An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects

Prednisone-induced insulin resistance may depend on either reduced sensitivity (receptor defect) or reduced response to insulin (postreceptor defect). To clarify the mechanism of prednisone-induced insulin resistance, a [3H]glucose infusion (1 μCi/min) was performed for 120 min before and during a euglycemic clamp repeated at ~100, ~1,000, and ~10,000 μU/ml steady state plasma insulin concentration in 10 healthy, normal weight subjects, aged 35 ± 7 yr. Each test was repeated after 7-d administration of placebo or prednisone (15 plus 15 mg/d per subject), in a randomized sequence with an interval of 1 mo between the two tests. Mean fasting blood glucose (89.5 ± 2.1 vs. 83.7 ± 1.9 mg/dl) and mean fasting plasma insulin values (17.8 ± 1.2 vs. 14.3 ± 0.8 μU/ml) were significantly higher (P < 0.01) after prednisone. The insulin sensitivity index (glucose metabolic clearance rate in ml/kg per min) was significantly lower (P < 0.001) after prednisone at all three steady state plasma insulin levels: 2.8 ± 0.3 vs. 7.4 ± 1.1 at ~100 μU/ml; 6.0 ± 0.5 vs. 12.2 ± 1.1 at ~1,000 μU/ml; 7.4 ± 0.6 vs. 14.4 ± 0.5 at ~10,000 μU/ml. Fasting glucose production (in mg/kg per min) was significantly higher after prednisone: 3.7 ± 0.2 vs. 2.9 ± 0.2, P < 0.001. Suppression of glucose production at steady state plasma insulin level of ~100 μU/ml was less after prednisone (1.01 ± 0.35 vs. 0.14 ± 0.13, NS), and total at ~1,000 and ~10,000 μU/ml after both prednisone and placebo. The metabolic kinetic parameters of insulin after prednisone were not significantly different from those after placebo. In addition, insulin binding and 3-ortho-methyl-glucose transport were studied in vitro on fat cells from 16 normal-weight surgical candidates aged 40 ± 8 yr (10 treated with placebo and 6 with prednisone as above). No significant difference was observed with regard to specific insulin binding (tested with 1 ng/ml hormone only), whereas significant transport differences were noted at the basal level (0.40 ± 0.10 vs. 0.54 ± 0.12 pmol/105 cells, P < 0.05), and at increasing concentrations up to the maximum stimulation values (5 ng/ml): 0.59 ± 0.04 vs. 0.92 ± 0.12 pmol/105 cells, P < 0.005. These results suggest that (a) administration of an antiinflammatory dose of prednisone for 7 d induces insulin resistance in man; (b) this is more dependent on depressed peripheral glucose utilization than on increased endogenous production; (c) total insulin binding on isolated adipocytes is not significantly affected; (d) insulin resistance is primarily the outcome of postreceptor defect (impaired glucose transport).