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Heterogeneity and endotypes in type 1 diabetes mellitus

Nature Reviews Endocrinology volume 19, pages 542–554 (2023)Cite this article

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Abstract

Despite major advances over the past decade, prevention and treatment of type 1 diabetes mellitus (T1DM) remain suboptimal, with large and unexplained variations in individual responses to interventions. The current classification schema for diabetes mellitus does not capture the complexity of this disease or guide clinical management effectively. One of the approaches to achieve the goal of applying precision medicine in diabetes mellitus is to identify endotypes (that is, well-defined subtypes) of the disease each of which has a distinct aetiopathogenesis that might be amenable to specific interventions. Here, we describe epidemiological, clinical, genetic, immunological, histological and metabolic differences within T1DM that, together, suggest heterogeneity in its aetiology and pathogenesis. We then present the emerging endotypes and their impact on T1DM prediction, prevention and treatment.

Key points

  • Type 1 diabetes mellitus (T1DM) is heterogeneous; defining endotypes, or disease subtypes each of which has a unique aetiopathogenesis that is amenable to a particular intervention, will help apply precision medicine to T1DM.

  • T1DM endotype 1 (T1DE1) includes T1DM diagnosed in early childhood and is characterized by extensive, early, β-cell destruction, aggressive insulitis with abundant CD8+ T and CD20+ B cells, aberrant proinsulin processing and an elevated circulating proinsulin to C-peptide ratio.

  • T1DM endotype 2 (T1DE2) includes T1DM diagnosed in adolescence or adulthood and is characterized by retention of many residual insulin-containing islets and without insulitis, fewer infiltrating CD8+ T cells, few CD20+ B cells, normal proinsulin processing and lower proinsulin to C-peptide ratio than T1DE2.

  • Evidence is emerging that T1DE1 might respond better than T1DE2 to interventional immunotherapy with agents targeted to specific immune cell subsets, such as rituximab or teplizumab, while GAD–alum therapy might be effective for treating T1DE2.

  • The T1DE2 endotype could underlie a spectrum of phenotypes with different degrees of severity of the autoimmune attack and thus, different rates of progression to insulin dependence, ranging from classic T1DM to latent autoimmune diabetes mellitus in adults or slowly progressive insulin-dependent diabetes mellitus.

  • Whether T1DM endotypes exist is still a matter of debate, but data are accumulating that support this framework, which will benefit from further research, including testing interventions directed to their underlying aetiopathogenesis.

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Fig. 1: Immunological heterogeneity in T1DM.
Fig. 2: Influence of type 2 diabetes mellitus-related factors on type 1 diabetes mellitus development, and the effect of ethnicity.
Fig. 3: Conceptual model for the distribution of type 1 diabetes mellitus endotypes by age at onset.
Fig. 4: Conceptual model for the variability in trajectory of insulin secretory capacity using the T1DM endotype framework.
Fig. 5: Conceptual model for the trajectory of insulin secretory capacity in slowly progressing forms of type 1 diabetes mellitus.

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Acknowledgements

M.J.R.’s research is supported by the National Institutes of Health (NIH) grants R01 DK124395, R01 DK121843 and U54 DK118638. Recent studies in N.G.M.’s laboratory have been supported by Diabetes UK, MRC, JDRF, EFSD and from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 115797 (INNODIA) and no. 945268 (INNODIA HARVEST). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme, EFPIA, JDRF and The Leona M. and Harry B. Helmsley Charitable Trust.

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  1. Paediatric Diabetes & Endocrinology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA

    Maria J. Redondo

  2. Exeter Centre of Excellence for Diabetes Research (EXCEED), Department of Clinical and Biomedical and Science, University of Exeter Medical School, Exeter, UK

    Noel G. Morgan

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Redondo, M.J., Morgan, N.G. Heterogeneity and endotypes in type 1 diabetes mellitus. Nat Rev Endocrinol 19, 542–554 (2023). https://doi.org/10.1038/s41574-023-00853-0

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