Beta-D-glucoside protects against advanced glycation end products (AGEs)-mediated diabetic responses by suppressing ERK and inducing PPAR gamma DNA binding

Accumulation of advanced glycation end products (AGES), due to excessive amounts of 3- or 4-carbon sugars derived from glucose; cause multiple consequences in diabetic patients and older persons. The transcription factor, peroxisome proliferator-activated receptor gamma (PPAR gamma), is down regulated in the diabetic condition. Drugs targeting PPAR gamma were developed for diabetes therapy. We found that AGE inhibited PPAR gamma activity in different cell types induced by PPAR gamma activators, like troglitazone, rosiglitazone, oleamide, and anandamide. AGE induced translocation of PPAR gamma from nucleus to cytoplasm, increased on activation of ERK in cells. Antioxidants that inhibit AGE-induced NF-kappa B activation by preventing ROI generation were unable to protect AGE-mediated decrease in PPAR gamma activity. Only mangiferin, a beta-D-glucoside, prevented AGE-mediated decrease in PPAR gamma activity and inhibited phosphorylation of ERK and cytoplasmic translocation of PPAR gamma. Mangiferin interacts with PPAR gamma and enhanced its DNA binding activity as predicted by in silico and shown by in vitro DNA-binding activity. Overall, the data suggest that (i) mangiferin inhibited AGE-induced ERK activation thereby inhibited PPAR gamma phosphorylation and cytoplasmic translocation; (ii) mangiferin interacts with PPAR gamma and enhances its DNA-binding ability. With these dual effects, mangiferin can be a likely candidate for developing therapeutic drug against diabetes. (C) 2012 Elsevier Inc. All rights reserved.