Reclassification of type 1 diabetes from a pathophysiological perspective

Abstract

For decades, type 1 diabetes (T1D) has been defined as an autoimmune disease characterized by β-cell destruction and diagnosed at the onset of hyperglycemia. However, advances in immunology, genetics, biomarker discovery, and longitudinal cohort studies have profoundly reshaped this concept. Current evidence demonstrates that T1D is a continuous, heterogeneous, and dynamic biological process that begins years before the clinical diagnosis of diabetes.

This evolving paradigm proposes that T1D should be classified according to its underlying pathophysiology rather than glycemic status alone. The appearance of islet autoimmunity, the progressive decline in β-cell mass and function, and the interaction between genetic susceptibility and environmental factors define a continuum of disease with variable rates of progression. Within this framework, the staging system (Stages 1, 2, and 3) represents far more than a research classification: it establishes the diagnosis before hyperglycemia develops, identifies individuals at risk of progression, and creates opportunities for surveillance and disease-modifying interventions.

At the same time, T1D is no longer viewed as a single homogeneous disorder. Increasing evidence supports the existence of distinct immunological and biological endotypes characterized by differences in age at onset, immune mechanisms, β-cell vulnerability, metabolic deterioration, and clinical progression. This heterogeneity provides the foundation for precision medicine in autoimmune diabetes and helps explain the variable responses observed in prevention trials and immunomodulatory therapies.

This lecture will review the pathophysiological basis supporting the current reclassification of T1D, emphasizing the transition from a glucose-based definition toward a biology-based model of disease. Particular attention will be given to the concepts of disease staging, biological heterogeneity, and endotypes, as well as their implications for screening strategies, risk stratification, therapeutic decision-making, and long-term clinical management. Understanding T1D as a progressive autoimmune disorder rather than an acute metabolic disease fundamentally changes the timing of diagnosis and expands the role of the diabetologist from treating established hyperglycemia to identifying disease in its earliest stages and, ultimately, delaying or preventing its clinical onset.