Improved metabolic status and insulin sensitivity in obese fatty (fa/fa) Zucker rats and Zucker Diabetic Fatty (ZDF) rats treated with the thiazolidinedione, MCC-555.
1. We examined the effect of chronic (21 days) oral treatment with the thiazolidinedione, MCC-555 ((+)-5-[[6-(2-fluorbenzyl)-oxy-2-naphy]methyl]-2,4-thiazo lid inedione) on metabolic status and insulin sensitivity in obese (fa/fa) Zucker rats and Zucker Diabetic Fatty (ZDF) rats which display an impaired glucose tolerance (IGT) or overt diabetic symptoms, respectively. 2. MCC-555 treatment to obese Zucker rats (10 and 30 mg kg(-1)) and diabetic ZDF rats (10 mg kg(-1)) reduced non-esterified fatty acid concentrations in both rat strains and reduced plasma glucose and triglyceride concentrations in the obese Zucker rats. Liver glycogen concentrations were significantly increased by chronic MCC-555 treatment in both obese Zucker rats (30 mg kg(-1) day(-1)) and diabetic ZDF rats (10 mg kg(-1) day(-1)), as compared with vehicle-treated lean and obese rats and there was a significant increase in hepatic glycogen synthase activity in MCC-555-treated diabetic ZDF rats as compared to vehicle-treated controls. 3. During a euglycaemic hyperinsulinaemic clamp, MCC-555-treated obese Zucker rats and diabetic ZDF rats required significantly higher glucose infusion rates to maintain stable glucose concentrations (2.01+/-0.19 mg min(-1) and 6.42+/-1.03 mg min(-1), respectively) than vehicle-treated obese controls (0.71+/-0.17 mg min(-1) and 2.09+/-0.71 mg min(-1); P<0.05), demonstrating improved insulin sensitivity in both Zucker and ZDF rats. MCC-555 treatment also enhanced insulin-induced suppression of hepatic glucose production in ZDF rats as measured using infusions of [6-3H]-glucose under clamp conditions. 4. In conclusion, we have demonstrated that MCC-555 improves metabolic status and insulin sensitivity in obese Zucker and diabetic ZDF rats. MCC-555 may prove a useful compound for alleviating the metabolic disturbances and IGT associated with insulin resistance in man.
Upton
R
R
Department of Medicine, University of Liverpool, UK.
Widdowson
P S
PS
Ishii
S
S
Tanaka
H
H
Williams
G
G
D000818:Animals; D001481:Basal Metabolism / Q000187:drug effects*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D005227:Fatty Acids / Q000097:blood; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D011924:Rats, Zucker; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D008112:Liver Glycogen; D013844:Thiazoles; D045162:Thiazolidinediones; D014280:Triglycerides; C115174:netoglitazone