The β-cell stress continuum: Molecular mechanisms driving diabetes progression and cellular failure

Diabetes mellitus encompasses heterogeneous disorders in which β-cell dysfunction contributes to impaired glucose regulation. Although the causes and sequence of disease processes differ across diabetes subtypes, β-cell stress has emerged as a potential convergent mechanism that may contribute to disease progression in some contexts. However, current evidence does not establish β-cell stress as the initiating event in all forms of type 1 diabetes (T1D) or type 2 diabetes (T2D). In T1D, autoimmune injury is a defining disease process, whereas in T2D, insulin resistance, genetic susceptibility, and environmental factors may precede or interact with β-cell dysfunction. This narrative review proposes the β-cell Stress Continuum as a testable conceptual framework for examining how β-cells may transition from adaptive responses to persistent dysfunction and, in some settings, loss of cellular identity or survival. The framework integrates immune, metabolic, oxidative, endoplasmic reticulum, mitochondrial, inflammatory, and genomic stress, while recognizing that their relative contributions and temporal sequence may vary among individuals and diabetes subtypes. It also considers interactions between islets and other organs, including the liver, adipose tissue, skeletal muscle, immune system, and nervous system. The β-cell Stress Continuum is intended to organize research questions about β-cell adaptation and diabetes progression; it is not presented as a universal mechanism or as a replacement for disease-specific models. The proposed framework may help guide the investigation of biomarkers, disease staging, and therapeutic strategies, but its applicability and clinical utility require validation in subtype-specific, longitudinal studies.