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 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.
Pickavance
L
L
Department of Medicine, University of Liverpool.
Widdowson
P S
PS
King
P
P
Ishii
S
S
Tanaka
H
H
Williams
G
G
D000367:Age Factors; D000818:Animals; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology / Q000517:prevention & control*; D004326:Drinking; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D011924:Rats, Zucker; D013844:Thiazoles / Q000627:therapeutic use*; D045162:Thiazolidinediones; D013997:Time Factors
D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D005947:Glucose; C115174:netoglitazone