Oral indole‐3‐propionic acid preserves β‐cell function and improves glucose homeostasis in diabetic mice via FOXA1 – SGPP1 – HSPA5 signalling

AIMS: Emerging evidence suggests that indole-3-propionic acid (IPA), a gut microbiota-derived tryptophan metabolite, confers metabolic benefits in type 2 diabetes (T2D). However, its direct role in preserving pancreatic β-cell function and the underlying molecular mechanisms remains largely undefined. This study aimed to investigate the role and underlying mechanisms of IPA in preserving β-cell function and alleviating endoplasmic reticulum (ER) stress under diabetogenic conditions. MATERIALS AND METHODS: High-fat diet-fed and db/db mice were treated with IPA via oral gavage. Glucose homeostasis, islet morphology, and insulin secretion were evaluated. In vitro studies in MIN6 cells and isolated islets assessed IPA's effects on ER stress, insulin secretion, and apoptosis. Proteomics, molecular docking, luciferase reporter assays, and gene expression analyses were conducted to identify key molecular targets. RESULTS: IPA significantly preserved islet architecture and enhanced insulin secretion. Proteomic analysis revealed downregulation of ER stress pathways and upregulation of SGPP1 upon IPA treatment. SGPP1 was essential for IPA-mediated suppression of ER stress and β-cell apoptosis through direct interaction with HSPA5. IPA stabilized and activated the transcription factor FOXA1, which in turn transcriptionally upregulated SGPP1 expression. CONCLUSION: IPA protects pancreatic β-cells by activating the FOXA1-SGPP1-HSPA5 signalling pathway, thereby alleviating ER stress and enhancing β-cell survival.