Defective insulin response of phosphorylase phosphatase in insulin-resistant humans.

Y Kida; I Raz; R Maeda; B L Nyomba; K Stone; C Bogardus; J Sommercorn; D M Mott

doi:10.1172/JCI115627

Defective insulin response of phosphorylase phosphatase in insulin-resistant humans.

Y Kida, I Raz, R Maeda, B L Nyomba, K Stone, C Bogardus, J Sommercorn, and D M Mott

Published February 1, 1992 - More info

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Abstract

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.

Defective insulin response of phosphorylase phosphatase in insulin-resistant humans.

Y Kida, I Raz, R Maeda, B L Nyomba, K Stone, C Bogardus, J Sommercorn, and D M Mott

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Defective insulin response of phosphorylase phosphatase in insulin-resistant humans.

Y Kida, I Raz, R Maeda, B L Nyomba, K Stone, C Bogardus, J Sommercorn, and D M Mott

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