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

Abstract

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 (<7 years), while the less aggressive profile (known as 'CD20Lo') is associated with later 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.

The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of age

“…In this case, we highlight a region associated with early-diagnosed type 1 diabetes, but this approach can be applied to heterogeneous diseases to more accurately identify the main genetic determinants in a particular subset. Analyses of the immunology and pancreas histology of type 1 diabetes do reveal distinct autoimmune features in children diagnosed under age 5 years [ 36 ]. Genetic findings such as ours will help to identify the key cells and tissues involved, pointing, in this case, to the thymus being particularly important in early, aggressive disease.…”

Fifty years of pancreatic islet pathology in human type 1 diabetes: insights gained and progress made

“…This implies that immune cells are recruited and retained primarily in response to factors emanating from their target beta cells, although the proportion of islets with inflammation varies, not simply in response to beta cell numbers, but also according to the age at disease onset. For example, among individuals diagnosed aged 13 years or older, the proportion of residual insulin-containing islets with insulitis is around 25%, whereas it is much higher (~80%) in those diagnosed in the very early years of life (<7 years of age) [ 22 ]. These statistics suggest that young children may have a more aggressive form of the disease.…”

Pancreatic autoantibodies and CD14+CD16+ monocytes subset are associated with the impairment of ß-cell function after simultaneous pancreas-kidney transplantation

“…Indeed, although the true mechanism remains a conundrum, in vitro studies have shown that activated monocytes and some of the chemokines secreted may induce endothelial senescence and T-CD4 cells expansion that eventually secretes lytic cytokines that may disrupt the endothelium allowing the T-cells to infiltrate different organs such as the pancreas. [31] Therefore, AAb may indirectly activate the immune process by promoting the activation of monocytes and CD4/CD8 T-cells. Monocytes are highly associated with TNF-α production which in turn expand T-lymphocytes secreting IL-17 cells [19].…”