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Abstract: Glucose infusion into rats causes skeletal muscle insulin resistance that initially occurs without changes in insulin signaling. The aim of the current study was to prolong glucose infusion and evaluate other events associated with the transition to muscle insulin resistance. Hyperglycemia was produced in rats by glucose infusion for 3, 5 and 8h. The rate of infusion required to maintain hyperglycemia was reduced at 5 and 8h. Glucose uptake into red quadriceps (RQ) and its incorporation into glycogen decreased between 3 and 5h, further decreasing at 8h. The earliest observed change in RQ was decreased AMPKα2 activity associated with large increases in muscle glycogen content at 3h. Activation of the mTOR pathway occurred at 5h. Akt phosphorylation (Ser473) was decreased at 8h compared to 3 and 5, although no decrease in phosphorylation of downstream GSK-3β (Ser9) and AS160 (Thr642) was observed. White quadriceps showed a similar but delayed pattern, with insulin resistance developing by 8h and decreased AMPKα2 activity at 5h. These results indicate that, in the presence of a nutrient overload, alterations in muscle insulin signaling occur, but after insulin resistance develops and appropriate changes in energy/nutrient sensing pathways occur. [Copyright &y& Elsevier]