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Effects of Streptozocin-Induced Diabetes and Islet Cell Transplantation on Insulin Signaling in Rat Skeletal Muscle¹

Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Dr. Laurie J. Goodyear, Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215. E-mail: goodyeal{at}joslab.harvard.edu

Streptozocin-induced diabetes is associated with alterations in insulin signaling in rat skeletal muscle, including increased insulin receptor substrate-1 phosphorylation and phosphotidylinositol 3-kinase activity. In the current study, we determined the effects of streptozocin-induced diabetes and treatment of diabetes by islet cell transplantation on several proximal insulin-activated signaling proteins. Three groups of male Lewis rats (untreated streptozocin-diabetic animals, islet cell-transplanted diabetic rats, and nondiabetic control rats) were studied in the basal state or 30 min after ip insulin injection (20 U/rat). Mixed hindlimb skeletal muscle lysates were used to determine the expression and enzymatic activities of the extracellular regulated kinase 2 (ERK2), p90 ribosomal S6 kinase (RSK2), Akt, and p70 S6 kinase (p70^S6k). In all three groups of rats, insulin significantly increased ERK2, RSK2, Akt, and p70^S6k activities. There was no effect of diabetes on insulin-stimulated ERK2 activity or ERK2 protein levels. RSK2 expression and insulin-stimulated RSK2 activity were significantly elevated in diabetic rats compared with those in the control animals. Insulin-stimulated Akt activity was also significantly greater in the diabetic animals, but there was no change in protein expression. In contrast, there was a decrease in insulin-stimulated p70^S6k activity with no change in protein expression in the diabetic rats. Islet transplantation partially (RSK2) or fully (Akt, p70^S6k) normalized these diabetes-induced changes in insulin signaling proteins. We conclude that streptozocin diabetes results in the dysregulation of several critical insulin-activated proteins in rat skeletal muscle, but islet cell transplantation is an effective therapy to partially correct these alterations in insulin signaling.

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