Roles of glucose transport and glucose phosphorylation in muscle insulin resistance of NIDDM

Exercise training has been found to reduce the muscle insulin resistance of the obese Zucker rat (fa/fa). The purpose of the present study was to determine whether this reduction in muscle insulin resistance was associated with an improvement in the glucose transport process and if it was fiber-type specific. Rats were randomly assigned to a sedentary or training group. Training consisted of treadmill running at 18 m/min up an 8% grade, 1.5 h/day, 5 days/wk, for 6–8 wk. The rate of muscle glucose transport was assessed in the absence of insulin and in the presence of a physiological (0.15 mU/ml), a submaximal (1.50 mU/ml), and a maximal (15.0 mU/ml) insulin concentration by determining the rate of 3-O-methyl-D-glucose (3-OMG) accumulation during hindlimb perfusion. The average 3-OMG transport rate of the red gastrocnemii (fast-twitch oxidative-glycolytic fibers) was significantly higher in the trained compared with the sedentary obese rats in the absence of insulin and in the presence of the three insulin concentrations. Significant improvements in 3-OMG transport were also observed in the plantarii (mixed fibers) of trained obese rats in the presence of 0, 0.15, and 15.0 mU/ml insulin. Training appeared to have little effect on the insulin-stimulated 3-OMG transport of the soleus (slow-twitch oxidative fibers) or white gastrocnemius (fast-twitch glycolytic fibers). The results suggest that the improvement in the muscle insulin resistance of the obese Zucker rat after moderate endurance training was associated with an improvement in the glucose transport process but that it was fiber-type specific.

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Restoring AS160 phosphorylation rescues skeletal muscle insulin resistance and fatty acid oxidation while not reducing intramuscular lipids

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90908.2008 ◽

2009 ◽

Vol 297 (5) ◽

pp. E1056-E1066 ◽

Cited By ~ 17

Author(s):

Hakam Alkhateeb ◽

Adrian Chabowski ◽

Jan F. C. Glatz ◽

Brendon Gurd ◽

Joost J. F. P. Luiken ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Transport ◽

Acid Oxidation ◽

Glut4 Translocation ◽

Muscle Insulin Resistance ◽

Palmitate Oxidation ◽

Skeletal Muscle Insulin Resistance ◽

Ampk Phosphorylation ◽

Intramuscular Lipids

We examined whether AICAR or leptin rapidly rescued skeletal muscle insulin resistance via increased palmitate oxidation, reductions in intramuscular lipids, and/or restoration of insulin-stimulated AS60 phosphorylation. Incubation with palmitate (2 mM, 0–18 h) induced insulin resistance in soleus muscle. From 12–18 h, palmitate was removed or AICAR or leptin was provided while 2 mM palmitate was maintained. Palmitate oxidation, intramuscular triacylglycerol, diacylglycerol, ceramide, AMPK phosphorylation, basal and insulin-stimulated glucose transport, plasmalemmal GLUT4, and Akt and AS160 phosphorylation were examined at 0, 6, 12, and 18 h. Palmitate treatment (12 h) increased intramuscular lipids (triacylglycerol +54%, diacylglycerol +11%, total ceramide +18%, C16:0 ceramide +60%) and AMPK phosphorylation (+118%), whereas it reduced fatty acid oxidation (−60%) and insulin-stimulated glucose transport (−70%), GLUT4 translocation (−50%), and AS160 phosphorylation (−40%). Palmitate removal did not rescue insulin resistance or associated parameters. The AICAR and leptin treatments did not consistently reduce intramuscular lipids, but they did rescue palmitate oxidation and insulin-stimulated glucose transport, GLUT4 translocation, and AS160 phosphorylation. Increased AMPK phosphorylation was associated with these improvements only when AICAR and leptin were present. Hence, across all experiments, AMPK phosphorylation did not correlate with any parameters. In contrast, palmitate oxidation and insulin-stimulated AS160 phosphorylation were highly correlated ( r = 0.83). We speculate that AICAR and leptin activate both of these processes concomitantly, involving activation of unknown kinases in addition to AMPK. In conclusion, despite the maintenance of high concentrations of palmitate (2 mM), as well as increased concentrations of intramuscular lipids (triacylglycerol, diacylglycerol, and ceramide), the rapid AICAR- and leptin-mediated rescue of palmitate-induced insulin resistance is attributable to the restoration of insulin-stimulated AS160 phosphorylation and GLUT4 translocation.

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Interactions of Impaired Glucose Transport and Phosphorylation in Skeletal Muscle Insulin Resistance: A Dose-Response Assessment Using Positron Emission Tomography

Diabetes ◽

10.2337/diabetes.50.9.2069 ◽

2001 ◽

Vol 50 (9) ◽

pp. 2069-2079 ◽

Cited By ~ 41

Author(s):

K. V. Williams ◽

J. C. Price ◽

D. E. Kelley

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Positron Emission Tomography ◽

Glucose Transport ◽

Dose Response ◽

Response Assessment ◽

Emission Tomography ◽

Muscle Insulin Resistance ◽

Skeletal Muscle Insulin Resistance ◽

Positron Emission

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Glucose transport: locus of muscle insulin resistance in obese Zucker rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1988.255.3.e374 ◽

1988 ◽

Vol 255 (3) ◽

pp. E374-E382 ◽

Cited By ~ 11

Author(s):

W. M. Sherman ◽

A. L. Katz ◽

C. L. Cutler ◽

R. T. Withers ◽

J. L. Ivy

Keyword(s):

Insulin Resistance ◽

Glucose Uptake ◽

Glucose Transport ◽

Glycogen Synthase ◽

Fiber Type ◽

Zucker Rats ◽

Muscle Insulin Resistance ◽

Obese Rats ◽

Obese Zucker Rats ◽

Fast Twitch

The purposes of this study were to determine whether the muscle insulin resistance of the obese rat is due to a defect in the glucose transport process and whether the insulin resistance is fiber-type specific. The hindlimbs of fasted, 14-wk-old obese (fa/fa) and lean (fa/?) Zucker rats were perfused with perfusate containing 8 mM glucose and no insulin or 8 mM glucose and either a physiological (0.15 mU/ml), a submaximal (1.50 mU/ml), or a maximal (15.0 mU/ml) insulin concentration. Glucose uptake was determined after which the initial rate of glucose transport was determined using 3-O-methyl-D-glucose (3-OMG). Glucose uptake of the obese rats was depressed by 40, 33, 42, and 47% in the absence of insulin and in the presence of the physiological, submaximal, and maximal insulin concentrations, respectively, when compared with lean littermates. Glucose transport in the absence and in the presence of the three insulin concentrations was significantly lower in the soleus (slow-twitch, oxidative fibers), red quadriceps (fast-twitch, oxidative, glycolytic fibers), and gastrocnemius (mixed fibers) of the obese rats when compared with lean rats. Glucose transport in the white quadriceps (fast-twitch, glycolytic fibers) was significantly lower in the obese rats in the absence of insulin and in the presence of the submaximal and maximal insulin concentrations. The glycogen concentration and the activity of hexokinase were the same and the glycogen synthase activity was higher in the muscles for the obese rats when compared to lean rats.(ABSTRACT TRUNCATED AT 250 WORDS)

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Improvement of obesity-linked skeletal muscle insulin resistance by strength and endurance training

Journal of Endocrinology ◽

10.1530/joe-17-0186 ◽

2017 ◽

Vol 234 (3) ◽

pp. R159-R181 ◽

Cited By ~ 26

Author(s):

Sergio Di Meo ◽

Susanna Iossa ◽

Paola Venditti

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Mitochondrial Dysfunction ◽

Endurance Training ◽

Glucose Transport ◽

Antioxidant Defenses ◽

Metabolic Dysfunction ◽

Muscle Insulin Resistance ◽

Insulin Resistant ◽

Skeletal Muscle Insulin Resistance

Obesity-linked insulin resistance is mainly due to fatty acid overload in non-adipose tissues, particularly skeletal muscle and liver, where it results in high production of reactive oxygen species and mitochondrial dysfunction. Accumulating evidence indicates that resistance and endurance training alone and in combination can counteract the harmful effects of obesity increasing insulin sensitivity, thus preventing diabetes. This review focuses the mechanisms underlying the exercise role in opposing skeletal muscle insulin resistance-linked metabolic dysfunction. It is apparent that exercise acts through two mechanisms: (1) it stimulates glucose transport by activating an insulin-independent pathway and (2) it protects against mitochondrial dysfunction-induced insulin resistance by increasing muscle antioxidant defenses and mitochondrial biogenesis. However, antioxidant supplementation combined with endurance training increases glucose transport in insulin-resistant skeletal muscle in an additive fashion only when antioxidants that are able to increase the expression of antioxidant enzymes and/or the activity of components of the insulin signaling pathway are used.

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