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

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Abstract
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‐thiazolidinedione) 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. 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. 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; P3H]‐glucose under clamp conditions. 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.