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 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

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 The role of islet lipid composition remodeling in regulation of beta-cell death via ADP-ribosyl-acceptor glycohydrolase ARH3 signaling in insulitis

2020 ◽  
Author(s):  
Ernesto S. Nakayasu ◽  
Cailin Deiter ◽  
Jennifer E. Kyle ◽  
Michelle A. Guney ◽  
Dylan Sarbaugh ◽  
...  
Keyword(s):  
Cell Death ◽  
Type 1 Diabetes ◽  
Lipid Metabolism ◽  
Lipid Composition ◽  
Antigen Processing ◽  
Human Islets ◽  
List Type ◽  
Β Cell ◽  
Induced Apoptosis

SummaryLipids have been implicated as mediators of insulitis and β-cell death in type 1 diabetes development, but the mechanisms underlying this association are poorly understood. Here, we investigated the changes in islet/β-cell lipid composition using three models of insulitis: human islets and EndoC-βH1 β-cells treated with the cytokines IL-1β and IFN-γ, and islets from non-obese diabetic mice. Across all three models, lipidomic analyses showed a consistent change in abundance of the lysophosphatidylcholine, phosphatidylcholine and triacylglycerol species. We also showed that lysophosphatidylcholine and its biosynthetic enzyme PLA2G6 are enriched in murine islets. We determined that the ADP-ribosyl-acceptor glycohydrolase ARH3 is regulated by cytokines downstream of PLA2G6, which in turn regulates proteins involved in apoptosis, lipid metabolism, antigen processing and presentation and chemokines. ARH3 reduced cytokine-induced apoptosis, which may represent a negative feedback mechanism. Overall, these data show the importance of lipid metabolism in regulating β-cell death in type 1 diabetes.HighlightsLipidomics of 3 insulitis models revealed commonly regulated lipid classes.Identification of 35 proteins regulated by cytokines via PLA2G6 signaling.ARH3 reduces cytokine-induced apoptosis via PLA2G6 regulation.ARH3 regulates the levels of proteins related to insulitis and type 1 diabetes.

scholarly journals Immune-mediated β-cell death in type 1 diabetes: lessons from human β-cell lines

2012 ◽  
Vol 42 (11) ◽  
pp. 1244-1251 ◽  
Author(s):  
Yaíma L. Lightfoot ◽  
Jing Chen ◽  
Clayton E. Mathews
Keyword(s):  
Cell Death ◽  
Type 1 Diabetes ◽  
Cell Lines ◽  
Β Cell ◽  
Immune Mediated

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.

The vicious cycle of apoptotic β ‐cell death in type 1 diabetes

2007 ◽  
Vol 85 (8) ◽  
pp. 582-589 ◽  
Author(s):  
Ayelet Kaminitz ◽  
Jerry Stein ◽  
Isaac Yaniv ◽  
Nadir Askenasy
Keyword(s):  
Cell Death ◽  
Type 1 Diabetes ◽  
Vicious Cycle ◽  
Β Cell

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.

Sign in / Sign up

Export Citation Format

Share Document