Review articleLife and death of β cells in Type 1 diabetes: A comprehensive review
Introduction
Despite the success of immune therapies in modifying the short term course of Type 1 diabetes (T1D), these treatments have not achieved long-term retention of insulin production, and their ability to improve clinical outcomes is uncertain. Therapies such as teplizumab and otelixizumab, that target the ε chain of the CD3 molecule on T cells, abatacept, that blocks CD28 costimulation by binding to B7.1 and B7.2, alefacept (soluble LFA3Ig) that binds CD2 and depletes T cells, and rituximab, that binds CD20 and depletes B cells have all significantly improved C-peptide responses and even glucose control with reduced use of exogenous insulin for 1–4 years compared to control groups [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. However, 6 months to a year after treatment, a decline in C-peptide responses occurred despite continuous administration of abatacept or re-administration of teplizumab. One possible explanation for the decline is that intrinsic β cellular factors that activate β cell death are involved. Previous notions of complete β cell death/ablation in T1D have become uncertain since a number of recent clinical studies have identified significant residual β cell function in individuals with long standing T1D [13], [14]. This indicates that in many individuals, either β cell killing ceases or β cell recovery occurs. In this review, we consider the mechanisms of β cell death in T1D, and changes to the cells that occur during disease progression. These mechanisms are relevant to the long term function and survival of β cells.
Section snippets
Mechanisms of β cell death in T1D
The ways in which β cells die may determine whether immune responses are activated. Necrotic cell death is considered to be a likely mechanism whereby cytolytic T cells, including those reactive with diabetes antigens, cause killing (Fig. 1). Findings from pancreatic biopsies and post-mortem studies of whole organs from islet donors are consistent with this mechanism, showing a predominance of infiltrating CD8+ T cells and macrophages which mediate necrosis [15]. Necrosis can occur following
Visualization of β cell mass and inflammation
Beta cell killing cannot be appreciated with metabolic studies alone. A number of environmental factors are known to modify β cell function, including fatty acids, glucose, as well as insulin sensitivity, which changes with adolescence [30], [31], [32]. The acute changes in β cells after onset and with immune therapy have been difficult to identify because of the absence of direct measures of inflammation and β cell mass. In a study of the islets in NOD mice at the time of onset of
Identifying β cell killing with molecular signatures
Unlike cells that do not transcribe insulin, CpG sites in the INS gene in β cells are generally unmethylated [42]. We took advantage of this epigenetic feature to identify β cells that had died and released their unmethylated INS DNA into the serum. A nested PCR reaction was performed in which a sequence from the Ins1 or INS genes was first amplified with primers non-specific for CpG sites. Subsequently, the products of this reaction were used as template in a second reaction with primers
Changes in β cells under immune assault
The β cell dysfunction during the progression of T1D implies that there are acquired functional changes in the cells, possibly as a result of immunologic stressors or metabolic demand. Islet cells from individuals with T1D show a partial ER stress response with induction of some components of the unfolded protein response [54]. Cytokines such as IL-1β, together with TNF and IFNγ have been found to inhibit insulin secretion in vitro [55], [56], [57]. In addition, cytokines released by
Changes in β cells following immune therapy
Unfortunately, there is relatively little data concerning the mechanisms that are involved in the ongoing losses after immune therapy. However, apoptosis has been observed in patients with long standing T1D, which, these investigators speculate, is due to ongoing autoimmunity or possibly toxicity from external factors such as glucose [59]. They also point out that in view of the ongoing cell death, there must be ongoing β cell replication. These and other observations from clinical trials
Conclusions
Despite the successes of immune therapies in improving C-peptide responses, permanent or even long term maintenance of C-peptide has not been achieved. Our understanding of the reasons for this failure has been hampered by the absence of tools to assess the destructive process that causes the disease. Novel tools for visualizing and quantifying β mass and killing may be useful in determining β cell changes that lead to the disease and following immune therapy. Future studies will require
Acknowledgments
Supported by grants U01 AI102011, DP3 DK10122, R01 DK057846, UC4 DK104205, R43 DK104522 from the NIH and grants 2014-158 from the Juvenile Diabetes Research Foundation and support from the Brehm Coalition and the Howalt family.
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