Studies in pancreas and plasma support the existence of two distinct aetiopathological subtypes of Type 1 diabetes associated with age at diagnosis

Background and Aims

Studies of pancreatic tissue gathered soon after onset of Type 1 diabetes have revealed the existence of two, age-related, immune phenotypes in inflamed islets (CD20Hi & CD20Lo). Since these also vary according to the proportion of residual insulin containing islets retained at diagnosis, we have now determined whether they display differential pancreatic proinsulin processing and secretion.

Materials and Methods 
The subcellular localisation of proinsulin and insulin was monitored in a blinded manner in pancreatic tissue from 21 patients diagnosed within 1y of T1D, at increasing ages (6 < 7y, 11 7-12y; 6 >13y) plus 8 controls. In parallel, 90 minute plasma C-peptide and proinsulin levels were measured after a mixed meal tolerance test in 191 T1D patients (87 diagnosed< 7y and 84>13y) studied >5y (median 13.3y) post diagnosis.

Results

Two distinct patterns of proinsulin localisation were observed in residual insulin-containing islets of children diagnosed < 7y and those >13y. Abnormal proinsulin/insulin colocalisation was found in almost all islets in the < 7y (CD20Hi) group (mean Manders overlap coefficient: 0.72±0.03 vs0.28±0.01 in controls;p< 0.0001), while most islets (78%) of those diagnosed at >13y (CD20Lo) did not display this phenomenon (overlap coefficient: 0.38±0.03;p< 0.0001). The distribution of proinsulin in islets of children diagnosed between 7-12y (3 CD20Lo; 5 CD20Hi) segregated precisely with their immune phenotype, where highest rates of colocalisation was restricted to the CD20Hi group.

Subjects with longstanding T1D (>5y) diagnosed < 7y had lower C-peptide levels than those diagnosed >13y (median(IQR)< 3(< 3-< 3)v34.5(< 3,151)pmol/l; p< 0.0001). In contrast, the proinsulin/C-peptide ratio (PI/CP) was increased markedly in the < 7y compared to >13y (0.18(0.10,0.31)v0.01(0.009,0.10)nmol/mmol;p< 0.0001).

Conclusion

Two distinct endotypes of T1D exist, which correlate with age at diagnosis. These differ according to their insulitic & proinsulin processing profiles, the proportion of residual insulin-containing islets and circulating C-peptide and proinsulin concentrations. These factors must be considered when designing immunotherapeutic strategies for T1D.