Identification of Ascorbic Acid and Gallic Acid as Novel Inhibitors of Secreted Frizzled-Related Protein for the Treatment of Obesity-Induced Type 2 Diabetes

Abstract

Type 2 diabetes mellitus (T2D) has been reported as major public health issue rising at an alarming rate worldwide, and obesity is the leading risk factor for the development of T2D. Secreted frizzled-related protein 4 ( SFRP4) released with inflammatory mediators from adipose tissues constrains the exocytosis of insulin containing granules from the pancreatic islets that leads towards the development to T2D. The significant overexpression of SFRP4 in diabetic patients and its involvement in islet dysfunction suggest its critical role in the development of diabetes. Thus, this study was designed to explore the potential of ascorbic acid (AA) and gallic acid (GA) against SFRP4 for the treatment of diabetes. Molecular docking approach was used for the prediction of binding interactions of AA and GA at the active pocket of SFRP4. Docking analysis indicated strong binding interactions of AA and GA to the amino acid residues at the active site of SFRP4. A significant reduction in the level of SFRP4 was observed in transfected cells treated with AA and GA. For the evaluation of the cytotoxicity of AA and GA against HepG2 cells, MTT assay was performed. The results of MTT assay demonstrated that AA and GA are non-cytotoxic towards HepG2 cells at concentration of 15 μM. The oral administration of AA and GA to diet-induced obese mice caused significant reduction in body weight, blood glucose level, and SFRP4 expression. The results of this study suggest that AA and GA have potential for the treatment of obesity-induced T2D.