An appraisal of the antidiabetic and hypolipidaemic activities of thiazolidin-4-ones with nicotinamide moiety in animal models

Abstract

The current study involves detailed pharmacological evaluation of four thiazolidine-4-one derivatives of nicotinic acid (NAT1-4), which have shown dual hypolipidaemic and anti-hyperglycaemic activities in preliminary studies. The in-vivo models included streptozotocin-induced, High-sucrose-diet (HSD) and High-fat-diet (HFD) fed mice models of diabetes. Mechanistic studies included effects on DPP-IV inhibition, glucose uptake, AMPK activation and expression of mediators like PPAR-and#945;/and#947;, NFand#61547;B, COX-II, Bax etc. NAT1-4 significantly lowered elevated blood glucose levels in HFD and HSD models and NAT-1and3 improved the insulin levels in HSD model. The elevated lipids levels in HFD and HSD models were decreased by NAT-1and3. Interestingly, all treatment (NAT 1-4) groups markedly increased HDL-cholesterol levels in both the models. Also, the molecules did not show any adverse effects on renal or liver functions. In in-vitro experiments, none of the drugs showed DPP-IV inhibition or AMPK activation but all drugs increased glucose uptake by hemi-diaphragm. NAT-1-4 alone and in combination with insulin increased glucose uptake in myotubes and pre-adipocytes. NAT-2,3and4 increased the levels of PPAR-and#945;/and#947; in the nuclear fractions of myotubes and pre-adipocytes. In RAW cells, NAT-3and4 reduced the levels of NFand#61547;B but none of the treatments had any effect on the COX-II expression, ROS and nitrite generation. NAT-1 increased and NAT-4 decreased the expression of BAX in LPS treated L6 myotubes. In conclusion, the drugs have shown effective glucose and lipid lowering effects in different in-vivo models and are found to increase translocation of transcription factors PPAR and#945;andand#947; and inhibition of NFand#61547;B expression which may have contributed to their anti-diabetic and hypolipidaemic activities.