To clarify the importance of the regulation of muscle glycogen synthase to the regulation of insulin-mediated glucose storage, we have made the following observations. In subjects with low insulin-mediated glucose storage rates, both the glycogen synthase activity and the glycogen synthesis rates are reduced to one quarter of the level observed in high storage rate subjects. These results suggest that alterations in the regulation of glycogen synthase activity coincide with the altered glucose storage observed in subjects with low insulin-mediated glucose disposal rates. In muscle tissue from normal glucose tolerant subjects, glycogen concentrations increase and glucose-6-phosphate concentrations decrease with increasing insulin and insulin- stimulated glucose disposal rates. In contrast, insulin infusion in diabetic subjects was characterized by reduced insulin- stimulated glucose disposal rates associated with decreases in muscle glycogen and increases in muscle glucose-6-phosphate concentrations. These observations are compatible with insulin regulation of glucose disposal in normal subjects by stimulation of metabolism beyond the glucose-6-phosphate pool and an abnormality in insulin-stimulated glucose metabolism in diabetics which also occurs beyond the glucose-6-phosphate pool. This abnormality appears to be caused by the reduced insulin stimulation of glycogen synthase and increased phosphorylase activity following insulin infusion in diabetic subjects. The abnormal regulation of glycogen metabolism appears to be at least partially caused by low glycogen synthase phosphatase activity in insulin-resistant subjects.
