Type 1 diabetes endotypes firmed up
medwireNews: Researchers provide further evidence to support two distinct type 1 diabetes endotypes characterized by a more or less aggressive autoimmune response and a younger or older age at onset.
Pia Leete and team from the University of Exeter Medical School in the UK previously proposed two categories of type 1 diabetes based on the extent of insulitis, with the “CD20Hi” category characterized by high levels of infiltrating CD20-positive B cells and found exclusively in children with a young age at onset (<7 years).
In this latest study, examination of pancreatic samples from children in this category obtained within 2 years after diabetes diagnosis revealed that proinsulin and insulin were “unexpectedly co-localised throughout the cytoplasm of the beta cells.” This was the case for all five children in this age category.
The team calls this endotype T1DE1, and summarizes that it “involves a highly aggressive, hyperimmune attack in which most islets are inflamed and aberrant proinsulin processing occurs.”
This results in secretion of both proinsulin and insulin into the plasma, causing an elevated circulating ratio of proinsulin to C-peptide, which was a median of 0.18 compared with 0.01 in children diagnosed when they were 13 years or older and 0.003 in children without diabetes.
The researchers suggest 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.”
In the second endotype (T1DE2), proinsulin was mostly located in a perinuclear compartment, whereas mature insulin was found predominantly in the cytoplasm. This was the case for six of seven children in the older age category, although the team notes that co-localization was also seen in a small subset of islets.
All of these older children also had lower levels of infiltrating CD20-positive B cells (CD20Lo), and examination of pancreatic samples from children more than 5 years after diagnosis revealed that they retained more insulin-containing islets than those with the T1DE1 endotype (48 vs 17%).
Both the CD20Hi and CD20Lo profiles were identified among children with intermediate diagnosis ages (ie, at 7–12 years). However, co-localization of proinsulin and insulin always occurred in tandem with being the CD20Hi category – and the researchers stress that the samples were categorized for proinsulin distribution and immune cell infiltration in a blinded manner.
This therefore supports that the differences seen were due to the presence of two distinct diabetes endotypes, rather than being an age-related continuum, they say.
“In advancing this proposal, we do not intend to imply that a simple dichotomy will ultimately be sufficient to account for the entire heterogeneity seen in people developing type 1 diabetes,” stress Leete et al in Diabetologia.
“Rather, it is probable that additional endotypes will be defined as further variables are considered.”
But they suggest that their findings will impact the design of immunotherapy trials. “Specifically, we propose that children diagnosed in the earliest years of life may require different immunotherapeutic options vs those who are older at onset.”
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