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

BackgroundFrontiers of health science increasingly emphasizes 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 (ISM), with its clinically validated multicomponent formulations offers a valuable resource for integrative therapeutic strategies with systemic mode of action. PurposeThe study investigates the incretin modulatory effect of Varanadi Kashayam (VA), an Ayurveda polyherbal formulation used in the clinical management of diabetes and its comorbidities. Experimental approachA high-fat diet induced Sprague-Dawley (SD) rat model was used to study the anti-diabetic, GLP-1 secretory, and anti-obesity effects of VA. In vitro studies using GLUTag cells assessed the GLP-1 secretion and DPP4 gene expression modulation; and studies using 3T3-L1 fibroblasts examined the anti-adipogenic effects. Computational methods including molecular docking and molecular dynamic simulations were used to identify the phytochemicals responsible for DPP4 inhibition. ResultsVA administration significantly improved fasting blood glucose and oral glucose tolerance in experimental animals, along with enhanced GLP-1 secretion. The in vitro results showed inhibition of DPP4 enzyme activity, increase in GLP-1 secretion and downregulation of DPP4 gene expression in GLUTag cells, and suppression of adipogenesis in 3T3-L1 fibroblast cells. Computational analyses ascertained Chebulinic acid, Chebulagic acid and Terchebin as top ranked phytochemicals responsible for DPP4 inhibition effect. ConclusionCombining 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/601306v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1d424fcorg.highwire.dtl.DTLVardef@c84555org.highwire.dtl.DTLVardef@40094borg.highwire.dtl.DTLVardef@225272_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIVaranadi Kashayam (VA) improved blood glucose and GLP-1 levels in diabetic rats. C_LIO_LIInhibited DPP4 activity and gene expression in GLUTag cells. C_LIO_LISuppressed adipogenesis and adipogenic markers in 3T3-L1 cells. C_LIO_LIChebulinic acid, Chebulagic acid, and Terchebin identified as key DPP4 inhibitors. C_LI