Bringing the human pancreas into focus: new paradigms for the understanding of Type 1 diabetes

• Published in: Diabetic medicine 2017-07, Vol.34 (7), p.879-886
• Main Author: Morgan, N. G.
• Format: Article
• Language: English
• Subjects: Age; Age of Onset; Animal models; Animals; Autoimmune Diseases - immunology; Autoimmune Diseases - pathology; Autoimmune Diseases - physiopathology; Beta cells; CD20 antigen; CD8 antigen; Children; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - physiopathology; Humans; Inflammation; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - immunology; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Insulitis; Islets of Langerhans; Lymphocytes T; Models, Biological; Pancreas; Pancreas - immunology; Pancreas - metabolism; Pancreas - pathology; Pancreas - physiopathology; Pancreas transplantation
• ISSN: 0742-3071; 1464-5491
• DOI: 10.1111/dme.13365

Type 1 diabetes affects increasingly large numbers of people globally (including at least half a million children under the age of 14 years) and it remains an illness with life‐long and often devastating consequences. It is surprising, therefore, that the underlying aetiology of Type 1 diabetes remains poorly understood. This is largely because the cellular and molecular processes leading to the loss of β cells in the pancreas have rarely been studied at, or soon after, the onset of disease. Where such studies have been undertaken, a number of surprises have emerged which serve to challenge conventional wisdom. In particular, it is increasingly understood that the process of islet inflammation (insulitis) is much less florid in humans than in certain animal models. Moreover, the profile of immune cells involved in the inflammatory attack on β cells is variable and this variation occurs at the level of individual patients. As a result, two distinct profiles of insulitis have now been defined that are differentially aggressive and that might, therefore, require specifically tailored therapeutic approaches to slow the progression of disease. In addition, the outcomes are also different in that the more aggressive form (termed ‘CD20Hi’) is associated with extensive β‐cell loss and an early age of disease onset (13 years) and the retention of a higher proportion of residual β cells. In the present review, these new findings are explained and their implications evaluated in terms of future therapies. What's new? Pancreatic histopathology has been studied in fewer than 200 people with recent‐onset Type 1 diabetes, worldwide. Human islets become inflamed during β‐cell loss but, typically, the number of influent immune cells is modest. Immune cells are frequently arranged peripherally around the islets and few penetrate the islet core. Two phenotypic profiles of insulitis can be defined. Both are characterized by a preponderance of CD8+ T cells but the proportion of CD20+ B cells is more variable. The more aggressive form of insulitis (CD20Hi) comprises roughly equal proportions of CD8+ and CD20+ cells, while the less aggressive form (CD20Lo) has fewer CD20 cells. The two forms of insulitis are associated with different ages of disease onset and with differing proportions of residual insulin‐containing islets at onset. An improved understanding of the significance of t