Defective insulin response of cyclic adenosine monophosphate-dependent protein kinase in insulin-resistant humans.
Insulin-stimulated glycogen synthase activity in human muscle correlates with insulin-mediated glucose disposal and is reduced in insulin-resistant subjects. Inhibition of the cyclic AMP-dependent protein kinase (A-kinase) is considered as a possible mechanism of insulin action for glycogen synthase activation. In this study, we investigated the time course of insulin action on human muscle A-kinase activity during a 2-h insulin infusion in 13 insulin-sensitive (group S) and 7 insulin-resistant subjects (group R). Muscle biopsies were obtained from quadriceps femoris muscle at times 0, 10, 20, 40, and 120 min. Insulin infusion resulted in significant inhibition of A-kinase activity at 20 and/or 40 min using 0.2, 0.6, and 1.0 microM cyclic AMP in group S. A-kinase activities both before and after insulin administration were lower in group S than in group R using 0.6 microM cyclic AMP. The decrease in apparent affinity for cyclic AMP during insulin infusion was larger for group S compared with group R. Glycogen synthase activity increased significantly after insulin infusion in both groups and was higher in group S compared with group R. The data suggest that a defective response of A-kinase to insulin in insulin-resistant subjects could contribute to their reduced insulin stimulation of skeletal muscle glycogen synthase.
Kida
Y
Y
Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016.
Nyomba
B L
BL
Bogardus
C
C
Mott
D M
DM
D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D006006:Glycogen Synthase / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D009132:Muscles / Q000187:drug effects / Q000201:enzymology; D047428:Protein Kinase Inhibitors; D044469:Racial Groups
D001786:Blood Glucose; D007328:Insulin; D047428:Protein Kinase Inhibitors; D000242:Cyclic AMP; D006006:Glycogen Synthase