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This study was aimed at exploring the capability of the pancreatic endocrine adaptive mechanisms of ageing Sprague-Dawley rats to counteract the metabolic challenge induced by the prolonged administration of dexamethasone (DEX)(0· 13 mg/kg per day for 13 days). DEX treatment induced peripheral insulin resistance in 3-, 18-and 26-month-old rats, as indicated by the significant and persistent rise of plasma insulin levels in each age group (plasma insulin in 3-, 18-and 26-monthold rats from basal values of 4· 30· 8, 4· 70· 5 and 5· 61· 0 ng/ml (means...) respectively, rose to 11· 91· 7, 29· 15· 5 and 27· 92· 7 ng/ml respectively, after 9 days of administration). However, plasma glucose concentrations remained unchanged during the treatment in young rats, whereas they increased up to frankly diabetic levels in most 18-month-old and in all 26-monthold animals after a few days of DEX administration. Plasma free fatty acid concentrations increased 2-fold in 3-and 26-month-old rats and 4-fold in 18-month-old rats and could possibly be involved in the glucocorticoid-induced enhancement in insulin resistance, although they showed no significant correlation with glycaemic values. Incubation of pancreatic islets obtained from treated rats showed that DEX administration increased the insulin responsiveness of islets from not only younger but also older donors. However, in the islets of ageing rats, which already showed an age-dependent impairment of the sensitivity to glucose and other secretagogues, this enhancing effect was clearly attenuated with respect to the younger counterpart. Furthermore, DEX treatment depressed significantly the …