Insulin resistance is an established consequence of glucocorticoid excess. In rats, administration of the synthetic glucocorticoid dexamethasone decreases the sensitivity of glucose oxidation to insulin in soleus muscle strips, but sensitivity of lactate formation is unimpaired. In rats, cortisol impairs pyruvate tolerance and, in man, dexamethasone decreases whole-body glucose oxidation. The present study explored possible mechanisms that might underlie these effects. Activation of the pyruvate dehydrogenase complex (PDC) promotes oxidative glucose disposal, whereas its inactivation prevents pyruvate oxidation and thereby facilitates lactate production. The pyruvate dehydrogenase kinases (PDK1-4) block glucose oxidation through inhibitory phosphorylation of PDC. Insulin deficiency (starvation, experimental diabetes) increases PDK4 expression and suppresses PDC activity in insulin target tissues. We examined the effects of glucocorticoid-induced insulin resistance on skeletal muscle PDK isoform protein expression. Dexamethasone was administered to adult rats via an osmotic minipump (100 microg/kg body weight per day) for 5 days. Glucose-insulin homeostasis was assessed in the post-absorptive state before and after intravenous glucose challenge (0.5 g/kg body wt.). Skeletal muscles sampled from ad libitum fed rats were analysed for PDK isoform protein expression using antibodies raised against individual recombinant PDK2 and PDK4. Basal hyperinsulinaemia (plasma insulin increased by 3.2-fold; P<0.01), together with impaired glucose disappearance after intravenous glucose (a 28% decrease) confirmed dexamethasone-induced insulin resistance. We observed selective increases in PDK4 protein expression relative to PDK2, PDC E1alpha and total protein in skeletal muscle, both slow-twitch (soleus) [1.7-fold, P < 0.001] and fast-twitch (anterior tibialis) [1.8-fold, P < 0.001]. The data demonstrate that PDK4 protein expression can be utilised as a downstream metabolic marker of impaired insulin action and indicate that dexamethasone treatment leads to redistribution of pyruvate from oxidation to maintain normal rates of lactate formation via up-regulation of muscle PDK protein expression.
03 - 04 Dec 2001
Society for Endocrinology