Finding “genius” in T1D’s heterogeneous nature

Finding “genius” in T1D’s heterogeneous nature

By: Hadeel Saab

In the 1990s, the asthma field came to an important realization that there were multiple pathophysiological pathways to asthma-related symptoms, with each pathway requiring its own tailored therapeutic strategy. These various pathways became known as “endotypes,” ushering in a critical advancement of asthma medications. Twenty years later researchers of Type 1 Diabetes (T1D) have recently reached a similar conclusion that the prevention, diagnosis and treatment of T1D isn’t as clear-cut as once thought. That is, in order to advance the field of T1D towards effective management of the disease, its heterogeneous nature must be considered.

A group of researchers introduced this endotype approach to T1D, and called upon the T1D field to consider heterogeneous factors such as T1D’s wide onset age-range, varying rates of progression, range of genetic susceptibility and variety of autoantibody types. They suggest that intervention and prevention therapies have been unable to progress beyond phase III clinical trials mainly because of the confounding effect of the disease’s heterogeneity. 

  • As an example, one of the binary endotype classifications they propose looking at is the specific islet cell autoantibody and its link to a genotype.
    • Previous studies have found that the Insulin Autoantibody (IAA) is strongly linked to the HLA-DR4 haplotype or collection of alleles, while the GAD autoantibodies are strongly linked to the HLA-DR3 haplotype.
  • Another possibility to define endotypes is a “palette” model – yes, like a color palette of a number of colors – whereby each color represents a major characteristic of T1D, or a systematic approach like metabolomics or genetics, where the shade of the color represents its level of presence / absence on a defined scale. 
    • Data from individuals’ own color palettes could then be analyzed to determine any clusters of endotypes that could then benefit from precision medicine.

What exactly is Precision Medicine and how does it relate to T1D?

Precision Medicine is an approach to the prevention, diagnosis, treatment, prognostics and monitoring of a disease that leverages multiple sources of data, including traditional data (clinical records) and big data (e.g., genomics, behavioral monitors / wearables). It’s “precise” in that patients with similar characteristics are grouped together so that each subgroup can be given care tailored to their specific shared characteristics. 

  • In 2018, the Precision Medicine in Diabetes Initiative (PMDI) was launched by the American Diabetes Association (ADA), in partnership with the European Association for the Study of Diabetes (EASD). The PMDI has a four-phase timeline that includes assessing evidence, promoting research, providing education and developing guidelines, with the ultimate goal being to advance precision diabetes medicine.

Ultimately, delineating T1D endotypes is a critical part to developing and implementing precision diabetes medicine. 

Sources

  • Battaglia, M., Ahmed, S., Anderson, M. S., Atkinson, M. A., Becker, D., Bingley, P. J., … & Gitelman, S. E. (2020). Introducing the endotype concept to address the challenge of disease heterogeneity in type 1 diabetes. Diabetes care, 43(1), 5-12. https://link.springer.com/article/10.1007/s00125-020-05181-w
  • McCarthy, M. I. (2017). Painting a new picture of personalised medicine for diabetes. Diabetologia, 60(5), 793-799.  https://pubmed.ncbi.nlm.nih.gov/28175964/
  • Chung, W. K., Erion, K., Florez, J. C., Hattersley, A. T., Hivert, M. F., Lee, C. G., … & Philipson, L. (2020). Precision medicine in diabetes: a Consensus Report from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia, 63(9), 1671-1693. https://pubmed.ncbi.nlm.nih.gov/31753960/

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