Wortmannin inhibits both insulin and contraction stimulated glucose uptake and transport in rat skeletal muscle. Wojtaszewski, Jírgen F.P., Bo F. Hansen, Birgitte Ursí and Erik A. Richter. Copenhagen Muscle Research Centre, August Krogh Institute, University of Copenhagen, Copenhagen, Denmark, Diabetes Research, Novo Nordisk, Bagsvaerd, Denmark, Hagedorn Research Center, Gentofte, Copenhagen, Denmark
APStracts 3:0235A, 1996.
The role of PI 3-kinase for insulin- and contraction-stimulated muscle glucose transport was investigated in rat skeletal muscle perfused with a cell-free perfusate. The insulin receptor substrate-1 associated PI 3-kinase activity was increased 6 fold upon insulin stimulation, but was unaffected by contractions. In addition the insulin-stimulated PI 3-kinase activity and muscle glucose uptake and transport in individual muscles were dose- dependently inhibited by wortmannin with IC50 values 10 nM and total inhibition at 1 ćM. This concentration of wortmannin also decreased the contraction-stimulated glucose transport and uptake by 30-70% without confounding effects neither on contractility nor on muscle ATP and CP concentrations. At higher concentrations (3 and 10 ćM) wortmannin completely blocked the contraction-stimulated glucose uptake, but also decreased the contractility. In conclusion, inhibition of PI 3-kinase with wortmannin in skeletal muscle coincides with inhibition of insulin-stimulated glucose uptake and transport. Furthermore, in contrast to recent findings in incubated muscle wortmannin also inhibited contraction-stimulated glucose uptake and transport. The inhibitory effect of wortmannin on contraction-stimulated glucose uptake may be independent of PI 3-kinase activity or due to inhibition of a subfraction of PI 3-kinase with low sensitivity to wortmannin. 

Received 1995; accepted in final form 1996.
APS Manuscript Number A177-6.
Article publication pending Am. J. Physiol. (Journal of Applied Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 19 May 96