Dexamethasone-induced impairment in skeletal muscle glucose transport is not reversed by inhibition of free fatty acid oxidation.

Our previous studies suggested a possible role for the glucose-free fatty acid (FFA) cycle, ie, preferential utilization of FFA by muscle at the expense of glucose, in dexamethasone (DEX)-induced insulin resistance. To determine whether this resistance could be reversed by inhibiting FFA utilization, we used etomoxir, a potent inhibitor of mitochondrial FFA oxidation. Male Sprague-Dawley rats were injected subcutaneously with 1 mg/kg DEX or the vehicle every other day for 10 days, and half of each group was administered 10 mg/kg etomoxir by gavage once per day and 1 hour before the experiment. As expected, etomoxir treatment increased serum FFA levels and inhibited FFA oxidation by diaphragm in vitro. Administration of etomoxir decreased serum glucose and insulin concentrations under basal conditions in both control and DEX-treated animals, implying enhanced insulin sensitivity. DEX treatment significantly increased endogenous glucose production and decreased whole-body glucose disposal, as well as 2-deoxyglucose (2-DG) uptake by skeletal muscle during euglycemic-hyperinsulinemic clamps. Administration of etomoxir led to small but significant increases in glucose disposal rates of both control (14%) and DEX (23%) groups, but had no effect on residual endogenous glucose production. Thus, DEX-induced insulin resistance was marginally ameliorated but not completely reversed by etomoxir. Depressed 2-DG uptake by individual muscle tissues observed in the present study in conjunction with the absence of free intracellular glucose in muscle tissue following glucose-insulin infusion strongly suggests that the primary defect in glucose metabolism is at the level of transport. Neither overall abundance of the insulin-sensitive glucose transporter (GLUT-4) in skeletal muscle nor its distribution between intracellular stores and plasma membrane were modified by DEX treatment, either, under basal conditions or in response to acute insulin stimulus. These results suggest a defect(s) in the inherent activity of plasma membrane-bound GLUT-4 as the likely mechanism for DEX-induced insulin resistance.