Diazoxide-induced insulin deficiency greatly reduced muscle protein synthesis in rats: Involvement of eIF4E

We have investigated the effect of a postprandial acute insulin deficiency induced by diazoxide injection on rat skeletal muscle protein synthesis. Diazoxide administration lowered plasma insulin >85% within 3 h after injection, whereas other hormones (insulin-like growth factor I, glucagon, corticosterone) involved in the regulation of muscle protein synthesis were not altered significantly compared with control animals. The fractional rate of muscle protein synthesis, measured in vivo, was reduced significantly (P < 0.05) in epitrochlearis (-46%), gastrocnemius (-41%), and soleus (-35%). The reduction in protein synthesis did not result from a reduced total RNA content but was associated with diminished translation efficiency. Analysis of ribosomal subunits revealed that the decreased translation efficiency resulted from an impairment in the initiation phase of protein synthesis. Diazoxide-induced insulin deficiency was associated with a dramatic decrease in eukaryotic initiation factor (eIF) 4G bound to eIF4E and a 2.5-fold increase in the amount of the eIF4E·4E-binding protein 1 (BP1) complex. In contrast, diazoxide injection did not change either the relative amount of eIF4E present in gastrocnemius or its phosphorylation state. These results indicate that an acute insulin deficiency significantly decreases postprandial muscle protein synthesis by modulating the interaction-between 4E-BP1, eIF4G, and eIF4E to control translation initiation.