Effects of exercise and insulin on insulin signaling proteins in human skeletal muscle

KOVAL, JANICE A.; MAEZONO, KATSUMI; PATTI, MARY ELIZABETH; PENDERGRASS, MERRI; DeFRONZO, RALPH A.; MANDARINO, LAWRENCE J.

Medicine & Science in Sports & Exercise:
Basic Sciences: Original Investigations
Abstract

Effects of exercise and insulin on insulin signaling proteins in human skeletal muscle. Med. Sci. Sports Exerc., Vol. 31, No. 7, pp. 998-1004, 1999. Insulin and exercise independently increase glucose metabolism in muscle. Moreover, exercise training or a prior bout of exercise increases insulin-stimulated glucose uptake in resting skeletal muscle. The present study was undertaken to compare how physiological hyperinsulinemia and moderate intensity aerobic exercise affect the tyrosine phosphorylation state and activity of insulin signaling molecules in healthy, physically inactive volunteers. Subjects had biopsies of the vastus lateralis muscle before and immediately after 30 min of either hyperinsulinemia (euglycemic insulin clamp) or moderate-intensity exercise on a cycle ergometer (∼60% of V̇O2max). Insulin receptor and IRS-1 tyrosine phosphorylation, association of the p85 regulatory subunit of PI 3-kinase with IRS-1, IRS-1 associated PI 3-kinase activity, and glycogen synthase activity were determined in muscle biopsy specimens taken from healthy subjects before and after insulin or exercise. Physiological hyperinsulinemia increased the rate of glucose disposal from 11.4 ± 1.5 to 25.6 ± 6.7 μmol·kg−1·min−1 (P < 0.01), insulin receptor and IRS-1 tyrosine phosphorylation (173 ± 19% and 159 ± 35% of basal values, respectively, P < 0.05), association of the p85 regulatory subunit of PI 3-kinase with IRS-1 (159 ± 10%, P < 0.05), and glycogen synthase fractional velocity (136 ± 11%, P < 0.01). Exercise also increased glucose disposal, from 10.4 ± 0.5 to 15.6 ± 1.7 μmol·kg−1·min−1 (P < 0.01) and glycogen synthase fractional velocity (253 ± 35% of basal, P < 0.01). The exercise-induced increase in glycogen synthase was greater than that due to insulin (P < 0.05). In contrast to insulin, exercise decreased tyrosine phosphorylation of the insulin receptor to 72 ± 10% of basal values (P < 0.05 vs basal and P < 0.05 vs insulin) and had no effect on IRS-1 tyrosine phosphorylation, or association of p85 with IRS-1. The exercise-induced decreased insulin receptor tyrosine phosphorylation could explain the well-known effect of exercise to enhance the sensitivity of muscle to insulin.

Author Information

The Division of Diabetes, Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX; and The Joslin Diabetes Center, Boston, MA

Submitted for publication June 1998.

Accepted for publication December 1998.

The excellent technical assistance of Andrea Barrentine and Jean Finlayson and the nursing aid of Patricia Diaz and Norma Ortiz are gratefully acknowledged. This study was supported in part by NIH grants R01DK47936 (LM) R01DK24092 (RAD), a General Clinical Research Center Grant RR01346 (General Clinical Research Center, Audie Murphy Memorial Veterans Hospital, San Antonio, Texas), and a Clinical Associate Physician award to Dr. Pendergrass. None of the authors have a conflict of interest with any company whose product may have been used in this study.

Address for correspondence: Lawrence J. Mandarino, Ph.D., Division of Diabetes, Department of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7886. E-mail: mandarino@uthscsa.edu.

Dr. Pendergrass' current address is Department of Medicine, Section of Endocrinology, Tulane University Medical Center, New Orleans, LA.

© 1999 Lippincott Williams & Wilkins, Inc.