British Journal of Pharmacology 1998-12-01

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.

R Upton, P S Widdowson, S Ishii, H Tanaka, G Williams

Index: Br. J. Pharmacol. 125(8) , 1708-14, (1998)

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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.