Transcriptomic Analysis Reveals Mechanisms of Phenyl-Gamma-Valerolactones in Protecting Pancreatic Beta Cells from Oxidative Stress

Introduction: Phenyl-Gamma-valerolactones, the main gut-derived metabolites of proanthocyanidins, have been shown to mitigate oxidative stress and inflammation, improving insulin secretion, insulin sensitivity and inhibiting pancreatic β-cell apoptosis. However, the mechanisms through which these effects occur are still poorly understood. Objective: This study aimed to investigate the molecular mechanisms underlying the protective effects of Phenyl-Gamma-valerolactones on pancreatic β -cells under oxidative stress conditions, using a transcriptomic analysis. Methodology: MIN6 cells were treated with cholesterol (320 μM), with or without the presence of  5-(3,4,5-trihydroxyphenyl)-gamma-valerolactone (THFGVL) and 5-(4-hydroxy-3-methoxyphenyl) γ-valerolactone (HMGVL) (15 uM) for 6 hours. RNA was extracted and microarray analysis was performed. Pathway enrichment analysis was performed using GeneTrail 3, with data source from KEGG, Biocarta, and Wikipathways databases. Oxidative parameters and insulin secretion were also analyzed. Discussion: A total of 3,475 genes differentially expressed were identified in cells treated with THFGVL and 1,397 genes in cells treated with HMGVL. These genes are involved with various processes, including inflammation (e.g., IFN I activation and inflammatory cytokine production, TGF beta signaling pathway, PI3K-AKT signaling pathway, interleukin-1 processing, NFKB activation in beta cells, and interleukin-7 signaling), metabolism (e.g., carbohydrate uptake, insulin resistance, insulin secretion, and oxidative stress-induced senescence). Moreover, both metabolites downregulated several microRNAs (miR) involved in inflammatory and metabolic pathways, notably miR-8114 and miR-137-3p, which are linked to NFKB pathway activation; miR-124a, when inhibited, increases FOXA2 expression, activate B cell gene transcription and induces Pdx1 expression; and miR-103, when inhibited, contributes to insulin and glucose homeostasis. Additionally, miR-690 was upregulated and involved in ameliorating endoplasmic reticulum stress. Furthermore, THFGVL decreased H₂O₂, SOD, and GPx activities, and improved insulin secretion. Otherwise, HMGVL improved insulin secretion. Conclusion: These findings suggest that proanthocyanidin gut derived-metabolites protect pancreatic β-cells from cholesterol-induced stress, and enhance cell function, by modulating inflammatory and oxidative stress pathways.