The role of vitamin D signalling in β cell apoptosis: a systematic review

Background Vitamin D signalling, primarily through the vitamin D receptor (VDR), regulates cellular survival and programmed cell death. This systematic review aims to synthesise current evidence on the role of vitamin D in pancreatic β-cell apoptosis. Methods Medline, Embase, and Scopus were searched for original studies investigating vitamin D, vitamin D analogues, or VDR-related interventions in experimental models of β-cell apoptosis or programmed cell death. Results 26 studies were included. Across in vitro, ex vivo, and in vivo models, vitamin D signalling protected β-cells against apoptosis induced by cytokine-mediated inflammation, oxidative stress, glucotoxicity, lipotoxicity, streptozotocin exposure, and diabetic stress. These effects were associated with reduced NF-κB signalling, nitric oxide and reactive oxygen species production, improved mitochondrial stability, modulation of Bcl-2 family proteins, inhibition of endoplasmic reticulum stress, and regulation of pyroptosis, ferroptosis, and autophagy-related survival mechanisms. VDR activation also supported β-cell identity, insulin secretion, and β-cell mass preservation. In contrast, calcitriol-associated growth inhibition and increased apoptosis were reported in βTC insulinoma models. Conclusion Vitamin D signalling generally appears cytoprotective in β-cells exposed to inflammatory, oxidative, and metabolic stress. However, its effects on β-cell survival are model- and context-dependent, reflecting differences in cellular background, experimental stressors, and methods used to assess cell death.