Elsevier

Journal of Autoimmunity

Volume 71, July 2016, Pages 51-58
Journal of Autoimmunity

Review article
Life and death of β cells in Type 1 diabetes: A comprehensive review

https://doi.org/10.1016/j.jaut.2016.02.001Get rights and content

Highlights

  • During progression of Type 1 diabetes beta cells most likely die from a combination of necrosis and apoptosis.

  • Methods to visualize beta cell inflammation and beta cell mass are being developed.

  • Molecular techniques have been applied to identify beta cell killing in vivo.

  • Studies with these methods suggests revision of previous models of the pathogenesis of the disease.

  • The cause of long term beta cell loss remains unclear. It is possible that ongoing beta cell destruction is intrinsic.

  • The basis for the long term loss of beta cell remains unclear. It is possible that ongoing beta cell destruction is intrinsic.

Abstract

Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic β cells. Immune modulators have achieved some success in modifying the course of disease progression in T1D. However, there are parallel declines in C-peptide levels in treated and control groups after initial responses. In this review, we discuss mechanisms of β cell death in T1D that involve necrosis and apoptosis. New technologies are being developed to enable visualization of insulitis and β cell mass involving positron emission transmission that identifies β cell ligands and magnetic resonance imaging that can identify vascular leakage. Molecular signatures that identify β cell derived insulin DNA that is released from dying cells have been described and applied to clinical settings. We also consider changes in β cells that occur during disease progression including the induction of DNA methyltransferases that may affect the function and differentiation of β cells. Our findings from newer data suggest that the model of chronic long standing β cell killing should be reconsidered. These studies indicate that the pathophysiology is accelerated in the peridiagnosis period and manifest by increased rates of β cell killing and insulin secretory impairments over a shorter period than previously thought. Finally, we consider cellular explanations to account for the ongoing loss of insulin production despite continued immune therapy that may identify potential targets for treatment. The progressive decline in β cell function raises the question as to whether β cell failure that is independent of immune attack may be involved.

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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