Use of a systems biology approach to understand pancreatic β-cell death in Type 1 diabetes

2008 ◽  
Vol 36 (3) ◽  
pp. 321-327 ◽  
Author(s):  
Decio L. Eizirik ◽  
Fabrice Moore ◽  
Daisy Flamez ◽  
Fernanda Ortis
Keyword(s):  
Cell Death ◽  
Type 1 Diabetes ◽  
Systems Biology ◽  
Gene Networks ◽  
Nuclear Factor Κb ◽  
Signal Transducer ◽  
Trial And Error ◽  
Β Cells ◽  
Β Cell

Accumulating evidence indicates that β-cells die by apoptosis in T1DM (Type 1 diabetes mellitus). Apoptosis is an active gene-directed process, and recent observations suggest that β-cell apoptosis depends on the parallel and/or sequential up- and down-regulation of hundreds of genes controlled by key transcription factors such as NF-κB (nuclear factor κB) and STAT-1 (signal transducer and activator of transcription 1). Understanding the regulation of these gene networks, and how they modulate β-cell death and the ‘dialogue’ between β-cells and the immune system, will require a systems biology approach to the problem. This will hopefully allow the search for a cure for T1DM to move from a ‘trial-and-error’ approach to one that is really mechanistically driven.

scholarly journals Effective Destruction of Fas-deficient Insulin-producing β Cells in Type 1 Diabetes

2003 ◽  
Vol 198 (7) ◽  
pp. 1103-1106 ◽  
Author(s):  
Irina Apostolou ◽  
Zhenyue Hao ◽  
Klaus Rajewsky ◽  
Harald von Boehmer
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Type 1 Diabetes ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Β Cells ◽  
Β Cell ◽  
Influenza Hemagglutinin ◽  
Insulin Promoter

In type 1 diabetes, autoimmune T cells cause destruction of pancreatic β cells by largely unknown mechanism. Previous analyses have shown that β cell destruction is delayed but can occur in perforin-deficient nonobese diabetic (NOD) mice and that Fas-deficient NOD mice do not develop diabetes. However, because of possible pleiotropic functions of Fas, it was not clear whether the Fas receptor was an essential mediator of β cell death in type 1 diabetes. To directly test this hypothesis, we have generated a β cell–specific knockout of the Fas gene in a transgenic model of type 1 autoimmune diabetes in which CD4+ T cells with a transgenic TCR specific for influenza hemagglutinin (HA) are causing diabetes in mice that express HA under control of the rat insulin promoter. Here we show that the Fas-deficient mice develop autoimmune diabetes with slightly accelerated kinetics indicating that Fas-dependent apoptosis of β cells is a dispensable mode of cell death in this disease.

scholarly journals Physiological β Cell Death Triggers Priming of Self-reactive T Cells by Dendritic Cells in a Type-1 Diabetes Model

2003 ◽  
Vol 198 (10) ◽  
pp. 1527-1537 ◽  
Author(s):  
Shannon Turley ◽  
Laurent Poirot ◽  
Masakazu Hattori ◽  
Christophe Benoist ◽  
Diane Mathis
Keyword(s):  
Cell Death ◽  
Type 1 Diabetes ◽  
Nod Mice ◽  
Mouse Strains ◽  
Β Cells ◽  
Β Cell ◽  
Diabetes Model ◽  
Pancreatic Lymph Nodes ◽  
Antigen Presenting

The prelude to type-1 diabetes is leukocyte infiltration into the pancreatic islets, or insulitis. This process begins in pancreatic lymph nodes when T lymphocytes reactive to islet β cells encounter antigen-presenting cells (APCs) displaying peptides derived from β cell proteins. We show here that a ripple of physiological β cell death, which occurs at 2 wk of age in all mouse strains, precipitates the arrival of such APCs, and that the relevant APC is a dendritic cell of CD11c+CD11b+CD8α− phenotype. These findings have significant implications concerning the nature of the diabetes-provoking deficits in NOD mice, the identity of the primordial diabetogenic antigens, and our understanding of the balance between immunity and tolerance in a pathological context.

scholarly journals Analysis of β-Cell Death in Type 1 Diabetes by Droplet Digital PCR

Endocrinology ◽  
2014 ◽  
Vol 155 (9) ◽  
pp. 3694-3698 ◽  
Author(s):  
Sahar Usmani-Brown ◽  
Jasmin Lebastchi ◽  
Andrea K. Steck ◽  
Craig Beam ◽  
Kevan C. Herold ◽  
...  
Keyword(s):  
Cell Death ◽  
Type 1 Diabetes ◽  
Digital Pcr ◽  
Droplet Digital Pcr ◽  
Β Cells ◽  
Β Cell ◽  
Indirect Measure ◽  
Control Subjects ◽  
Nondiabetic Control

Abstract Type 1 diabetes (T1D) and other forms of diabetes are due to the killing of β-cells. However, the loss of β-cells has only been assessed by functional studies with a liquid meal or glucose that can be affected by environmental factors. As an indirect measure of β-cell death, we developed an assay using a novel droplet digital PCR that detects INS DNA derived from β-cells. The release of INS DNA with epigenetic modifications (unmethylated CpG) identifies the β-cellular source of the DNA. The assay can detect unmethylated DNA between a range of approximately 600 copies/μL and 0.7 copies/μL, with a regression coefficient for the log transformed copy number of 0.99. The assay was specific for unmethylated INS DNA in mixtures with methylated INS DNA. We analyzed the levels of unmethylated INS DNA in patients with recent onset T1D and normoglycemia subjects at high risk for disease and found increased levels of unmethylated INS DNA compared with nondiabetic control subjects (P < .0001). More than one-third of T1D patients and one-half of at-risk subjects had levels that were more than 2 SD than the mean of nondiabetic control subjects. We conclude that droplet digital PCR is a useful method to detect β-cell death and is more specific and feasible than other methods, such as nested real-time PCR. This new method may be a valuable tool for analyzing pathogenic mechanisms and the effects of treatments in all forms of diabetes.

scholarly journals Alterations in β-Cell Sphingolipid Profile Associated with ER Stress and iPLA2β: Another Contributor to β-Cell Apoptosis in Type 1 Diabetes

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6361
Author(s):  
Tomader Ali ◽  
Xiaoyong Lei ◽  
Suzanne E. Barbour ◽  
Akio Koizumi ◽  
Charles E. Chalfant ◽  
...  
Keyword(s):  
Cell Death ◽  
Type 1 Diabetes ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Β Cells ◽  
Β Cell ◽  
Promote Cell Survival ◽  
Student’S T ◽  
The Impact

Type 1 diabetes (T1D) development, in part, is due to ER stress-induced β-cell apoptosis. Activation of the Ca2+-independent phospholipase A2 beta (iPLA2β) leads to the generation of pro-inflammatory eicosanoids, which contribute to β-cell death and T1D. ER stress induces iPLA2β-mediated generation of pro-apoptotic ceramides via neutral sphingomyelinase (NSMase). To gain a better understanding of the impact of iPLA2β on sphingolipids (SLs), we characterized their profile in β-cells undergoing ER stress. ESI/MS/MS analyses followed by ANOVA/Student’s t-test were used to assess differences in sphingolipids molecular species in Vector (V) control and iPLA2β-overexpressing (OE) INS-1 and Akita (AK, spontaneous model of ER stress) and WT-littermate (AK-WT) β-cells. As expected, iPLA2β induction was greater in the OE and AK cells in comparison with V and WT cells. We report here that ER stress led to elevations in pro-apoptotic and decreases in pro-survival sphingolipids and that the inactivation of iPLA2β restores the sphingolipid species toward those that promote cell survival. In view of our recent finding that the SL profile in macrophages—the initiators of autoimmune responses leading to T1D—is not significantly altered during T1D development, we posit that the iPLA2β-mediated shift in the β-cell sphingolipid profile is an important contributor to β-cell death associated with T1D.

scholarly journals β Cell death and dysfunction during type 1 diabetes development in at-risk individuals

2015 ◽  
Vol 125 (3) ◽  
pp. 1163-1173 ◽  
Author(s):  
Kevan C. Herold ◽  
Sahar Usmani-Brown ◽  
Tara Ghazi ◽  
Jasmin Lebastchi ◽  
Craig A. Beam ◽  
...  
Keyword(s):  
At Risk ◽  
Cell Death ◽  
Type 1 Diabetes ◽  
Β Cell ◽  
Diabetes Development

scholarly journals Nonlinear Analysis for a Type-1 Diabetes Model with Focus on T-Cells and Pancreatic β-Cells Behavior

2020 ◽  
Vol 25 (2) ◽  
pp. 23
Author(s):  
Diana Gamboa ◽  
Carlos E. Vázquez ◽  
Paul J. Campos
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Cell Population ◽  
Closed Loop ◽  
Pancreatic Β Cell ◽  
Activated Macrophages ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

Type-1 diabetes mellitus (T1DM) is an autoimmune disease that has an impact on mortality due to the destruction of insulin-producing pancreatic β -cells in the islets of Langerhans. Over the past few years, the interest in analyzing this type of disease, either in a biological or mathematical sense, has relied on the search for a treatment that guarantees full control of glucose levels. Mathematical models inspired by natural phenomena, are proposed under the prey–predator scheme. T1DM fits in this scheme due to the complicated relationship between pancreatic β -cell population growth and leukocyte population growth via the immune response. In this scenario, β -cells represent the prey, and leukocytes the predator. This paper studies the global dynamics of T1DM reported by Magombedze et al. in 2010. This model describes the interaction of resting macrophages, activated macrophages, antigen cells, autolytic T-cells, and β -cells. Therefore, the localization of compact invariant sets is applied to provide a bounded positive invariant domain in which one can ensure that once the dynamics of the T1DM enter into this domain, they will remain bounded with a maximum and minimum value. Furthermore, we analyzed this model in a closed-loop scenario based on nonlinear control theory, and proposed bases for possible control inputs, complementing the model with them. These entries are based on the existing relationship between cell–cell interaction and the role that they play in the unchaining of a diabetic condition. The closed-loop analysis aims to give a deeper understanding of the impact of autolytic T-cells and the nature of the β -cell population interaction with the innate immune system response. This analysis strengthens the proposal, providing a system free of this illness—that is, a condition wherein the pancreatic β -cell population holds and there are no antigen cells labeled by the activated macrophages.

Harnessing immune cells to enhance β-cell mass in type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 14-20 ◽  
Author(s):  
Ercument Dirice ◽  
Rohit N Kulkarni
Keyword(s):  
Type 1 Diabetes ◽  
Mononuclear Cells ◽  
Islet Cells ◽  
Cell Mass ◽  
Cell Loss ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Autoimmune Attack

Type 1 diabetes is characterized by early β-cell loss leading to insulin dependence in virtually all patients with the disease in order to maintain glucose homeostasis. Most studies over the past few decades have focused on limiting the autoimmune attack on the β cells. However, emerging data from patients with long-standing diabetes who continue to harbor functional insulin-producing cells in their diseased pancreas have prompted scientists to examine whether proliferation of existing β cells can be enhanced to promote better glycemic control. In support of this concept, several studies indicate that mononuclear cells that infiltrate the islets have the capacity to trigger proliferation of islet cells including β cells. These observations indicate the exciting possibility of identifying those mononuclear cell types and their soluble factors and harnessing their ability to promote β-cell growth concomitant with autoimmune therapy to prevent the onset and/or halt the progression of the disease.

Role of NF-κB in β-cell death

2008 ◽  
Vol 36 (3) ◽  
pp. 334-339 ◽  
Author(s):  
Danielle Melloul
Keyword(s):  
Cell Death ◽  
Lymphocytic Infiltration ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Cell Protection ◽  
Β Cells ◽  
Β Cell ◽  
Ifn Γ ◽  
Induced Apoptosis

Apoptotic β-cell death appears to be central to the pathogenesis of Type 1 diabetes mellitus and in islet graft rejection. The β-cell destruction is partially mediated by cytokines, such as IL-1β (interleukin 1β), TNFα (tumour necrosis factor α) and IFN-γ (interferon γ). IL-1β and TNFα mediate activation of the transcription factor NF-κB (nuclear factor κB) pathway. Use of a degradation-resistant NF-κB protein inhibitor (ΔNIκBα), specifically expressed in β-cells, significantly reduced IL-1β+IFN-γ-induced apoptosis. Moreover, in vivo, it protected against multiple low-dose streptozocin-induced diabetes, with reduced intra-islet lymphocytic infiltration. Thus β-cell-specific activation of NF-κB is a key event in the progressive loss of β-cells in diabetes. Inhibition of this process could be a potential effective strategy for β-cell protection.

scholarly journals Integrated Model of Metabolism and Autoimmune Response in β-Cell Death and Progression to Type 1 Diabetes

PLoS ONE ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e51909 ◽  
Author(s):  
Tijana Marinković ◽  
Marko Sysi-Aho ◽  
Matej Orešič
Keyword(s):  
Cell Death ◽  
Type 1 Diabetes ◽  
Integrated Model ◽  
Autoimmune Response ◽  
Β Cell

scholarly journals Potential Mimicry of Viral and Pancreatic β Cell Antigens Through Non-Spliced and cis-Spliced Zwitter Epitope Candidates in Type 1 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Michele Mishto ◽  
Artem Mansurkhodzhaev ◽  
Teresa Rodriguez-Calvo ◽  
Juliane Liepe
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Viral Infections ◽  
Hla Class I ◽  
Class I ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

Increasing evidence suggests that post-translational peptide splicing can play a role in the immune response under pathological conditions. This seems to be particularly relevant in Type 1 Diabetes (T1D) since post-translationally spliced epitopes derived from T1D-associated antigens have been identified among those peptides bound to Human Leucocyte Antigen (HLA) class I and II complexes. Their immunogenicity has been confirmed through CD4+ and CD8+ T cell-mediated responses in T1D patients. Spliced peptides theoretically have a large sequence variability. This might increase the frequency of viral-human zwitter peptides, i.e. peptides that share a complete sequence homology irrespective of whether they originate from human or viral antigens, thereby impinging upon the discrimination between self and non-self antigens by T cells. This might increase the risk of autoimmune responses triggered by viral infections. Since enteroviruses and other viral infections have historically been associated with T1D, we investigated whether cis-spliced peptides derived from selected viruses might be able to trigger CD8+ T cell-mediated autoimmunity. We computed in silico viral-human non-spliced and cis-spliced zwitter epitope candidates, and prioritized peptide candidates based on: (i) their binding affinity to HLA class I complexes, (ii) human pancreatic β cell and medullary thymic epithelial cell (mTEC) antigens’ mRNA expression, (iii) antigen association with T1D, and (iv) potential hotspot regions in those antigens. Neglecting potential T cell receptor (TCR) degeneracy, no viral-human zwitter non-spliced peptide was found to be an optimal candidate to trigger a virus-induced CD8+ T cell response against human pancreatic β cells. Conversely, we identified some zwitter peptide candidates, which may be produced by proteasome-catalyzed peptide splicing, and might increase the likelihood of pancreatic β cells recognition by virus-specific CD8+ T cell clones, therefore promoting β cell destruction in the context of viral infections.

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