TY - JOUR
T1 - Decreased insulin action in skeletal muscle from patients with McArdle's disease
AU - Nielsen, Jakob N
AU - Vissing, John
AU - Wojtaszewski, Jørgen F P
AU - Haller, Ronald G
AU - Begum, Najma
AU - Richter, Erik A
PY - 2002/6
Y1 - 2002/6
N2 - 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.
AB - 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.
KW - Adult
KW - Blood Glucose/metabolism
KW - Calcium-Calmodulin-Dependent Protein Kinases/metabolism
KW - Fatty Acids, Nonesterified/blood
KW - Female
KW - Glucose/metabolism
KW - Glucose Clamp Technique
KW - Glucose Tolerance Test
KW - Glycogen/metabolism
KW - Glycogen Phosphorylase/metabolism
KW - Glycogen Storage Disease Type V/physiopathology
KW - Glycogen Synthase/metabolism
KW - Glycogen Synthase Kinase 3
KW - Glycogen Synthase Kinases
KW - Humans
KW - Insulin/pharmacology
KW - Insulin Resistance
KW - Male
KW - Muscle, Skeletal/drug effects
KW - Oxidation-Reduction
KW - Phosphoprotein Phosphatases/metabolism
KW - Phosphorylation
KW - Protein Phosphatase 1
KW - Protein Serine-Threonine Kinases
KW - Proto-Oncogene Proteins/metabolism
KW - Proto-Oncogene Proteins c-akt
U2 - 10.1152/ajpendo.00526.2001
DO - 10.1152/ajpendo.00526.2001
M3 - Journal article
C2 - 12006356
SN - 0193-1849
VL - 282
SP - E1267-75
JO - American Journal of Physiology: Endocrinology and Metabolism
JF - American Journal of Physiology: Endocrinology and Metabolism
IS - 6
ER -