular to extracellular 3- O-[3H] methyl-d-glucose (which distributes on the basis of the TSGG) were used to calculate ranges of possible glucose concentrations ([G]) at the inner and outer sarcolemmal surfaces ([G]imand [G]om, respectively). Soleus Rgwas increased in Ins and further increased in Ex. In Ins, total soleus glucose, [G]om, and the TSGG were decreased compared with Bas, while [G]imremained near 0. In Ex, total soleus glucose and [G]imwere increased compared with Bas, and there was not a decrease in [G]omas was observed in Ins. In addition, accumulation of intracellular free 2-deoxy-[3H]glucose occurred in soleus in both Ex and Ins. Taken together, these data indicate that, in Ex, glucose phosphorylation becomes an important limitation to soleus glucose uptake. In Ins, both glucose delivery and glucose phosphorylation influence the rate of soleus glucose uptake more than under basal conditions.

Interactions of exercise training and lipoic acid on skeletal muscle glucose transport in obese Zucker rats

2001 ◽  
Vol 91 (1) ◽  
pp. 145-153 ◽  
Author(s):  
Vitoon Saengsirisuwan ◽  
Tyson R. Kinnick ◽  
Melanie B. Schmit ◽  
Erik J. Henriksen
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Glucose Transport ◽  
Insulin Action ◽  
Combined Treatment ◽  
Protein Carbonyl ◽  
Insulin Resistant ◽  
Glut 4 ◽  
Obese Zucker Rat ◽  
Muscle Glucose Transport

Exercise training (ET) or the antioxidant R(+)-α-lipoic acid (R-ALA) individually increases insulin action in the insulin-resistant obese Zucker rat. The purpose of the present study was to determine the interactions of ET and R-ALA on insulin action and oxidative stress in skeletal muscle of the obese Zucker rat. 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 for 6 wk. During an oral glucose tolerance test, ET alone or in combination with R-ALA resulted in a significant lowering of the glucose (26–32%) and insulin (29–30%) responses compared with sedentary controls. R-ALA alone decreased (19%) the glucose-insulin index (indicative of increased insulin sensitivity), and this parameter was reduced (48–52%) to the greatest extent in the ET and combined treatment groups. ET or R-ALA individually increased insulin-mediated glucose transport activity in isolated epitrochlearis (44–48%) and soleus (37–57%) muscles. The greatest increases in insulin action in these muscles (80 and 99%, respectively) were observed in the combined treatment group. Whereas the improvement in insulin-mediated glucose transport in soleus due to R-ALA was associated with decreased protein carbonyl levels (an index of oxidative stress), improvement because of ET was associated with decreased protein carbonyls as well as enhanced GLUT-4 protein. However, there was no interactive effect of ET and R-ALA on GLUT-4 protein or protein carbonyl levels. These results indicate that ET and R-ALA interact in an additive fashion to improve insulin action in insulin-resistant skeletal muscle. Because the further improvement in muscle glucose transport in the combined group was not associated with additional upregulation of GLUT-4 protein or a further reduction in oxidative stress, the mechanism for this interaction must be due to additional, as yet unidentified, factors.

Regulation of glucose transporters by insulin and extracellular glucose in C2C12 myotubes

2006 ◽  
Vol 291 (4) ◽  
pp. E817-E828 ◽  
Author(s):  
Taku Nedachi ◽  
Makoto Kanzaki
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
C2c12 Myotubes ◽  
Glut4 Translocation ◽  
Insulin Stimulation ◽  
Extracellular Glucose ◽  
Insulin Dependent ◽  
Stimulation Of

It is well established that insulin stimulation of glucose uptake in skeletal muscle cells is mediated through translocation of GLUT4 from intracellular storage sites to the cell surface. However, the established skeletal muscle cell lines, with the exception of L6 myocytes, reportedly show minimal insulin-dependent glucose uptake and GLUT4 translocation. Using C2C12 myocytes expressing exofacial-Myc-GLUT4-enhanced cyan fluorescent protein, we herein show that differentiated C2C12 myotubes are equipped with basic GLUT4 translocation machinery that can be activated by insulin stimulation (∼3-fold increase as assessed by anti-Myc antibody uptake and immunostaining assay). However, this insulin stimulation of GLUT4 translocation was difficult to demonstrate with a conventional 2-deoxyglucose uptake assay because of markedly elevated basal glucose uptake via other glucose transporter(s). Intriguingly, the basal glucose transport activity in C2C12 myotubes appeared to be acutely suppressed within 5 min by preincubation with a pathophysiologically high level of extracellular glucose (25 mM). In contrast, this activity was augmented by acute glucose deprivation via an unidentified mechanism that is independent of GLUT4 translocation but is dependent on phosphatidylinositol 3-kinase activity. Taken together, these findings indicate that regulation of the facilitative glucose transport system in differentiated C2C12 myotubes can be achieved through surprisingly acute glucose-dependent modulation of the activity of glucose transporter(s), which apparently contributes to obscuring the insulin augmentation of glucose uptake elicited by GLUT4 translocation. We herein also describe several methods of monitoring insulin-dependent glucose uptake in C2C12 myotubes and propose this cell line to be a useful model for analyzing GLUT4 translocation in skeletal muscle.

The role of group I p21-activated kinases in contraction-stimulated skeletal muscle glucose transport

2020 ◽  
Author(s):  
Lisbeth L. V. Møller ◽  
Ida L. Nielsen ◽  
Jonas R. Knudsen ◽  
Nicoline R. Andersen ◽  
Thomas E. Jensen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Contraction ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Alternative Pathway ◽  
Whole Body ◽  
Increase Glucose Uptake ◽  
Group I ◽  
Edl Muscle ◽  
Muscle Glucose Transport

AbstractAimMuscle contraction stimulates skeletal muscle glucose transport. Since it occurs independently of insulin, it is an important alternative pathway to increase glucose uptake in insulin-resistant states, but the intracellular signalling mechanisms are not fully understood. Muscle contraction activates group I p21-activated kinases (PAKs) in mouse and human skeletal muscle. PAK1 and PAK2 are downstream targets of Rac1, which is a key regulator of contraction-stimulated glucose transport. Thus, PAK1 and PAK2 could be downstream effectors of Rac1 in contraction-stimulated glucose transport. The current study aimed to test the hypothesis that PAK1 and/or PAK2 regulate contraction-induced glucose transport.MethodsGlucose transport was measured in isolated soleus and extensor digitorum longus (EDL) mouse skeletal muscle incubated either in the presence or absence of a pharmacological inhibitor (IPA-3) of group I PAKs or originating from whole-body PAK1 knockout (KO), muscle-specific PAK2 (m)KO or double whole-body PAK1 and muscle-specific PAK2 knockout mice.ResultsIPA-3 attenuated (−22%) the increase in muscle glucose transport in response to electrically-stimulated contraction. PAK1 was dispensable for contraction-stimulated glucose uptake in both soleus and EDL muscle. Lack of PAK2, either alone (−13%) or in combination with PAK1 (−14%), reduced contraction-stimulated glucose transport compared to control littermates in EDL, but not soleus muscle.ConclusionContraction-stimulated glucose transport in isolated glycolytic mouse EDL muscle is partly dependent on PAK2, but not PAK1.

Effect of AMPK activation on muscle glucose metabolism in conscious rats

1999 ◽  
Vol 276 (5) ◽  
pp. E938-E944 ◽  
Author(s):  
Raynald Bergeron ◽  
Raymond R. Russell ◽  
Lawrence H. Young ◽  
Jian-Ming Ren ◽  
Melissa Marcucci ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Additive Effect ◽  
Medial Gastrocnemius ◽  
Ampk Activation ◽  
Transport Activity ◽  
Muscle Glucose Transport

The effect of AMP-activated protein kinase (AMPK) activation on skeletal muscle glucose metabolism was examined in awake rats by infusing them with 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR; 40 mg/kg bolus and 7.5 mg ⋅ kg−1 ⋅ min−1constant infusion) along with a variable infusion of glucose (49.1 ± 2.4 μmol ⋅ kg−1 ⋅ min−1) to maintain euglycemia. Activation of AMPK by AICAR caused 2-deoxy-d-[1,2-3H]glucose (2-DG) uptake to increase more than twofold in the soleus and the lateral and medial gastrocnemius compared with saline infusion and occurred without phosphatidylinositol 3-kinase activation. Glucose uptake was also assessed in vitro by use of the epitrochlearis muscle incubated either with AICAR (0.5 mM) or insulin (20 mU/ml) or both in the presence or absence of wortmannin (1.0 μM). AICAR and insulin increased muscle 2-DG uptake rates by ∼2- and 2.7-fold, respectively, compared with basal rates. Combining AICAR and insulin led to a fully additive effect on muscle glucose transport activity. Wortmannin inhibited insulin-stimulated glucose uptake. However, neither wortmannin nor 8-(p-sulfophenyl)-theophylline (10 μM), an adenosine receptor antagonist, inhibited the AICAR-induced activation of glucose uptake. Electrical stimulation led to an about threefold increase in glucose uptake over basal rates, whereas no additive effect was found when AICAR and contractions were combined. In conclusion, the activation of AMPK by AICAR increases skeletal muscle glucose transport activity both in vivo and in vitro. This cellular pathway may play an important role in exercise-induced increase in glucose transport activity.

Protein kinase C modulates insulin action in human skeletal muscle

2000 ◽  
Vol 278 (3) ◽  
pp. E553-E562 ◽  
Author(s):  
Ronald N. Cortright ◽  
John L. Azevedo ◽  
Qian Zhou ◽  
Madhur Sinha ◽  
Walter J. Pories ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Insulin Action ◽  
Human Skeletal Muscle ◽  
Kinase C ◽  
Pkc Activation

There is good evidence from cell lines and rodents that elevated protein kinase C (PKC) overexpression/activity causes insulin resistance. Therefore, the present study determined the effects of PKC activation/inhibition on insulin-mediated glucose transport in incubated human skeletal muscle and primary adipocytes to discern a potential role for PKC in insulin action. Rectus abdominus muscle strips or adipocytes from obese, insulin-resistant, and insulin-sensitive patients were incubated in vitro under basal and insulin (100 nM)-stimulated conditions in the presence of GF 109203X (GF), a PKC inhibitor, or 12-deoxyphorbol 13-phenylacetate 20-acetate (dPPA), a PKC activator. PKC inhibition had no effect on basal glucose transport. GF increased ( P < 0.05) insulin-stimulated 2-deoxyglucose (2-DOG) transport approximately twofold above basal. GF plus insulin also increased ( P < 0.05) insulin receptor tyrosine phosphorylation 48% and phosphatidylinositol 3-kinase (PI 3-kinase) activity ∼50% ( P< 0.05) vs. insulin treatment alone. Similar results for GF on glucose uptake were observed in human primary adipocytes. Further support for the hypothesis that elevated PKC activity is related to insulin resistance comes from the finding that PKC activation by dPPA was associated with a 40% decrease ( P < 0.05) in insulin-stimulated 2-DOG transport. Incubation of insulin-sensitive muscles with GF also resulted in enhanced insulin action (∼3-fold above basal). These data demonstrate that certain PKC inhibitors augment insulin-mediated glucose uptake and suggest that PKC may modulate insulin action in human skeletal muscle.

scholarly journals Differential effects of palmitate and palmitoleate on insulin action and glucose utilization in rat L6 skeletal muscle cells

2006 ◽  
Vol 399 (3) ◽  
pp. 473-481 ◽  
Author(s):  
Nikolaos Dimopoulos ◽  
Maria Watson ◽  
Kei Sakamoto ◽  
Harinder S. Hundal
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Insulin Action ◽  
Glucose Utilization ◽  
Insulin Signalling ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
L6 Skeletal Muscle Cells

An increase in circulating levels of specific NEFAs (non-esterified fatty acids) has been implicated in the pathogenesis of insulin resistance and impaired glucose disposal in skeletal muscle. In particular, elevation of SFAs (saturated fatty acids), such as palmitate, has been correlated with reduced insulin sensitivity, whereas an increase in certain MUFAs and PUFAs (mono- and poly-unsaturated fatty acids respectively) has been suggested to improve glycaemic control, although the underlying mechanisms remain unclear. In the present study, we compare the effects of palmitoleate (a MUFA) and palmitate (a SFA) on insulin action and glucose utilization in rat L6 skeletal muscle cells. Basal glucose uptake was enhanced approx. 2-fold following treatment of cells with palmitoleate. The MUFA-induced increase in glucose transport led to an associated rise in glucose oxidation and glycogen synthesis, which could not be attributed to activation of signalling proteins normally modulated by stimuli such as insulin, nutrients or cell stress. Moreover, although the MUFA-induced increase in glucose uptake was slow in onset, it was not dependent upon protein synthesis, but did, nevertheless, involve an increase in the plasma membrane abundance of GLUT1 and GLUT4. In contrast, palmitate caused a substantial reduction in insulin signalling and insulin-stimulated glucose transport, but was unable to antagonize the increase in transport elicited by palmitoleate. Our findings indicate that SFAs and MUFAs exert distinct effects upon insulin signalling and glucose uptake in L6 muscle cells and suggest that a diet enriched with MUFAs may facilitate uptake and utilization of glucose in normal and insulin-resistant skeletal muscle.

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