The systemic anti-diabetic effect of polyherbal formulation Varanadi Kashayam is mediated through GLP-1 secretion and DPP4 inhibition

BACKGROUND: Frontiers of health science increasingly emphasize systems and network medicine approaches for managing complex lifestyle diseases such as diabetes. In this context, systemic targets like incretin hormones and their modulators, particularly DPP4 inhibitors have gained prominence. Ayurveda, the Indian System of Medicine, with its clinically validated multicomponent formulations, offers a valuable resource for integrative therapeutic strategies with systemic mode of action. OBJECTIVES: The study investigates the incretin modulatory effect of Varanadi Kashayam (VA), an Ayurveda polyherbal formulation used in the clinical management of diabetes and its comorbidities. METHODS: A high-fat diet and low dose STZ-induced Sprague-Dawley (SD) rat model was used to study anti-diabetic, GLP-1 secretory, and anti-obesity effects of VA. In vitro studies using GLUTag cells assessed GLP-1 secretion and DPP4 gene expression modulation; and studies using 3T3-L1 fibroblasts examined anti-adipogenic effects. Computational methods including molecular docking and molecular dynamic simulations identified phytochemicals potentially contributing to DPP4 inhibition. RESULTS: VA administration significantly improved fasting blood glucose and oral glucose tolerance in experimental animals, along with enhanced GLP-1 secretion. In vitro results showed significant inhibition of DPP4 enzyme activity, increased GLP-1 secretion, and downregulation of DPP4 gene expression in GLUTag cells, and suppression of adipogenesis in 3T3-L1 fibroblasts. Computational analyses ascertained Chebulinic acid, Chebulagic acid, and Terchebin as top-ranked phytochemicals that could potentially inhibit DPP4. CONCLUSION: Combining in vitro, in vivo, and in silico findings, this study provides valuable insight into the incretin modulatory effect of VA in treating diabetes and associated metabolic diseases.