Study Identifies Two Distinct Type 1 Diabetes 'Endotypes'

Miriam E. Tucker

March 18, 2020

Two histologically distinct "endotypes" of type 1 diabetes, T1DE1 and T1DE2, have been identified in children based on their age at diagnosis.

The findings were published online March 15 in Diabetologia by Pia Leete, PhD, of the Institute of Biomedical and Clinical Science, University of Exeter Medical School, UK, and colleagues.

The results suggest that the immune attack is far more aggressive and the islets more inflamed in the younger-onset group (T1DE1) and less intense in the older-onset group (T1DE2), the authors explain. 

"We're extremely excited to find evidence that type 1 diabetes is two separate conditions: T1DE1 and T1DE2. The significance of this could be enormous in helping us to understand what causes the illness and in unlocking avenues to prevent future generations of children from getting type 1 diabetes," said senior author Noel G. Morgan, PhD, also of the University of Exeter, in a statement.

Morgan added that the discovery "might also lead to new treatments if we can find ways to reactivate dormant insulin-producing cells in the older age group. This would be a significant step towards the holy grail to find a cure for some people."

Recognition of Endotypes Can Inform Future Immune Interventions

The study involved an immunohistological analysis of proinsulin and insulin distribution in the islets of pancreas samples recovered from 19 youth who died soon after (<2 years) onset of type 1 diabetes and from 13 with onset more than 5 years prior to harvesting. Those results were compared with C-peptide and proinsulin measurements in 171 living individuals with type 1 diabetes of longer than 5 year's duration.

The Exeter team has previously reported that the immune cell profiles in the inflamed islets of children younger than 7 years of age soon after the diagnosis of type 1 diabetes seem to be distinctly different for those in children aged 13 and older at diagnosis. The younger group at diagnosis (termed "T1DE1") retained a lower proportion of insulin-containing islets than did the older-onset group ("T1DE2").

Those aged 7-12 at diagnosis could belong to either group, but there was no continuum. Rather, they appeared to align distinctly with one or the other "endotype," Leete and colleagues say.

In the new analysis, proinsulin processing was aberrant to a much greater degree among children diagnosed with type 1 diabetes prior to age 7 years than among those diagnosed after age 12 years, with the profiles of proinsulin processing correlating with the previously defined immune cell profiles.

For those aged 7-12, the proinsulin distribution in islets directly correlated with their immune phenotypes, either T1DE1 or T1DE2.  

And among the living patients, circulating proinsulin:C-peptide ratios were elevated in the <7-year onset group compared with the ≥13-year group, even 5 years after diagnosis.

"Together, these data imply that, when considered alongside age at diagnosis, measurement of the ratio of proinsulin to C-peptide may represent a convenient biomarker to distinguish the endotypes defined here," Leete and colleagues say.

The two-endotype proposal isn't meant to suggest that "a simple dichotomy will ultimately be sufficient to account for the entire heterogeneity seen in people developing type 1 diabetes," the authors stress. Rather, additional endotypes will likely be defined as more variables are considered.

They write, "Recognition of such differences should inform the design of future immunotherapeutic interventions designed to arrest disease progression."

The research was sponsored by Diabetes UK and JDRF.

Diabetologia. Published online March 15, 2020. Full text

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