THE EFFECT OF CORTISOL ON GLUCOSE GLUCOSE-6-PHOSPHATE CYCLE ACTIVITY AND INSULIN ACTION/

Increased glucose/glucose-6-phosphate (G/G6P) substrate cycle activity may be an early marker of disordered hepatic glucose metabolism. To i nvestigate the effects of glucocorticoids on G/G6P cycle activity and insulin resistance, we studied eight normal subjects using the euglyce mic glucose clamp technique with high pressure liquid chromatography-p urified [2(3)H]- and [6-H-3]glucose tracers at insulin infusion rates of 0.4 and 2.0 mU/kg.min after 24-h cortisol (2 mu g/kg.min) and salin e infusions. Endogenous glucose production ([6-H-3]glucose) was greate r after cortisol than saline in the postabsorptive state (13.3 +/- 0.5 vs. 12.2 +/- 0.5 mu mol/kg.min; P < 0.05) and during 0.4-mU insulin i nfusion (10.5 +/- 0.7 vs. 5.0 +/- 0.8 mu mol/kg.min; P < 0.005). Durin g 2.0-mU insulin infusion, endogenous glucose production was suppresse d similarly (5.1 +/- 0.4 vs. 4.1 +/- 0.5 mu mol/kg.min), but glucose d isappearance was less after cortisol than saline (38.7 +/- 3.5 vs. 64. 6 +/- 4.3 mu mol/kg.min; P < 0.001). G/G6P cycle activity after cortis ol and saline was similar in the postabsorptive state and during 0.4 m U insulin. During 2.0 mU insulin, cycle activity was greater after cor tisol than saline (3.6 +/- 0.9 vs. 0.8 +/- 0.5 mu mol/kg.min; P < 0.00 5). In conclusion, cortisol induces hepatic insulin resistance without significantly changing G/G6P cycle activity. At high glucose turnover rates, G/G6P cycle activity is increased by cortisol; however, reduce d glucose disappearance is the main cause of impaired insulin action.