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 SKAP2, a candidate gene for type 1 diabetes, regulates β-cell apoptosis and glycaemic control in newly diagnosed patients

2020 ◽  
Author(s):  
Ada Admin ◽  
Tina Fløyel ◽  
Kira Meyerovich ◽  
Michala C. Prause ◽  
Simranjeet Kaur ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glycaemic Control ◽  
Candidate Gene ◽  
Cell Function ◽  
Human Islets ◽  
Newly Diagnosed ◽  
Β Cell ◽  
Functional Studies ◽  
Induced Apoptosis

The single nucleotide polymorphism rs7804356 located in the Src kinase-associated phosphoprotein 2<i> </i>(SKAP2) gene<i> </i>is associated with type 1 diabetes (T1D) suggesting <i>SKAP2</i> as a causal candidate gene. The objective of the study was to investigate if SKAP2 has a functional role in the β-cells in relation to T1D. In a cohort of children with newly diagnosed T1D, rs7804356 predicted glycaemic control and residual β-cell function during first year after diagnosis. In INS-1E cells and rat and human islets, pro-inflammatory cytokines reduced the content of SKAP2. Functional studies revealed that knockdown of SKAP2 aggravated cytokine-induced apoptosis in INS-1E cells and primary rat b-cells, suggesting an anti-apoptotic function of SKAP2. In support of this, overexpression of SKAP2 afforded protection against cytokine-induced apoptosis which correlated with reduced nuclear content of S536-phosphorylated NFκB subunit p65, lower nitric oxide production and diminished C/EBP-homologues protein (CHOP) expression indicative of decreased endoplasmic reticulum stress. Knockdown of CHOP partially counteracted the increase in cytokine-induced apoptosis caused by SKAP2 knockdown. In conclusion, our results suggest that SKAP2 controls β-cell sensitivity to cytokines possibly by affecting the NFκB-iNOS-ER stress pathway.

scholarly journals SKAP2, a candidate gene for type 1 diabetes, regulates β-cell apoptosis and glycaemic control in newly diagnosed patients

2020 ◽  
Author(s):  
Ada Admin ◽  
Tina Fløyel ◽  
Kira Meyerovich ◽  
Michala C. Prause ◽  
Simranjeet Kaur ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glycaemic Control ◽  
Candidate Gene ◽  
Cell Function ◽  
Human Islets ◽  
Newly Diagnosed ◽  
Β Cell ◽  
Functional Studies ◽  
Induced Apoptosis

The single nucleotide polymorphism rs7804356 located in the Src kinase-associated phosphoprotein 2<i> </i>(SKAP2) gene<i> </i>is associated with type 1 diabetes (T1D) suggesting <i>SKAP2</i> as a causal candidate gene. The objective of the study was to investigate if SKAP2 has a functional role in the β-cells in relation to T1D. In a cohort of children with newly diagnosed T1D, rs7804356 predicted glycaemic control and residual β-cell function during first year after diagnosis. In INS-1E cells and rat and human islets, pro-inflammatory cytokines reduced the content of SKAP2. Functional studies revealed that knockdown of SKAP2 aggravated cytokine-induced apoptosis in INS-1E cells and primary rat b-cells, suggesting an anti-apoptotic function of SKAP2. In support of this, overexpression of SKAP2 afforded protection against cytokine-induced apoptosis which correlated with reduced nuclear content of S536-phosphorylated NFκB subunit p65, lower nitric oxide production and diminished C/EBP-homologues protein (CHOP) expression indicative of decreased endoplasmic reticulum stress. Knockdown of CHOP partially counteracted the increase in cytokine-induced apoptosis caused by SKAP2 knockdown. In conclusion, our results suggest that SKAP2 controls β-cell sensitivity to cytokines possibly by affecting the NFκB-iNOS-ER stress pathway.

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 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 Is Nitric Oxide Really the Primary Mediator of Pancreatic β-Cell Death in Type 1 Diabetes?

2015 ◽  
Vol 290 (16) ◽  
pp. 10570-10570 ◽  
Author(s):  
Ewa Gurgul-Convey ◽  
Sigurd Lenzen
Keyword(s):  
Nitric Oxide ◽  
Cell Death ◽  
Type 1 Diabetes ◽  
Pancreatic Β Cell ◽  
Β Cell

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 SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets

2014 ◽  
Vol 307 (8) ◽  
pp. E664-E673 ◽  
Author(s):  
Catherine Hajmrle ◽  
Mourad Ferdaoussi ◽  
Gregory Plummer ◽  
Aliya F. Spigelman ◽  
Krista Lai ◽  
...  
Keyword(s):  
Cell Death ◽  
Insulin Secretion ◽  
Caspase 3 ◽  
Nuclear Translocation ◽  
Human Islets ◽  
Inos Expression ◽  
Β Cell ◽  
Intracellular Ca ◽  
Induced Apoptosis ◽  
The Impact

Posttranslational modification by the small ubiquitin-like modifier (SUMO) peptides, known as SUMOylation, is reversed by the sentrin/SUMO-specific proteases (SENPs). While increased SUMOylation reduces β-cell exocytosis, insulin secretion, and responsiveness to GLP-1, the impact of SUMOylation on islet cell survival is unknown. Mouse islets, INS-1 832/13 cells, or human islets were transduced with adenoviruses to increase either SENP1 or SUMO1 or were transfected with siRNA duplexes to knockdown SENP1. We examined insulin secretion, intracellular Ca2+ responses, induction of endoplasmic reticulum stress markers and inducible nitric oxide synthase (iNOS) expression, and apoptosis by TUNEL and caspase 3 cleavage. Surprisingly, upregulation of SENP1 reduces insulin secretion and impairs intracellular Ca2+ handling. This secretory dysfunction is due to SENP1-induced cell death. Indeed, the detrimental effect of SENP1 on secretory function is diminished when two mediators of β-cell death, iNOS and NF-κB, are pharmacologically inhibited. Conversely, enhanced SUMOylation protects against IL-1β-induced cell death. This is associated with reduced iNOS expression, cleavage of caspase 3, and nuclear translocation of NF-κB. Taken together, these findings identify SUMO1 as a novel antiapoptotic protein in islets and demonstrate that reduced viability accounts for impaired islet function following SENP1 up-regulation.

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 Exocytosis Protein DOC2B as a Biomarker of Type 1 Diabetes

2018 ◽  
Vol 103 (5) ◽  
pp. 1966-1976 ◽  
Author(s):  
Arianne Aslamy ◽  
Eunjin Oh ◽  
Miwon Ahn ◽  
Abu Saleh Md Moin ◽  
Mariann Chang ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Islet Transplantation ◽  
Ex Vivo ◽  
Human Subjects ◽  
Cell Mass ◽  
Nod Mice ◽  
Human Islets ◽  
Β Cell ◽  
New Onset

Abstract Context Efforts to preserve β-cell mass in the preclinical stages of type 1 diabetes (T1D) are limited by few blood-derived biomarkers of β-cell destruction. Objective Platelets are proposed sources of blood-derived biomarkers for a variety of diseases, and they show distinct proteomic changes in T1D. Thus, we investigated changes in the exocytosis protein, double C2 domain protein-β (DOC2B) in platelets and islets from T1D humans, and prediabetic nonobese diabetic (NOD) mice. Design, Patients, and Main Outcome Measure Protein levels of DOC2B were assessed in platelets and islets from prediabetic NOD mice and humans, with and without T1D. Seventeen new-onset T1D human subjects (10.3 ± 3.8 years) were recruited immediately following diagnosis, and platelet DOC2B levels were compared with 14 matched nondiabetic subjects (11.4 ± 2.9 years). Furthermore, DOC2B levels were assessed in T1D human pancreatic tissue samples, cytokine-stimulated human islets ex vivo, and platelets from T1D subjects before and after islet transplantation. Results DOC2B protein abundance was substantially reduced in prediabetic NOD mouse platelets, and these changes were mirrored in the pancreatic islets from the same mice. Likewise, human DOC2B levels were reduced over twofold in platelets from new-onset T1D human subjects, and this reduction was mirrored in T1D human islets. Cytokine stimulation of normal islets reduced DOC2B expression ex vivo. Remarkably, platelet DOC2B levels increased after islet transplantation in patients with T1D. Conclusions Reduction of DOC2B is an early feature of T1D, and DOC2B abundance may serve as a valuable in vivo indicator of β-cell mass and an early biomarker of T1D.

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