Figure 1: Challenges to the Eisenbarth model of the natural history of type 1 diabetes.

Key events of the Eisenbarth model³ over the course of the disease (measured in years) are shown by dotted lines at different time points. Challenges to this model, taking into account the increasing complexity of type 1 diabetes, include the following: precipitating immune events that might occur prenatally (A); large variation in starting β-cell mass and function, defects in one or both could be developmentally programmed (B); initiation of autoimmunity is measured by autoantibodies, but other immunological abnormalities probably precede the presence of detectable pancreatic antibodies (C); the patient’s environment could affect their entire disease course (D); β-cell loss could relapse or remit (E); dysglycaemia occurs before clinical diagnosis (F); decline in β-cell function might not mirror decline in β-cell mass—methods to measure β-cell mass have not been established (G); and residual C-peptide is detectable in many people who have long duration type 1 diabetes (H). Furthermore, progression through stages A–C is heterogeneous, and will be affected by immune, genetic, environment, and key demographic features (ie, age, body-mass index). Adapted from Atkinson et al.⁴