Euglycemic and hypolipidemic activity of PAT5A: a unique thiazolidinedione with weak peroxisome proliferator activated receptor gamma activity.

ABSTRACT

The euglycemic and hypolipidemic activities of PAT5A, a novel pyridine analog of thiazolidinedione, have been evaluated in different animal models. Administration of PAT5A to db/db mice resulted in dose-dependent decreases in plasma glucose, triglyceride, and insulin levels, and an improved glucose tolerance. The glucose-lowering activity of PAT5A was better than that of troglitazone and comparable to that of rosiglitazone. In addition, PAT5A showed better lipid-lowering activity than troglitazone or rosiglitazone. A similar profile was seen in ob/ob mice. In high-fat-fed Sprague Dawley rats, PAT5A treatment reduced plasma triglyceride and total cholesterol levels. An in vitro peroxisome proliferator activated receptor gamma (PPARgamma) transactivation assay in HEK-293 cells showed poor transactivation for PAT5A compared with rosiglitazone. PAT5A did not show any PPARalpha- or PPARdelta-activating properties. Ex vivo study in db/db mice treated with PAT5A showed decreased activity of liver glucose 6-phosphatase, a key enzyme in gluconeogenesis. A 28-day probe toxicity study in Wistar rats did not show any treatment-related alterations in hematologic and biochemical parameters, nor any macroscopic and microscopic changes in the vital organs, whereas rosiglitazone treatment increased liver and heart weights. Our results indicate that PAT5A is a potent insulin sensitizer and hypolipidemic compound with a weak PPARgamma activation potential. Both in vivo and in vitro results suggest that PAT5A improves glucose kinetics and lipid levels through mechanisms not related to PPAR activation.