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

L. Pickavance, P. S. Widdowson, P. King, S. Ishii, H. Tanaka, G. Williams

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43 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)767-770
Number of pages4
JournalBritish Journal of Pharmacology
Issue number4
Publication statusPublished - 1998
Externally publishedYes


  • Diabetes
  • Impaired glucose tolerance
  • Insulin
  • MCC-555
  • Thiazolidinediones
  • ZDF rats

ASJC Scopus subject areas

  • Pharmacology


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