Involvement of the rapamycin-sensitive pathway in the insulin regulation of muscle protein synthesis in streptozotocin-diabetic rats

Insulin resistance in 3-day streptozotocin (STZ)-treated rats was manifeste d by the lack of antiproteolytic action of insulin as well as by a reductio n of its stimulatory effect on protein synthesis (-60% compared with the co ntrol group) in epitrochlearis muscle incubated in vitro. In the present st udy, we have investigated the diabetes-associated alterations in the insuli n signalling cascade, especially the phosphatidylinositol-3 kinase (PI-3 ki nase)/p70 S6 kinase (p70(S6K)) pathway, in rat skeletal muscle. LY 294002, a specific inhibitor of PI-3 kinase, markedly decreased the basal rate of p rotein synthesis and completely prevented insulin-mediated stimulation of t his process both in control and diabetic rats. Thus, PI-3 kinase is require d for insulin-stimulated muscle protein synthesis in diabetic rats as in th e controls. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) , had no effect on the basal rate of protein synthesis in either of the exp erimental groups. In control rats, the stimulatory action of insulin on mus cle protein synthesis was diminished by 36% in the presence of rapamycin, w hereas in diabetic muscles this reduction amounted to 68%. The rapamycin-se nsitive pathway makes a relatively greater contribution to the stimulatory effect of insulin on muscle protein synthesis in diabetic rats compared wit h the controls, due presumably to the preferential decrease in the rapamyci n-insensitive component of protein synthesis. Neither basal nor insulin-sti mulated p70(S6K) activity, a signalling element lying downstream of mTOR, w ere modified by STZ-diabetes.