The immunopathology of human type 1 diabetes – evidence for distinct endotypes of disease

Type 1 diabetes is an autoimmune condition in which the islets of Langerhans become infiltrated by lymphocytes which then mediate beta cell dysfunction and loss. This model has been developed mainly from studies in rodents but it is less clear whether equivalent processes occur in humans. To address this, we have studied human pancreas samples recovered at autopsy to characterise the process of islet inflammation and beta cell demise in people who died soon after the onset of type 1 diabetes. This has revealed the existence of two distinct patterns of insulitis which vary according to the absolute numbers and relative proportions of influent immune cells and in relation to the age at onset of disease. Among children diagnosed in the earliest years of life (<7y) the autoimmune attack is relatively aggressive and leads to early and extensive loss of beta cells.  In those diagnosed in their teenage years (>12y) islet inflammation is less intense and associated with the maintenance of a greater proportion of insulin-containing islets (typically ~40%) at onset. Detailed analysis of the distribution of insulin and proinsulin in the residual insulin-containing islets of children diagnosed <7y reveals that the two are highly co-localised, suggesting a marked defect in prohormone processing. Among people diagnosed >12y, this defect is also evident but only in a small subset of insulin-containing islets. Importantly, the pattern of proinsulin processing correlates closely with the defined immune phenotype. This was seen most clearly when studying children diagnosed in the intermediate age range (7-12y) where the proportion of islets displaying aberrant proinsulin processing correlated firmly with the islet immune phenotype. These observations imply that type 1 diabetes in children comprises two distinct endotypes which are readily distinguished by pancreatic immunohistology. Understanding these differences will be crucial to the design of immunotherapies intended to minimise beta cell loss.