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.

Abstract

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.

• Authors: R Upton, P S Widdowson, S Ishii, H Tanaka, G Williams
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 125 Issue 8 Pg. 1708-14 (Dec 1998) ISSN: 0007-1188 [Print] England
• PMID: 9886762 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Blood Glucose
• Fatty Acids
• Hypoglycemic Agents
• Insulin
• Liver Glycogen
• Thiazoles
• Thiazolidinediones
• Triglycerides
• netoglitazone

Topics

• Animals
• Basal Metabolism (drug effects)
• Blood Glucose (drug effects, metabolism)
• Body Weight (drug effects)
• Diabetes Mellitus, Experimental (drug therapy)
• Fatty Acids (blood)
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Insulin (blood, pharmacology)
• Insulin Resistance
• Liver Glycogen (metabolism)
• Male
• Obesity (drug therapy)
• Rats
• Rats, Zucker
• Thiazoles (pharmacology, therapeutic use)
• Thiazolidinediones
• Treatment Outcome
• Triglycerides (blood)