Rates of protein synthesis are reduced in severely diabetic rats. A potential mechanism through which insulin can stimulate protein synthesis is modulation of the activity of eukaryotic initiation factor 2B (eIF2B). The activity of this factor is elevated after exercise in nondiabetic rats but is markedly lower in skeletal muscle from nonexercised severely diabetic rats. We tested the hypothesis that a failure to increase eIF2B activity after exercise is one potential reason for a failure of severely diabetic rats to increase rates of protein synthesis after resistance exercise. Diabetic (partial pancreatectomy, plasma glucose >475 mg/dl) and nondiabetic male Sprague-Dawley rats (approximately 300 g) performed acute moderate-intensity resistance exercise or remained sedentary. Rates of protein synthesis were higher in nondiabetic rats and increased significantly with exercise, while no elevation was found in severely diabetic rats. The activity of eIF2B was higher (P < 0.05) in exercised nondiabetic than in sedentary nondiabetic rats (0.096 +/- 0.016 and 0.064 +/- 0.02 pmol GDP exchanged/min, respectively), but no difference was observed between sedentary and exercised diabetic rats (0.037 +/- 0.001 and 0.044 +/- 0.008 pmol GDP exchanged/min, respectively), and these activities were lower (P < 0.05) than in nondiabetic animals. These data suggest that severe hypoinsulinemia is associated with an inability to increase eIF2B activity in response to exercise.