Palmitate oxidation rate and action on glycogen synthase in myoblasts from insulin-resistant subjects

2000 ◽  
Vol 279 (3) ◽  
pp. E561-E569 ◽  
Author(s):  
David M. Mott ◽  
Cristen Hoyt ◽  
Rael Caspari ◽  
Karen Stone ◽  
Richard Pratley ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glycogen Synthase ◽  
Glucose Disposal ◽  
Nonesterified Fatty Acid ◽  
Palmitate Oxidation ◽  
Oxidation Rates ◽  
Glycogen Synthase Activity

Elevated plasma lipid and nonesterified fatty acid concentrations reduce insulin-mediated glucose disposal in skeletal muscle. Cultured myoblasts from 21 subjects were studied for rates of palmitate oxidation and the effect of palmitate on glycogen synthase activity at the end of an 18-h incubation in serum- and glucose-free media. Oxidation rates of 40 μM palmitate in cultured myoblasts correlated with the fasting glucose ( r = 0.71, P = 0.001), log fasting insulin ( r = 0.52, P = 0.03), and insulin-mediated glucose storage rate ( r = −0.50, P = 0.04) of the muscle donors. Myoblast glycogen synthase activity can be regulated by 240 μM palmitate, but the changes are associated with the basal respiratory quotient and not with the insulin resistance of the muscle donor. These results indicate that myoblasts producing elevated palmitate oxidation rates in vitro can be used to identify skeletal muscle abnormalities which are primary contributors to insulin resistance in vivo. Effects of 240 μM palmitate on myoblast glycogen synthase activity appear to be mechanistically different from the relationship between myoblast palmitate oxidation rates and insulin resistance of the muscle donor.

Effect of increased free fatty acid supply on glucose metabolism and skeletal muscle glycogen synthase activity in normal man

1992 ◽  
Vol 82 (2) ◽  
pp. 219-226 ◽  
Author(s):  
A. B. Johnson ◽  
M. Argyraki ◽  
J. C. Thow ◽  
B. G. Cooper ◽  
G. Fulcher ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Lipid Oxidation ◽  
Muscle Glycogen ◽  
Glucose Oxidation ◽  
Glycogen Synthase ◽  
Whole Body ◽  
Glucose Disposal ◽  
Oxidation Rates ◽  
Glycogen Synthase Activity

1. Experimental elevation of plasma non-esterified fatty acid concentrations has been postulated to decrease insulin-stimulated glucose oxidation and storage rates. Possible mechanisms were examined by measuring skeletal muscle glycogen synthase activity and muscle glycogen content before and during hyperinsulinaemia while fasting plasma non-esterified fatty acid levels were maintained. 2. Fasting plasma non-esterified fatty acid levels were maintained in seven healthy male subjects by infusion of 20% (w/v) Intralipid (1 ml/min) for 120 min before and during a 240 min hyperinsulinaemic euglycaemic clamp (100 m-units h−1 kg−1) combined with indirect calorimetry. On the control day, 0.154 mol/l NaCl was infused. Vastus lateralis muscle biopsy was performed before and at the end of the insulin infusion. 3. On the Intralipid study day serum triacylglycerol (2.24 ± 0.20 versus 0.67 ± 0.10 mmol/l), plasma non-esterified fatty acid (395 ± 13 versus 51 ± 1 μmol/l), blood glycerol (152 ± 2 versus 11 ± 1 μmol/l) and blood 3-hydroxybutyrate clamp levels [mean (95% confidence interval)] [81 (64–104) versus 4 (3–5) μmol/l] were all significantly higher (all P < 0.001) than on the control study day. Lipid oxidation rates were also elevated (1.07 ± 0.07 versus 0.27 ± 0.08 mg min−1 kg−1, P < 0.001). During the clamp with Intralipid infusion, insulin-stimulated whole-body glucose disposal decreased by 28% (from 8.53 ± 0.77 to 6.17 ± 0.71 mg min−1 kg−1, P < 0.005). This was the result of a 48% decrease in glucose oxidation (3.77 ± 0.32 to 1.95 ± 0.21 mg min−1 kg−1, P<0.001), with no significant change in nonoxidative glucose disposal (4.76 ± 0.49 to 4.22 ± 0.57 mg min−1 kg−1, not significant). 4. Basal and insulin-stimulated glycogen synthase activities (13.1 ± 1.9 versus 11.4 ± 2.3% and 30.8 ± 2.3 versus 27.6 ± 4.5%, respectively) were unaffected by the increased plasma non-esterified fatty acid levels. Similarly, basal (36.1 ± 2.7 versus 37.2 ± 1.4 μmol/g) and stimulated (40.0 ± 0.6 versus 37.6 ± 4.4 μmol/g) muscle glycogen levels were unaltered. Insulin-stimulated hexokinase activity was also not affected (0.52 ± 0.08 versus 0.60 ± 0.08 units/g wet weight). 5. Maintenance of plasma non-esterified fatty acid levels at fasting values resulted in an increase in lipid oxidation and was associated with a decrease in insulin-stimulated whole-body glucose uptake and glucose oxidation rates, but no change in non-oxidative glucose disposal. Increased plasma non-esterified fatty acid levels did not appear to have a direct inhibitory effect on glycogen synthase activity or storage of glucose as glycogen at these insulin levels.

Fasting and diabetes alter adipose tissue glycogen synthase

1984 ◽  
Vol 247 (5) ◽  
pp. E581-E584
Author(s):  
H. R. Kaslow ◽  
R. D. Eichner
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Enzyme Purification ◽  
Glycogen Synthase ◽  
Streptozotocin Diabetes ◽  
Positive Cooperativity ◽  
Maximal Activation ◽  
Glucose Incorporation ◽  
Glycogen Synthase Activity

In a previous report (J. Biol. Chem. 254: 4678-4683, 1979), we showed that fasting blunted the ability of insulin to promote glucose incorporation into glycogen in vitro. In addition, we showed that glycogen synthase activity was altered in two ways: the concentration of glucose 6-P causing half-maximal activation increased, and positive cooperativity appeared in the glucose 6-P activation of the enzyme. We now show that streptozotocin-diabetes causes the same changes in glucose incorporation and glycogen synthase activity. We show that these changes in glycogen synthase activity persist during enzyme purification; thus it is likely the changes are a result of a structural alteration of the enzyme. Because glycogenolysis of a glycogen particle from rabbit skeletal muscle also caused the appearance of positive cooperativity, we propose that both phosphorylation and glycogenolysis are involved in the appearance of positive cooperativity.

Polymyxin B selectively inhibits insulin effects on transport in isolated muscle

1987 ◽  
Vol 252 (2) ◽  
pp. E248-E254
Author(s):  
T. Gremeaux ◽  
J. F. Tanti ◽  
E. Van Obberghen ◽  
Y. Le Marchand-Brustel
Keyword(s):  
Skeletal Muscle ◽  
Glucose Transport ◽  
Glycogen Synthase ◽  
Polymyxin B ◽  
Acid Uptake ◽  
Insulin Effect ◽  
Insulin Receptor Tyrosine Kinase ◽  
Free System

Polymyxin B (PMB), a cyclic decapeptide antibiotic, inhibits the hypoglycemic effect of insulin in vivo. To elucidate the mechanism of PMB action, we have studied its effect in vitro on insulin-stimulated pathways in the mouse skeletal muscle. PMB, added to the incubation mixture, specifically inhibited insulin-stimulated 2-deoxyglucose transport and alpha-aminoisobutyric acid uptake in the isolated soleus muscle but did not affect the basal rates of transport (measured in the absence of insulin). PMB did not alter insulin binding and hexokinase activity. PMB effect was observed at all deoxyglucose concentrations tested, and PMB was also able to inhibit vanadate-stimulated glucose transport. By contrast, insulin activation of glycogen synthase was not prevented by PMB. Basal and maximally insulin-stimulated insulin receptor tyrosine kinase activity, tested in a cell-free system, was similar for both autophosphorylation and phosphorylation of exogenous substrates in the absence or in the presence of PMB. Furthermore, the insulin sensitivity of the kinase was increased in the presence of PMB. Our results suggest that the anti-insulin effect of PMB observed in vivo is due to an inhibition of insulin-stimulated glucose transport in the skeletal muscle perhaps through a specific blockade of the insulin-induced translocation of the glucose carriers.

Modulation of muscle insulin resistance by selective inhibition of GSK-3 in Zucker diabetic fatty rats

2003 ◽  
Vol 284 (5) ◽  
pp. E892-E900 ◽  
Author(s):  
Erik J. Henriksen ◽  
Tyson R. Kinnick ◽  
Mary K. Teachey ◽  
Matthew P. O'Keefe ◽  
David Ring ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Transport ◽  
Glycogen Synthase ◽  
Oral Glucose ◽  
Type I ◽  
Insulin Resistant ◽  
Zucker Diabetic Fatty Rats ◽  
Zdf Rats ◽  
Glycogen Synthase Activity

A role for elevated glycogen synthase kinase-3 (GSK-3) activity in the multifactorial etiology of insulin resistance is now emerging. However, the utility of specific GSK-3 inhibition in modulating insulin resistance of skeletal muscle glucose transport is not yet fully understood. Therefore, we assessed the effects of novel, selective organic inhibitors of GSK-3 (CT-98014 and CT-98023) on glucose transport in insulin-resistant muscles of Zucker diabetic fatty (ZDF) rats. Incubation of type IIb epitrochlearis and type I soleus muscles from ZDF rats with CT-98014 increased glycogen synthase activity (49 and 50%, respectively, P < 0.05) but did not alter basal glucose transport (2-deoxyglucose uptake). In contrast, CT-98014 significantly increased the stimulatory effects of both submaximal and maximal insulin concentrations in epitrochlearis (37 and 24%) and soleus (43 and 26%), and these effects were associated with increased cell-surface GLUT4 protein. Lithium enhanced glycogen synthase activity and both basal and insulin-stimulated glucose transport in muscles from ZDF rats. Acute oral administration (2 × 30 mg/kg) of CT-98023 to ZDF rats caused elevations in GSK-3 inhibitor concentrations in plasma and muscle. The glucose and insulin responses during a subsequent oral glucose tolerance test were reduced by 26 and 34%, respectively, in the GSK-3 inhibitor-treated animals. Thirty minutes after the final GSK-3 inhibitor treatment, insulin-stimulated glucose transport was significantly enhanced in epitrochlearis (57%) and soleus (43%). Two hours after the final treatment, insulin-mediated glucose transport was still significantly elevated (26%) only in the soleus. These results indicate that specific inhibition of GSK-3 enhances insulin action on glucose transport in skeletal muscle of the insulin-resistant ZDF rat. This unique approach may hold promise as a pharmacological treatment against insulin resistance of skeletal muscle glucose disposal.

Impaired insulin action in subcutaneous adipocytes from women with visceral obesity

2001 ◽  
Vol 280 (1) ◽  
pp. E40-E49 ◽  
Author(s):  
Julia A. Johnson ◽  
Susan K. Fried ◽  
F. Xavier Pi-Sunyer ◽  
Jeanine B. Albu
Keyword(s):  
Insulin Resistance ◽  
Visceral Obesity ◽  
Nonesterified Fatty Acid ◽  
Obese Women ◽  
Black And White ◽  
Adenosine Receptor Agonist ◽  
Impaired Insulin Action ◽  
Visceral Adipose

Visceral obesity is associated with resistance to the antilipolytic effect of insulin in vivo. We investigated whether subcutaneous abdominal and gluteal adipocytes from viscerally obese women exhibit insulin resistance in vitro. Subjects were obese black and white premenopausal nondiabetic women matched for visceral adipose tissue (VAT), total adiposity, and age. Independently of race and adipocyte size, increased VAT was associated with decreased sensitivity to insulin's antilipolytic effect in subcutaneous abdominal and gluteal adipocytes. Absolute lipolytic rates at physiologically relevant concentrations of insulin or the adenosine receptor agonist N 6-(phenylisopropyl)adenosine were higher in subjects with the highest vs. lowest VAT area. Independently of cell size, abdominal adipocytes were less sensitive to the antilipolytic effect of insulin than gluteal adipocytes, which may partly explain increased nonesterified fatty acid fluxes in upper vs. lower body obese women. Moreover, increased VAT was associated with decreased responsiveness, but not decreased sensitivity, to insulin's stimulatory effect on glucose transport in abdominal adipocytes. These data suggest that insulin resistance of subcutaneous abdominal and, to a lesser extent, gluteal adipocytes may contribute to increased systemic lipolysis in both black and white viscerally obese women.

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