ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This review describes the heterogeneity in type 1 diabetes (T1D), the emerging concept of endotypes, and their impact on T1D prediction, prevention and treatment.

Growing evidence supports the existence of heterogeneity in T1D genetic background, pathogenesis, clinical course, susceptibility to complications and response to emerging immunotherapy (1,2). This has led to the concept that T1D is not a single disease; instead there are distinct subtypes known as ‘endotypes’ (1-3).

Previous studies have led to the characterization of two main endotypes: T1DE1 and T1DE2, which are associated with age at clinical diagnosis. T1DE1 includes cases of T1D diagnosed in early childhood and is characterized by a hyperimmune pattern of insulitis with high numbers of CD8⁺ T and CD20⁺ B cells, limited residual insulin-containing islets, abnormal proinsulin processing and an elevated circulating proinsulin-to-C-peptide ratio. In contrast, T1DE2 includes cases of T1D diagnosed in adolescence or adulthood and is characterized by more residual insulin-containing islets and without insulitis, fewer infiltrating CD8⁺ T and CD20⁺ B cells, normal proinsulin processing and lower proinsulin-to-C-peptide ratio than T1DE1.

There is emerging evidence that these 2 endotypes might respond differently to some immunotherapies. In particular, the T1DE1 might respond better than T1DE1 to agents directed to specific immune cell subsets, such as rituximab or teplizumab, while GAD–alum therapy might be effective for treating T1DE2.

Recognising T1D heterogeneity and further characterisation of endotypes could provide critical information for a more personalized approach and the design of more targeted immunotherapies to arrest or slow T1D progression.

References: 1. den Hollander, N.H.M. and B.O. Roep, From Disease and Patient Heterogeneity to Precision Medicine in Type 1 Diabetes. Front Med (Lausanne). 2022;9:932086.2. Battaglia, M., et al., Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes. Diabetes Care. 2020;43(1):5-12.3. Parviainen, A., et al., Heterogeneity of Type 1 Diabetes at Diagnosis Supports Existence of Age-Related Endotypes. Diabetes Care. 2022;45(4):871-879.