Food regulation of incretin axis: Molecular mechanisms and clinical outlook in diabetes

Diabetes, particularly type 2 diabetes mellitus (T2DM), is a global metabolic disorder characterized by insulin resistance, β-cell dysfunction, and incretin axis dysregulation. Incretin hormones (GLP-1 and GIP) are critical for glucose homeostasis via the gut-islet axis, but their activity is impaired in T2DM, necessitating novel dietary interventions. This review synthesizes current research on how natural food components (dietary fiber, lipids, amino acids, probiotics, polyphenols, piperine) modulate the incretin axis. Mechanisms including SCFA-mediated receptor activation, DPP-IV inhibition, and gut microbiota regulation are analyzed, with emphasis on molecular pathways and clinical evidence. Dietary fibers (e.g., β-glucan, inulin) are fermented into SCFAs (acetate, butyrate) to activate FFAR2/3 and GPR43 on intestinal L cells, enhancing GLP-1 secretion and improving glycemia in T2DM. Lipids and certain amino acids modulate incretins via GPCR activation (e.g., GPR120, FFAR1) and metabolic pathways (e.g., α-KG, cAMP). Probiotics (e.g., Lactobacillus reuteri) and bioactives (polyphenols, piperine) promote GLP-1 through SCFA production, bile acid signaling, or DPP-IV inhibition. These interventions offer multitarget, low-toxicity benefits for T2DM management, with synergistic effects in combinations (e.g., synbiotics). Future research should prioritize precision nutrition using multi-omics biomarkers and food technologies (e.g., nanodelivery) to enhance bioavailability and personalized efficacy. This review, based on the beneficial effects of incretin-based therapies on diabetes, summarizes the regulatory effects of food components on incretins and their underlying molecular mechanisms. • Incretin axis (GLP-1/GIP) regulates glucose; diabetes impairs GLP-1 secretion and β-cell response. • Dietary fibers ferment to SCFAs, activating FFAR/GPR receptors to boost GLP-1 in diabetes. • MUFAs/PUFAs and BCAAs/glutamine enhance incretin secretion via GPCRs and metabolic pathways. • Probiotics and polyphenols modulate GLP-1 through SCFAs and DPP-IV inhibition. • Precision nutrition via food tech and biomarkers aims to optimize incretin-based diabetes interventions.