Activity of insulin receptor kinase and glycogen synthase in skeletal muscle from patients with chronic renal failure

1989 ◽  
Vol 121 (5) ◽  
pp. 744-750 ◽  
Author(s):  
Jens F. Bak ◽  
Ole Schmitz ◽  
Søren S. Sørensen ◽  
Jens Frøkjær ◽  
Torben Kjær ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Renal Failure ◽  
Chronic Renal Failure ◽  
Insulin Receptor ◽  
Glycogen Synthase ◽  
Insulin Receptors ◽  
Receptor Function ◽  
Uremic Patients ◽  
Glycogen Synthase Activity

Abstract. To examine subcellular mechanisms behind the pathogenesis of peripheral insulin resistance in chronic uremic patients, insulin receptor function and glycogen synthase activity were studied in biopsies of skeletal muscle obtained during renal transplant surgery in 9 non-diabetic uremic patients. The results were compared with values obtained in an age- and sex-matched group of subjects with normal renal function, undergoing surgery for urological or gynecological diseases. The recovery of solubilized, wheat germ agglutinin-purified insulin receptors from skeletal muscle was increased among the uremic patients: 49.3 ± 6.1 vs 31.4 ± 2.8 fmol/100 mg muscle in healthy controls (p < 0.03). Basal as well as insulin-stimulated kinase activities of the insulin receptors, expressed as phosphorylation of the synthetic peptide poly(Glu-Tyr(4:1)) were similar. In addition, the maximal activity of the glycogen synthase was enhanced in uremic muscle: 26.6 ± 2.8 vs 19.5 ± 1.8 nmol · (mg protein)−1 · min−1 (p < 0.05), whereas the half-maximal activation constant for glucose-6-phosphate was identical in the two groups. Likewise, the muscle glycogen concentrations were similar in the uremic patients and the normal controls. In conclusion, our data suggest that neither impaired insulin receptor function nor a reduced maximal glycogen synthase activity of skeletal muscle are involved in the pathogenesis of the insulin resistance of patients with chronic renal failure.

Effects of hyperinsulinemia and hyperglycemia on insulin receptor function and glycogen synthase activation in skeletal muscle of normal man

Metabolism ◽  
1991 ◽  
Vol 40 (8) ◽  
pp. 830-835 ◽  
Author(s):  
Jens Friss Bak ◽  
Niels Møller ◽  
Ole Schmitz ◽  
Erik A. Richter ◽  
Oluf Pedersen
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Glycogen Synthase ◽  
Receptor Function ◽  
Normal Man

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.

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.

scholarly journals Functional Studies of Akt Isoform Specificity in Skeletal Muscle in Vivo; Maintained Insulin Sensitivity Despite Reduced Insulin Receptor Substrate-1 Expression

2007 ◽  
Vol 21 (1) ◽  
pp. 215-228 ◽  
Author(s):  
Mark E. Cleasby ◽  
Tracie A. Reinten ◽  
Gregory J. Cooney ◽  
David E. James ◽  
Edward W. Kraegen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Glycogen Synthase ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Short Hairpin

Abstract The phosphoinositide 3-kinase/Akt pathway is thought to be essential for normal insulin action and glucose metabolism in skeletal muscle and has been shown to be dysregulated in insulin resistance. However, the specific roles of and signaling pathways triggered by Akt isoforms have not been fully assessed in muscle in vivo. We overexpressed constitutively active (ca-) Akt-1 or Akt-2 constructs in muscle using in vivo electrotransfer and, after 1 wk, assessed the roles of each isoform on glucose metabolism and fiber growth. We achieved greater than 2.5-fold increases in total Ser473 phosphorylation in muscles expressing ca-Akt-1 and ca-Akt-2, respectively. Both isoforms caused hypertrophy of muscle fibers, consistent with increases in p70S6kinase phosphorylation, and a 60% increase in glycogen accumulation, although only Akt-1 increased glycogen synthase kinase-3β phosphorylation. Akt-2, but not Akt-1, increased basal glucose uptake (by 33%, P = 0.004) and incorporation into glycogen and lipids, suggesting a specific effect on glucose transport. Consistent with this, short hairpin RNA-mediated silencing of Akt-2 caused reductions in glycogen storage and glucose uptake. Consistent with Akt-mediated insulin receptor substrate 1 (IRS-1) degradation, we observed approximately 30% reductions in IRS-1 protein in muscle overexpressing ca-Akt-1 or ca-Akt-2. Despite this, we observed no decrease in insulin-stimulated glucose uptake. Furthermore, a 68% reduction in IRS-1 levels induced using short hairpin RNAs targeting IRS-1 also did not affect glucose disposal after a glucose load. These data indicate distinct roles for Akt-1 and Akt-2 in muscle glucose metabolism and that moderate reductions in IRS-1 expression do not result in the development of insulin resistance in skeletal muscle in vivo.

scholarly journals Valsartan Alleviates Insulin Resistance in Skeletal Muscle of Chronic Renal Failure Rats

2018 ◽  
Vol 24 ◽  
pp. 2413-2419 ◽  
Author(s):  
Yang Wang ◽  
Ri-bao Wei ◽  
Yue Yang ◽  
Ting-Yu Su ◽  
Meng-Jie Huang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Renal Failure ◽  
Chronic Renal Failure

Abdominal obesity is associated with insulin resistance and reduced glycogen synthase activity in skeletal muscle

Metabolism ◽  
1993 ◽  
Vol 42 (8) ◽  
pp. 998-1005 ◽  
Author(s):  
Steen B. Pedersen ◽  
Jens D. Børglum ◽  
Ole Schmitz ◽  
Jens F. Bak ◽  
Niels Schwartz Sørensen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Abdominal Obesity ◽  
Glycogen Synthase ◽  
Glycogen Synthase Activity

Defective insulin signaling in skeletal muscle of the hypertensive TG(mREN2)27 rat

2005 ◽  
Vol 288 (6) ◽  
pp. E1074-E1081 ◽  
Author(s):  
Julie A. Sloniger ◽  
Vitoon Saengsirisuwan ◽  
Cody J. Diehl ◽  
Betsy B. Dokken ◽  
Narissara Lailerd ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Insulin Receptor ◽  
Signaling Pathway ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Insulin Signaling Pathway ◽  
Whole Body

Essential hypertension is frequently associated with insulin resistance of skeletal muscle glucose transport, with a potential role of angiotensin II in the pathogenesis of both conditions. The male heterozygous TG(mREN2)27 rat harbors the mouse transgene for renin, exhibits local elevations in angiotensin II, and is an excellent model of both hypertension and insulin resistance. The present study was designed to investigate the potential cellular mechanisms for insulin resistance in this hypertensive animal model, including an assessment of elements of the insulin-signaling pathway. Compared with nontransgenic, normotensive Sprague-Dawley control rats, male heterozygous TG(mREN2)27 rats displayed elevated ( P < 0.05) fasting plasma insulin (74%), an exaggerated insulin response (108%) during an oral glucose tolerance test, and reduced whole body insulin sensitivity. TG(mREN2)27 rats also exhibited decreased insulin-mediated glucose transport and glycogen synthase activation in both the type IIb epitrochlearis (30 and 46%) and type I soleus (22 and 64%) muscles. Importantly, there were significant reductions (∼30–50%) in insulin stimulation of tyrosine phosphorylation of the insulin receptor β-subunit and insulin receptor substrate-1 (IRS-1), IRS-1 associated with the p85 subunit of phosphatidylinositol 3-kinase, Akt Ser473 phosphorylation, and Ser9 phosphorylation of glycogen synthase kinase-3β in epitrochlearis and soleus muscles of TG(mREN2)27 rats. Soleus muscle triglyceride concentration was 25% greater in the transgenic group compared with nontransgenic animals. Collectively, these data provide the first evidence that the insulin resistance of the hypertensive male heterozygous TG(mREN2)27 rat can be attributed to specific defects in the insulin-signaling pathway in skeletal muscle.

Levodopa with carbidopa diminishes glycogen concentration, glycogen synthase activity, and insulin-stimulated glucose transport in rat skeletal muscle

2004 ◽  
Vol 97 (6) ◽  
pp. 2339-2346 ◽  
Author(s):  
Jill L. Smith ◽  
Jeong-Sun Ju ◽  
Bithika M. Saha ◽  
Brad A. Racette ◽  
Jonathan S. Fisher
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Tyrosine Phosphorylation ◽  
Glucose Transport ◽  
Glycogen Synthase ◽  
Glycogen Concentration ◽  
Adrenergic Antagonist ◽  
Glycogen Synthase Activity

We hypothesized that levodopa with carbidopa, a common therapy for patients with Parkinson's disease, might contribute to the high prevalence of insulin resistance reported in patients with Parkinson's disease. We examined the effects of levodopa-carbidopa on glycogen concentration, glycogen synthase activity, and insulin-stimulated glucose transport in skeletal muscle, the predominant insulin-responsive tissue. In isolated muscle, levodopa-carbidopa completely prevented insulin-stimulated glycogen accumulation and glucose transport. The levodopa-carbidopa effects were blocked by propranolol, a β-adrenergic antagonist. Levodopa-carbidopa also inhibited the insulin-stimulated increase in glycogen synthase activity, whereas propranolol attenuated this effect. Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate (IRS)-1 was reduced by levodopa-carbidopa, although Akt phosphorylation was unaffected by levodopa-carbidopa. A single in vivo dose of levodopa-carbidopa increased skeletal muscle cAMP concentrations, diminished glycogen synthase activity, and reduced tyrosine phosphorylation of IRS-1. A separate set of rats was treated intragastrically twice daily for 4 wk with levodopa-carbidopa. After 4 wk of treatment, oral glucose tolerance was reduced in rats treated with drugs compared with control animals. Muscles from drug-treated rats contained at least 15% less glycogen and ∼50% lower glycogen synthase activity compared with muscles from control rats. The data demonstrate β-adrenergic-dependent inhibition of insulin action by levodopa-carbidopa and suggest that unrecognized insulin resistance may exist in chronically treated patients with Parkinson's disease.

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