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

Background

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.

Scope and approach

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.

Key findings and conclusions

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.