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

Abstract

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.

Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats

“…In keeping with this, body weight was not affected when haloperidol was administered orally to male rats for three or six weeks (Minet-Ringuet et al, 2005; Pouzet et al, 2003), and was even suppressed under the longer treatment period of 80 weeks (Yoshida et al, 1995 51(7--8): 1129--1136, 2006 adipose tissue under the influence of hormonal changes such as increased serum levels of insulin (Cusin et al, 1990), corticosterone (Guillaume-Gentil et al, 1993) and growth hormone (Ho et al, 1996) and reduced serum levels of thyroid hormones (Kyle et al, 1966), IGF-1 (Shaw et al, 2003), and testosterone (Mudali and Dobs, 2004). However, our data show that not only does chronic haloperidol administration to male rats have no effect on body weight or food intake, it also has no effect on adiposity or the serum levels of many of the hormones that modulate body composition.…”

Metabolic action of peroxisome proliferator-activated receptor γ agonism in rats with exogenous hypercorticosteronemia

“…59,60 Treatment with RSG modestly decreased serum NEFA but was unable to fully counteract the effect of HiCORT. This may possibly relate to the additive effect of HiCORT and RSG on ATGL expression, which may not have been efficiently counteracted by recycling/oxidation pathways.…”

Dexamethasone impairs muscle energetics, studied by 31P NMR, in rats

“…GCTC-induced insulin resistance results in decreased insulin-stimulated glucose uptake in muscle [6], and increased plasma concentrations of NEFA, insulin and leptin [7,8], with troglitazone antagonising this effect [7]. At the whole body level, increased GCTC concentrations are known to increase oxygen consumption [9][10][11], and decrease food intake [12,13] resulting in a more negative energy balance than in pair-fed animals.…”