Relationship of skeletal muscle glucose 6-phosphate to glucose disposal rate and glycogen synthase activity in insulin-resistant and non-insulin-dependent diabetic rhesus monkeys

Diabetologia ◽  
1994 ◽  
Vol 37 (2) ◽  
pp. 127-133 ◽  
Author(s):  
H. K. Ortmeyer ◽  
N. L. Bodkin ◽  
B. C. Hansen
Keyword(s):  
Skeletal Muscle ◽  
Rhesus Monkeys ◽  
Glycogen Synthase ◽  
Glucose Disposal ◽  
Insulin Resistant ◽  
Insulin Dependent ◽  
Insulin Dependent Diabetic ◽  
Relationship Of ◽  
Glycogen Synthase Activity ◽  
Glucose Disposal Rate

Insulin-mediated glycogen synthase activity in muscle of spontaneously insulin-resistant and diabetic rhesus monkeys

1993 ◽  
Vol 265 (3) ◽  
pp. R552-R558 ◽  
Author(s):  
H. K. Ortmeyer ◽  
N. L. Bodkin ◽  
B. C. Hansen
Keyword(s):  
Rhesus Monkey ◽  
Beta Cell ◽  
Rhesus Monkeys ◽  
Insulin Action ◽  
Glycogen Synthase ◽  
Intravenous Glucose ◽  
Insulin Resistant ◽  
Cell Responses ◽  
Insulin Dependent ◽  
Glycogen Synthase Activity

Altered insulin action on glycogen synthase activity has been well recognized in non-insulin-dependent diabetes, and some prior evidence has suggested this alteration may be one of the earliest disturbances preceding the development of diabetes. The present study, using the spontaneously insulin-resistant and diabetic rhesus monkey, examined insulin's effect on glycogen synthase at the earliest point of identification of developing diabetes. The normal monkeys (n = 11) had a greater insulin-mediated change in glycogen synthase-independent activity compared with the hyperinsulinemic (n = 8) (P < 0.05) and diabetic (n = 8) (P < 0.01) monkeys. Compared with normal monkeys, the diabetic monkeys had lower basal and insulin-stimulated total glycogen synthase activity (P < 0.05). Monkeys with normal beta-cell responsiveness to intravenous glucose had greater insulin-mediated change in glycogen synthase fractional velocity compared with those with exaggerated (P < 0.01) or absent beta-cell responses to glucose (P < 0.05). We conclude that an alteration in insulin action on glycogen synthase is present as early as beta-cell hyperresponsiveness, one of the earliest detected abnormalities in the progression toward diabetes.

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.

Lack of defect in insulin action on hepatic glycogen synthase and phosphorylase in insulin-resistant monkeys

1998 ◽  
Vol 274 (6) ◽  
pp. G1005-G1010
Author(s):  
Heidi K. Ortmeyer ◽  
Noni L. Bodkin
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Muscle Glycogen ◽  
Rhesus Monkeys ◽  
Insulin Action ◽  
Glycogen Phosphorylase ◽  
Glycogen Synthase ◽  
Liver Glycogen ◽  
Hepatic Glycogen ◽  
Insulin Resistant

It is well known that an alteration in insulin activation of skeletal muscle glycogen synthase is associated with insulin resistance. To determine whether this defect in insulin action is specific to skeletal muscle, or also present in liver, simultaneous biopsies of these tissues were obtained before and during a euglycemic hyperinsulinemic clamp in spontaneously obese insulin-resistant male rhesus monkeys. The activities of glycogen synthase and glycogen phosphorylase and the concentrations of glucose 6-phosphate and glycogen were measured. There were no differences between basal and insulin-stimulated glycogen synthase and glycogen phosphorylase activities or in glucose 6-phosphate and glycogen contents in muscle. Insulin increased the activities of liver glycogen synthase ( P < 0.05) and decreased the activities of liver glycogen phosphorylase ( P ≤ 0.001). Insulin also caused a reduction in liver glucose 6-phosphate ( P = 0.05). We conclude that insulin-resistant monkeys do not have a defect in insulin action on liver glycogen synthase, although a defect in insulin action on muscle glycogen synthase is present. Therefore, tissue-specific alterations in insulin action on glycogen synthase are present in the development of insulin resistance in rhesus monkeys.

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.

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.

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