Efficacy of Chemical Chaperones (TUDCA, 4-PBA) in Restoring Glucose-Stimulated Insulin Secretion and Mitigating Endoplasmic Reticulum Stress in Pancreatic Beta-Cells: A Systematic Review and Bayesian Meta-Analysis

The progressive failure of pancreatic beta-cells under chronic glucolipotoxicity drives the pathogenesis of type 2 diabetes mellitus (T2DM). This metabolic stress overwhelms the folding capacity of the endoplasmic reticulum (ER), hyperactivates the unfolded protein response (UPR), engages terminal pro-apoptotic signaling (CHOP), and promotes beta-cell dedifferentiation. In this systematic review and meta-analysis, registered with PROSPERO (CRD420261370436), we evaluated the preclinical efficacy of the low-molecular-weight chemical chaperones tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyrate (4-PBA) in preserving beta-cell exocytotic identity and mitigating ER stress. Following PRISMA 2020 guidelines, a systematic search of PubMed, Scopus, and Web of Science (January 2016–May 2026) identified four eligible experimental studies. Preclinical models (INS-1 and βTC-6 cell lines, Wistar rats, and C57BL/6 mice) exposed to high-fat or high-fat/high-fructose diets, cholesterol loading, or protein restriction followed by high-fat feeding showed impaired or dysregulated glucose-stimulated insulin secretion (GSIS) and upregulated ER stress markers. Co-administration of TUDCA or 4-PBA consistently reversed these defects, restoring the GSIS stimulation index and reducing pro-apoptotic markers. A hierarchical Bayesian random-effects meta-analysis estimated a robust pooled restoration ratio of 1.87 (95% credible interval [CrI]: 1.39 to 2.46), with the entire credible mass above the null (posterior probability of benefit > 0.99) and modest between-study heterogeneity. In conclusion, TUDCA and 4-PBA act as structural ER scaffolds that prevent terminal UPR activation and preserve the beta-cell exocytotic machinery, positioning them as candidate disease-modifying agents that merit confirmatory clinical evaluation.