Abstract:
AIMS/HYPOTHESIS:It is unclear whether type 1 diabetes is a single disease or if endotypes exist. Our aim was to use a unique collection of pancreas samples recovered soon after disease onset to resolve this issue. METHODS:Immunohistological analysis was used to determine the distribution of proinsulin and insulin in the islets of pancreas samples recovered soon after type 1 diabetes onset (<2 years) from young people diagnosed at age <7 years, 7-12 years and ≥13 years. The patterns were correlated with the insulitis profiles in the inflamed islets of the same groups of individuals. C-peptide levels and the proinsulin:C-peptide ratio were measured in the circulation of a cohort of living patients with longer duration of disease but who were diagnosed in these same age ranges. RESULTS:Distinct patterns of proinsulin localisation were seen in the islets of people with recent-onset type 1 diabetes, which differed markedly between children diagnosed at <7 years and those diagnosed at ≥13 years. Proinsulin processing was aberrant in most residual insulin-containing islets of the younger group but this was much less evident in the group ≥13 years (p < 0.0001). Among all individuals (including children in the middle [7-12 years] range) aberrant proinsulin processing correlated with the assigned immune cell profiles defined by analysis of the lymphocyte composition of islet infiltrates. C-peptide levels were much lower in individuals diagnosed at <7 years than in those diagnosed at ≥13 years (median <3 pmol/l, IQR <3 to <3 vs 34.5 pmol/l, IQR <3-151; p < 0.0001), while the median proinsulin:C-peptide ratio was increased in those with age of onset <7 years compared with people diagnosed aged ≥13 years (0.18, IQR 0.10-0.31) vs 0.01, IQR 0.009-0.10 pmol/l; p < 0.0001). CONCLUSIONS/INTERPRETATION:Among those with type 1 diabetes diagnosed under the age of 30 years, there are histologically distinct endotypes that correlate with age at diagnosis. Recognition of such differences should inform the design of future immunotherapeutic interventions designed to arrest disease progression.
journal_name
Diabetologiajournal_title
Diabetologiaauthors
Leete P,Oram RA,McDonald TJ,Shields BM,Ziller C,TIGI study team.,Hattersley AT,Richardson SJ,Morgan NGdoi
10.1007/s00125-020-05115-6subject
Has Abstractpub_date
2020-06-01 00:00:00pages
1258-1267issue
6eissn
0012-186Xissn
1432-0428pii
10.1007/s00125-020-05115-6journal_volume
63pub_type
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