Involvement of non-esterified fatty acid oxidation in glucocorticoid-induced peripheral insulin resistance in vivo in rats

• Published in: Diabetologia 1993-10, Vol.36 (10), p.899-906
• Main Authors: Guillaume-Gentil, C, Assimacopoulos-Jeannet, F, Jeanrenaud, B
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose - drug effects; Blood Glucose - metabolism; Carnitine O-Palmitoyltransferase - antagonists & inhibitors; Corticosterone - pharmacology; Epoxy Compounds - pharmacology; Fatty Acids, Nonesterified - blood; Gluconeogenesis - drug effects; Glucose - metabolism; Glucose Clamp Technique; Glucose Transporter Type 4; Glycogen - biosynthesis; Hypoglycemic Agents - pharmacology; Insulin - blood; Insulin - pharmacology; Insulin Resistance - physiology; Liver - drug effects; Liver - metabolism; Male; Monosaccharide Transport Proteins - biosynthesis; Muscle Proteins; Muscles - drug effects; Muscles - metabolism; Rats; Rats, Zucker; RNA, Messenger - analysis; RNA, Messenger - biosynthesis
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/bf02374470

The mechanism by which glucocorticoids induce insulin resistance was studied in normal rats administered for 2 days with corticosterone then tested by euglycaemic hyperinsulinaemic clamps. Corticosterone administration induced a slight hyperglycaemia, hyperinsulinaemia and increased non-esterified fatty acid levels. It impaired insulin-stimulated total glucose utilization (corticosterone 15.7 +/- 0.7; controls 24.6 +/- 0.8 mg.kg-1 x min-1), as well as residual hepatic glucose production (corticosterone 4.9 +/- 1.0; controls 2.0 +/- 0.7 mg.kg-1 x min-1). During the clamps, insulin did not decrease the elevated non-esterified fatty acid levels in corticosterone-administered rats (corticosterone 1.38 +/- 0.15, controls 0.22 +/- 0.04 mmol/l). Corticosterone administration decreased the in vivo insulin-stimulated glucose utilization index by individual muscles by 62 +/- 6%, and the de novo glycogen synthesis by 78 +/- 2% (n = 8-9 muscles). GLUT4 protein and mRNA levels were either unchanged or slightly increased by corticosterone administration. Inhibition of lipid oxidation by etomoxir prevented corticosterone-induced muscle but not hepatic insulin resistance. In conclusion, glucocorticoid-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 translocation or activity or both.