INVOLVEMENT OF NONESTERIFIED FATTY-ACID OXIDATION IN GLUCOCORTICOID-INDUCED PERIPHERAL INSULIN-RESISTANCE IN-VIVO IN RATS

The mechanism by which glucocorticoids induce insulin resistance was s tudied in normal rats administered for 2 days with corticosterone then tested by euglycaemic hyperinsulinaemic clamps. Corticosterone admini stration induced a slight hyperglycaemia, hyperinsulinaemia and increa sed non-esterified fatty acid levels. It impaired insulin-stimulated t otal glucose utilization (corticosterone 15.7 +/- 0.7; controls 24.6 /- 0.8 mg.kg-1.min-1), as well as residual hepatic glucose production (corticosterone 4.9 +/- 1.0; controls 2.0 +/- 0.7 mg. kg-1.min-1). Dur ing the clamps, insulin did not decrease the elevated non-esterified f atty acid levels in corticosterone-administered rats (corticosterone 1 .38 +/- 0.15, controls 0.22 +/- 0.04 mmol/l). Corticosterone administr ation decreased the in vivo insulin-stimulated glucose utilization ind ex by individual muscles by 62 +/- 6%, and the de novo glycogen synthe sis by 78 +/- 2% (n = 8-9 muscles). GLUT 4 protein and mRNA levels wer e either unchanged or slightly increased by corticosterone administrat ion. Inhibition of lipid oxidation by etomoxir prevented corticosteron e-induced muscle but not hepatic insulin resistance. In conclusion, gl ucocorticoid-induced muscle insulin resistance is due to excessive non -esterified fatty acid oxidation, possibly via increased glucose fatty -acid cycle ultimately inhibiting glucose transport, or via decreased glycogen synthesis, or by a direct effect on glucose transporter trans location or activity or both.