Vitamin D in Diabetes Mellitus: Immunomodulatory and Epigenetic Mechanisms Beyond Glycemic Control

Diabetes mellitus is a multifactorial metabolic disorder characterized not only by persistent hyperglycemia but also by immune dysregulation, chronic low-grade inflammation, oxidative stress, and progressive pancreatic β-cell dysfunction. In addition to disturbances in glucose metabolism, type 1 and type 2 diabetes involve complex interactions between genetic susceptibility, environmental triggers, and immunometabolic pathways. In recent years, vitamin D has emerged as a pleiotropic secosteroid hormone with biological functions extending far beyond its classical role in calcium and bone homeostasis. Accumulating experimental and epidemiological evidence indicates that vitamin D influences insulin secretion, insulin sensitivity, immune tolerance, inflammatory signaling, and cellular survival pathways. Vitamin D deficiency is highly prevalent worldwide and occurs disproportionately among individuals with diabetes. Suboptimal serum 25- hydroxyvitamin D levels have been associated with increased insulin resistance, impaired glucose-stimulated insulin secretion, heightened inflammatory cytokine production, and an increased risk of microvascular and macrovascular diabetic complications. Mechanistic studies have demonstrated that vitamin D receptor activation modulates key pathways involved in β-cell preservation, adipokine regulation, oxidative stress reduction, and immune cell differentiation. Emerging research has further highlighted vitamin D’s role in epigenetic regulation through effects on DNA methylation, histone modification, and microRNA expression, as well as its influence on gut microbiota composition and the gut–pancreas–immune axis. This review synthesizes current evidence regarding the immunometabolic, epigenetic, and gut-mediated actions of vitamin D in diabetes mellitus. It critically examines the inconsistencies observed in randomized supplementation trials and explores factors such as baseline deficiency, genetic variability, and disease stage. Finally, the review outlines future research priorities and precision-based strategies aimed at optimizing vitamin D interventions in comprehensive diabetic care.