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

Abstract

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 beta-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 beta-cell function. MCC-555 may thus be beneficial in humans with IGT, to prevent or delay the progression of diabetes.

• Authors: L Pickavance, P S Widdowson, P King, S Ishii, H Tanaka, G Williams
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 125 Issue 4 Pg. 767-70 (Oct 1998) ISSN: 0007-1188 [Print] England
• PMID: 9831913 (Publication Type: Journal Article)

Chemical References

• Hypoglycemic Agents
• Thiazoles
• Thiazolidinediones
• Glucose
• netoglitazone

Topics

• Age Factors
• Animals
• Body Weight
• Diabetes Mellitus, Type 2 (physiopathology, prevention & control)
• Drinking
• Glucose (metabolism)
• Glucose Intolerance
• Hypoglycemic Agents (therapeutic use)
• Male
• Rats
• Rats, Zucker
• Thiazoles (therapeutic use)
• Thiazolidinediones
• Time Factors