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 ...
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.