Short-Chain Fatty Acids as Endogenous Inhibitors of DPP-IV Enzyme: Implications in GLP-1 Stability and Metabolic Health

Abstract Dipeptidyl peptidase-IV (DPP-IV/CD26) is a circulating serine protease that rapidly degrades incretin hormones, including glucagon-like peptide-1 (GLP-1), limiting incretin activity and glucose homeostasis. Short-chain fatty acids (SCFAs), major gut microbiota-derived metabolites, influence metabolic health through multiple mechanisms; whether they directly inhibit DPP-IV remains unknown. Here, we investigated the inhibitory activity and mechanism of acetate, propionate, and butyrate against recombinant human DPP-IV. All three SCFAs inhibited DPP-IV concentration-dependently, with an average IC50 of 0.62 ± 0.13 mM. Michaelis–Menten, Lineweaver–Burk, Dixon, and Cornish–Bowden analyses demonstrated reversible mixed-mode inhibition, whereas sitagliptin exhibited competitive inhibition (Ki = 2.6 nM). SCFAs protected GLP-1 from DPP-IV mediated degradation and preserved GLP-1-induced calcium signaling in INS-1 cells. Molecular docking indicated preferential SCFA interactions within the DPP-IV β-propeller domain. These findings identify SCFAs as direct, reversible DPP-IV modulators, providing a molecular link between gut microbial metabolites and incretin regulation.