Exploring the multifaceted roles of beta-defensins in prediabetes: a detailed review

Prediabetes represents a critical window of immune-metabolic dysregulation during which insulin resistance, low-grade inflammation, and barrier dysfunction emerge before overt diabetes. Human β-defensins (HBDs), classically described as antimicrobial peptides, are increasingly recognized as modulators of epithelial integrity, inflammatory signaling, and host-microbiota interactions process central to early metabolic deterioration. Evidence from genetic, experimental, and clinical studies indicates that alterations in HBD expression accompany insulin resistance, β-cell stress, and gut barrier impairment, with tissue-specific patterns observed across the dysglycemic spectrum. While most human data derive from established diabetes, animal models and limited human observations suggest that defensin dysregulation may arise earlier and contribute to the transition from prediabetes to diabetes. Importantly, HBDs are detectable in saliva, serum, and tissues, supporting their feasibility as accessible biomarkers of early immune-metabolic stress. However, heterogeneity in assay platforms, sample matrices, and study design currently limit clinical translation. This review synthesizes current evidence linking β-defensins to early metabolic dysfunction, distinguishes associative human findings from mechanistic experimental data, and highlights critical gaps in prediabetes-focused research. We propose that β-defensins represent promising early immune-metabolic indicators whose validation in longitudinal prediabetes cohorts may improve risk stratification and enable earlier intervention.