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Studies of insulin and proinsulin in pancreas and serum support the existence of aetiopathological endotypes of type 1 diabetes associated with age at diagnosis – published online 15/03/2020

Pia Leete, Richard A. Oram, Timothy J. McDonald, Beverley M. Shields, Clemens Ziller, TIGI study team, Andrew T. Hattersley, Sarah J. Richardson, Noel G. Morgan

The aetiology of type 1 diabetes has been difficult to explore in the pancreas due to the limited availability of suitable specimens for study. In this issue, Leete et al (https://doi.org/10.1007/s00125-020-05115-6) employed the world’s largest collections of pancreas samples recovered from young people with recent-onset type 1 diabetes to demonstrate that abnormalities in insulin processing occurred at high frequency in the beta cells of the youngest donors (those diagnosed at <7 years of age) but were much less evident in those who were older at diabetes onset (≥13 years of age). These differences correlated with previously defined immune phenotypes found in the islets of people of equivalent ages. Importantly, among children in the intermediate age range (7–12 years), abnormalities in insulin processing also correlated closely with islet immune phenotype. These histological differences were mirrored by proinsulin:C-peptide ratio in the blood. From these findings, the authors suggest that type 1 diabetes exists as two mechanistically distinct endotypes, which they coin ‘type 1 diabetes endotype 1 (T1DE1)’ and ‘type 1 diabetes endotype 2 (T1DE2)’. They conclude that stratification of children and young people according to endotype will be important in the effective design of future immunotherapeutic trials in type 1 diabetes.

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