Defective insulin response of phosphorylase phosphatase in insulin-resistant humans.
Insulin-stimulated glycogen synthase activity in human muscle is reduced in insulin-resistant subjects. Insulin regulation of human muscle glycogen synthase may require activation of a type-1 protein phosphatase (PP-1). We investigated the change of phosphorylase phosphatase and glycogen synthase activities in muscle biopsies obtained during a 2-h hyperinsulinemic euglycemic clamp in 12 insulin-sensitive (group S) and 8 insulin-resistant (group R) subjects. Fasting phosphorylase phosphatase activity was lower in group R than in group S, and did not increase significantly with insulin infusion in group R until 20 min. In group S, phosphorylase phosphatase was significantly stimulated by 10 min, remaining significantly higher than in group R at all time points. The insulin-mediated changes in phosphatase activities were not decreased by 3 nM okadaic acid but were completely inhibited by 1 microM okadaic acid, thereby verifying that insulin-stimulated phosphorylase phosphatase is accounted for by a PP-1. Subcellular fractionation demonstrated reduced fasting PP-1 activities in both the glycogen and cytosolic fractions of muscle obtained from subjects in group R compared to those in group S. These results suggest that insulin activation of PP-1 could contribute to the stimulation of glycogen synthase by this hormone in human muscle. Lower fasting PP-1 activity in cytosol and glycogen fractions plus lower insulin-stimulated PP-1 activity could explain, in part, reduced insulin-stimulated glycogen synthase in skeletal muscle of insulin-resistant subjects.
Kida
Y
Y
Clinical Diabetes & Nutrition Section, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizonia 85016.
Raz
I
I
Maeda
R
R
Nyomba
B L
BL
Stone
K
K
Bogardus
C
C
Sommercorn
J
J
Mott
D M
DM
D000328:Adult; D004988:Ethers, Cyclic / Q000494:pharmacology; D005260:Female; D006006:Glycogen Synthase / Q000032:analysis; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D009132:Muscles / Q000201:enzymology; D019319:Okadaic Acid; D010765:Phosphorylase Phosphatase / Q000032:analysis*; D010766:Phosphorylation
D004988:Ethers, Cyclic; D007328:Insulin; D019319:Okadaic Acid; D006006:Glycogen Synthase; D010765:Phosphorylase Phosphatase