Insulin action and signalling in fat and muscle from dexamethasone-treated rats

Glucocorticoids initiate whole body insulin resistance and the aim of the present study was to investigate effects of dexamethasone protein expression and insulin signalling in muscle and fat tissue. Rats were injected with dexamethasone (1 mg/kg/day, i.p.) or for I I days before insulin sensitivity was evaluated in vitro in soleus and epitrochlearis muscles and in isolated epididymal Dexamethasone treatment reduced insulin-stimulated glucose uptake and glycogen synthesis by 30-70% in epitrochlearis and soleus, insulin-stimulated glucose uptake by similar to 40% in adipocytes. 8-bromo-cAMP-stimulated lipolysis was similar to 2-fold higher in adipocytes dexamethasone-treated rats and insulin was less effective to inhibit cAMP-stimulated lipolysis. A main finding was that decreased expression of PKB and insulin-stimulated Ser(473) and Thr(308) phosphorylation in both muscles and adipocytes. Expression GSK-3 was not influenced by dexamethasone treatment in muscles or adipocytes and insulin-stimulated GSK-3 beta Ser(9) was reduced in muscles only. A novel finding was that glycogen synthase (GS) Ser(7) phosphorylation was higher in both muscles dexamethasone-treated rats. GS expression decreased (by 50%) in adipocytes only. Basal and insulin-stimulated GS Ser(641) and Ser(645,649,653,657) phosphorylation was elevated in epitrochlearis and soleus muscles and GS fractional activity was reduced ingly. In conclusion, dexamethasone treatment (1) decreases PKB expression and insulin-stimulated phosphorylation in both and adipocytes, and (2) increases GS phosphorylation (reduces GS fractional activity) in muscles and decreases GS expression in adipocytes. We suggest PKB and GS as major targets for dexamethasone-induced insulin resistance. (C) 2008 Elsevier Inc. All rights reserved.