Trajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab – published online 19/11/2024

Alfonso Galderisi, Emily K. Sims, Carmella Evans‑Molina, Alessandra Petrelli, David Cuthbertson, Brandon M. Nathan, Heba M. Ismail, Kevan C. Herold, Antoinette Moran

The TrialNet Anti-CD3 Prevention Trial (TN10) has previously demonstrated the efficacy of teplizumab in delaying the onset of clinical (stage 3) type 1 diabetes. In this issue, Galderisi et al (https://doi.org/10.1007/s00125-024-06323-0) use the oral minimal model to track disease progression in individuals with stage 2 (pre-clinical) type 1 diabetes enrolled in TN10. Metabolic modelling revealed heterogeneity of stage 2 type 1 diabetes and highlighted differential metabolic trajectories of rapid and slow progressors among both teplizumab- and placebo-treated participants. The authors show that loss of >25% of beta cell function over a 3 month period is a strong predictor of rapid disease progression (<2 years) regardless of treatment arm. They also identified that reduced insulin clearance characterises slow progressors in both groups, suggesting the presence of an adaptive mechanism to maintain circulating insulin levels in the presence of declining beta cell function. The authors propose that these findings could be used to stratify risk for progression in stage 2 type 1 diabetes and to identify early responders to disease-modifying treatments in type 1 diabetes prevention trials.