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
2015 ◽  
Vol 125 (3) ◽  
pp. 1163-1173 ◽  
Author(s):  
Kevan C. Herold ◽  
Sahar Usmani-Brown ◽  
Tara Ghazi ◽  
Jasmin Lebastchi ◽  
Craig A. Beam ◽  
...  

2008 ◽  
Vol 36 (3) ◽  
pp. 321-327 ◽  
Author(s):  
Decio L. Eizirik ◽  
Fabrice Moore ◽  
Daisy Flamez ◽  
Fernanda Ortis

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.


PLoS ONE ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e51909 ◽  
Author(s):  
Tijana Marinković ◽  
Marko Sysi-Aho ◽  
Matej Orešič

2020 ◽  
Author(s):  
Ernesto S. Nakayasu ◽  
Cailin Deiter ◽  
Jennifer E. Kyle ◽  
Michelle A. Guney ◽  
Dylan Sarbaugh ◽  
...  

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.


2003 ◽  
Vol 198 (7) ◽  
pp. 1103-1106 ◽  
Author(s):  
Irina Apostolou ◽  
Zhenyue Hao ◽  
Klaus Rajewsky ◽  
Harald von Boehmer

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.


2020 ◽  
Author(s):  
Diana Catarino ◽  
Diana Silva ◽  
Joana Guiomar ◽  
Cristina Ribeiro ◽  
Luísa Ruas ◽  
...  

Abstract Background: The American Diabetes Association proposed two subcategories for type 1 diabetes mellitus : type 1A or immune-mediated diabetes (IDM) and type 1B or idiopathic diabetes. The absence of β-cell autoimmune markers, permanent insulinopenia and prone to ketoacidosis define the second category, whose pathogenesis remains unclear. Only a minority of patients fall into this category, also designated non-immune-mediated (NIDM), which is considered by several authors similar to type 2 diabetes. The aim of this study is to evaluate differences at the diagnosis and ten years later of two categories. Methods: Retrospective cohort study of patients with β-cell autoimmune markers performed at diagnosis and undetectable c-peptide. Were excluded patients with suspicion of another specific type of diabetes. We obtained two groups: IDM (≥ 1 positive antibody) and NIDM (negative antibodies). Age, family history, anthropometry, duration of symptoms, clinical presentation, blood glucose at admission, A1C, lipid profile, arterial hypertension, total diary dose of insulin (TDDI), microvascular and macrovascular complications were evaluated. Results were considered statistically significant with p<0.05. Results: 37 patients, 29 with IDM and 8 patients with NIDM. The age of diagnosis of IDM group (23 years) was significantly different (p=0.004) from the NIDM group (38.1). The body mass index (BMI) at the diagnosis did not differ significantly (p=0.435). The duration of symptoms was longer in the NIDM (p=0.003). The disease presentation (p=0.744), blood glucose (p=0.482) and HbA1C (p=0.794) at admission and TDID at discharge (p=0.301) did not differ significantly. Total and LDL cholesterol levels were higher in NIDM group but did not differ significantly (p=0.585 and p=0.579, respectively). After ten years BMI did not differ between groups(p=0.079). Patients with IDM showed a significantly higher HbA1C (p=0,008) and TDID (p=0.017). Relative to the lipid profile, there was no significant difference, however the LDL cholesterol and triglycerides were higher on the NIDM group, as the percentage of hypertension. Microvascular complications were higher in the IDM group, but no significant difference was found. Conclusion: Patients with IDM had a poor metabolic control and higher insulin requirement. Patients with NIDM were older and showed higher cardiovascular risk, resembling a clinical phenotype of type 2 diabetes.


2003 ◽  
Vol 198 (10) ◽  
pp. 1527-1537 ◽  
Author(s):  
Shannon Turley ◽  
Laurent Poirot ◽  
Masakazu Hattori ◽  
Christophe Benoist ◽  
Diane Mathis

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.


2007 ◽  
Vol 85 (8) ◽  
pp. 582-589 ◽  
Author(s):  
Ayelet Kaminitz ◽  
Jerry Stein ◽  
Isaac Yaniv ◽  
Nadir Askenasy

2021 ◽  
Vol 43 (2) ◽  
pp. 22-26
Author(s):  
Staci A. Weaver ◽  
Jamie L. Felton ◽  
Carmella Evans-Molina

The year 2021 marks the 100th anniversary of the discovery of insulin, a therapy that transformed type 1 diabetes (T1D) from a once fatal diagnosis into a chronic condition that can be successfully managed with exogenous insulin administration. In this article, we celebrate the remarkable journey that led to the discovery of insulin and our subsequent understanding of T1D as a disease of immune-mediated β-cell destruction. Further, we discuss an alternative and parallax view of disease development, highlighting maladaptive β-cell responses that act to amplify immune responses and have been implicated in diabetes development.


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