The development of overt diabetes in young Zucker Diabetic Fatty (ZDF) rats and the effects of chronic MCC‐555 treatment

1 Young (6‐week‐old) pre‐diabetic Zucker Diabetic Fatty (ZDF) rats displaying impaired glucose tolerance (IGT), moderate hyperglycaemia and hyperinsulinaemia were treated with the novel thiazolidinedione, MCC‐555, for 28 days, during which time β‐cell failure and progression to overt diabetes occurs. 2 Treated ZDF rats exhibited consistently lower blood glucose levels than vehicle‐treated diabetic controls, with a delayed rise and lower plateau levels. MCC‐555 maintained plasma insulin levels throughout the treatment period, whereas these fell by 40% in untreated ZDF rats. 3 The rise in body weight was maintained in MCC‐555‐treated rats, whereas vehicle‐treated rats exhibited blunted body weight gain after 8 weeks of age. Daily food intake was higher in diabetic, as compared to non‐diabetic rats, but treatment did not modify food intake in diabetic rats. Water intake was lower in treated ZDF rats, concomitant with lowering of blood glucose. 4 The hyperinsulinaemic‐euglycaemic clamp technique was applied to all rats after treatment to examine the effects of MCC‐555 on insulin sensitivity. The glucose infusion rate to maintain normoglycaemia was lower in diabetic than in non‐diabetic rats, demonstrating reduced glucose entry into insulin‐sensitive tissues in diabetic rats. Increased glucose infusion rates were required to maintain euglycaemia in treated diabetic rats, demonstrating increased insulin sensitivity in these animals. 5 In conclusion, chronic MCC‐555 treatment of young ZDF rats displaying IGT attenuates the development of overt diabetes through improved insulin sensitivity and maintenance of β‐cell function. MCC‐555 may thus be beneficial in humans with IGT, to prevent or delay the progression of diabetes.British Journal of Pharmacology (1998) 125 , 767–770; doi: 10.1038/sj.bjp.0702158