Thottappillil, A.; Kouser, S.; Badiger, A. V.; Pinto, P. G.; Ramachandran, S.; Janadri, S.; Mudagal, M. P.; Kukkupuni, S. K.; Mohan S, S.; Chethala N, V.

Managing complex disease like diabetes requires a systems and network medicine approach. Polyherbal formulations used in Indian Systems of Medicines (ISMs) like Ayurveda and their multi-targeted mode of action could be an effective way to bring out this systems biology pharmacology effect required for chronic diseases. These multi-component formulations are also served as sources for identifying novel ligands that interact with drug targets having systemic effects. The present study uses Varanadi Kashayam (VK), a polyherbal preparation used in Ayurveda clinical management of diabetes and its comorbidities, to demonstrate the systemic pharmacological action exerted by a formulation with a special focus on incretin modulation. In-vitro assays demonstrated the inhibitory potential of VA on -glucosidase and DPP4 enzymes and adipogenesis. It also showed an increase in GLP-1 secretion from GLUTag cells. These observations were corroborated in the in-vivo high-fat fed model of SD rats where VA increased GLP-1 secretion, improved the oral glucose tolerance and reduced body weight. Bioinformatics and computational biology analysis further identified Chebulinic acid, Terchebin and Chebulagic acid as the three major molecules showing stable docking and interactions with DPP4 when compared to the standard drug Vildagliptin. Network pharmacology analysis of VA revealed the potential involvement of AGE-RAGE signalling, Insulin resistance, Insulin signalling and lipid and atherosclerosis pathway along with other important signalling like FOXO signalling, cAMP and PI3K-AKT signalling in exerting the anti-diabetic and anti-obesity action. The present work provided a biological insight into the multi-targeted mode of action of a poly-herbal formulation the possible pharmacological networking through which the formulation modulates diverse disease related targets.