Cortisol-Induced Insulin Resistance in Man: Impaired Suppression of Glucose Production and Stimulation of Glucose Utilization due to a Postreceptor Defect of Insulin Action

The present studies were undertaken to assess the mechanisms responsible for cortisol-induced insulin resistance in man. The insulin dose-response characteristics for suppression of glucose production and stimulation of glucose utilization and their relationship to monocyte and erythrocyte insulin receptor binding were determined in six normal volunteers after 24-h infusion of cortisol and 24-h infusion of saline. The infusion of cortisol (2 μg kg^-1 min^-1) increased the plasma cortisol concentration approximately 4-fold (37 ± 3 us. 14 ± 1 μg/dl; P < 0.01) to values observed during moderately severe stress in man. This hypercortisolemia increased postabsorptive plasma glucose (126 ± 2 us. 97 ± 2 mg/dl; P < 0.01) and plasma insulin (16 ± 2 us. 10 ± 2 μU/ml; P < 0.01) concentrations and rates of glucose production (2.4 ± 0.1 us. 2.1 ± "0.1 mg kg^-1 min^-1; P < 0.01) and utilization (2.5 ± 0.1 us. 2.1 ± 0.1 mg kg^-1 min^-1; P < 0.01). Insulin dose-response curves for both suppression of glucose production (half-maximal response at 81 ± 19 us. 31 ± 5 μU/ml; P < 0.05) and stimulation of glucose utilization (half-maximal response at 104 ± 9 us. 64 ± 7 μU/ml; P < 0.01) were shifted to the right, with preservation of normal maximal responses to insulin. Neither monocyte nor erythrocyte insulin binding was decreased. However, except at near-maximal insulin receptor occupancy, the action of insulin on glucose production and utilization per number of monocyte and erythrocyte insulin receptors occupied was decreased. These results indicate that the cortisol-induced insulin resistance in man is due to a decrease in both hepatic and extrahepatic sensitivity to insulin. Assuming that insulin binding to monocytes and erythrocytes reflects insulin binding in insulin-sensitive tissues, this decrease in insulin action can be explained on the basis of a postreceptor defect.