Journal of agricultural and food chemistryOct 12, 2026

Short-Chain Fatty Acids May Slow DPP-IV Enzyme to Help Keep GLP-1 Stable and Support Metabolic Health

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 13, 2026

Abstract

Short-chain fatty acids inhibited DPP-IV with an average IC50 of 0.62 ± 0.13 mM.

All three tested short-chain fatty acids—acetate, propionate, and butyrate—showed concentration-dependent inhibition of DPP-IV.
The inhibition mechanism was characterized as reversible mixed-mode, differing from the competitive inhibition observed with the drug sitagliptin.
Short-chain fatty acids prevented the degradation of glucagon-like peptide-1 (GLP-1) by DPP-IV.
Preservation of GLP-1-induced calcium signaling was observed in insulin-secreting cells treated with short-chain fatty acids.
Molecular docking studies suggested that short-chain fatty acids preferentially interact with a specific region of the DPP-IV enzyme.

Simplified

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.

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Short-Chain Fatty Acids May Slow DPP-IV Enzyme to Help Keep GLP-1 Stable and Support Metabolic Health

Abstract

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