Probing islet stress in type 1 diabetes

disorder of immune tolerance, whereby autoreactive T cells infiltrate, recognize, and destroy insulin-producing islet β cells. Despite this understanding, immunetargeted therapies in the setting of T1D have neither uniformly nor durably preserved insulin secretory capacity. The picture of immune cell infiltration into islets (known as “insulitis”) was first described in the early 1900s, many years before the discovery of insulin itself. The presence of insulitis has subsequently come to define a pathologic hallmark of T1D. Yet, in recent years the analysis of postmortem tissues from donors with T1D has revealed an unexpected finding: namely, that aggressive T cell-mediated insulitis and rapid loss of β-cell mass has not proved uniformly true in humans. For example, postmortem studies show that fewer than 24% of T1D individuals have any detectable pathologic evidence of insulitis [1], and still other studies show both a pre-diabetic increase in proinsulin/C-peptide ratio and a striking persistence of proinsulin secretion, indicating a preservation of β cells even in longstanding T1D [2]. Likewise, loss of islet β-cell mass displays striking variability, with some individuals exhibiting insulin-positivity in up to 50% of islets at T1D onset [3]. How, then, does one reconcile the notion that aggressive autoimmunity results in the loss of β-cell mass in T1D with the findings that significant numbers of β cells, however hypofunctioning, persist many years after the onset of disease? One perspective posits that T1D is a disease of both autoimmunity and the β cell, where the susceptibility of the latter to the immunemediated death or dysfunction might play a crucial role in the development of hyperglycemia.