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 di splaying impaired glucose tolerance (IGT), moderate hyperglycaemia and hyperinsulinaemia were treated with the novel thiazolidinedione, MCC- 555, for 28 days, during which time beta-cell failure and progression to overt diabetes occurs. 2 Treated ZDF rats exhibited consistently lo wer blood glucose levels than vehicle-treated diabetic controls, with a delayed rise and lower plateau levels. MCC-555 maintained plasma ins ulin levels throughout the treatment period, whereas these fell by 40% in untreated ZDF rats. 3 The rise in body weight was maintained in MC C-555-treated rats, whereas vehicle-treated rats exhibited blunted bod y weight gain after 8 weeks of age. Daily food intake was higher in di abetic, as compared to non-diabetic rats, but treatment did not modify food intake in diabetic rats. Water intake was lower in treated ZDF r ats, concomitant with lowering of blood glucose. 4 The hyperinsulinaem ic-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 i n non-diabetic rats, demonstrating reduced glucose entry into insulin- sensitive tissues in diabetic rats. Increased glucose infusion rates w ere required to maintain euglycaemia in treated diabetic rats, demonst rating increased insulin sensitivity in these animals. 5 In conclusion , chronic MCC-555 treatment of young ZDF rats displaying IGT attenuate s the development of overt diabetes through improved insulin sensitivi ty and maintenance of beta-cell function. MCC-555 may thus be benefici al in humans with IGT, to prevent or delay the progression of diabetes .