title: Decreased insulin action in skeletal muscle from patients with McArdle's disease.
abstract: Insulin action is decreased by high muscle glycogen concentrations in skeletal muscle. Patients with McArdle's disease have chronic high muscle glycogen levels and might therefore be at risk of developing insulin resistance. In this study, six patients with McArdle's disease and six matched control subjects were subjected to an oral glucose tolerance test and a euglycemic-hyperinsulinemic clamp. The muscle glycogen concentration was 103 +/- 45% higher in McArdle patients than in controls. Four of six McArdle patients, but none of the controls, had impaired glucose tolerance. The insulin-stimulated glucose utilization and the insulin-stimulated increase in glycogen synthase activity during the clamp were significantly lower in the patients than in controls (51.3 +/- 6.0 vs. 72.6 +/- 13.1 micromol x min(-1) x kg lean body mass(-1), P < 0.05, and 53 +/- 15 vs. 79 +/- 9%, P < 0.05, n = 6, respectively). The difference in insulin-stimulated glycogen synthase activity between the pairs was significantly correlated (r = 0.96, P < 0.002) with the difference in muscle glycogen level. The insulin-stimulated increase in Akt phosphorylation was smaller in the McArdle patients than in controls (45 +/- 13 vs. 76 +/- 13%, P < 0.05, respectively), whereas basal and insulin-stimulated glycogen synthase kinase 3alpha and protein phosphatase-1 activities were similar in the two groups. Furthermore, the ability of insulin to decrease and increase fat and carbohydrate oxidation, respectively, was blunted in the patients. In conclusion, these data show that patients with McArdle's glycogen storage disease are insulin resistant in terms of glucose uptake, glycogen synthase activation, and alterations in fuel oxidation. The data further suggest that skeletal muscle glycogen levels play an important role in the regulation of insulin-stimulated glycogen synthase activity.
authors: Copenhagen Muscle Research Center, Department of Human Physiology, Institute of Exercise and Sport Sciences, University of Copenhagen, DK-2400 Copenhagen, Denmark. JNNielsen@aki.ku.dk
authors: Jakob N
authors: JN
authors: Nielsen
authors: John
authors: J
authors: Vissing
authors: Jørgen F P
authors: JF
authors: Wojtaszewski
authors: Ronald G
authors: RG
authors: Haller
authors: Najma
authors: N
authors: Begum
authors: Erik A
authors: EA
authors: Richter
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000378:metabolism; D006012:Glycogen Storage Disease Type V / Q000503:physiopathology*; D006006:Glycogen Synthase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D011518:Proto-Oncogene Proteins; D006003:Glycogen; D024981:Glycogen Phosphorylase; D006006:Glycogen Synthase; D038341:Glycogen Synthase Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D005947:Glucose