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Mechanisms of β-Cell Destruction in Type 1 Diabetes
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Mechanisms of β-Cell Destruction in Type 1 Diabetes

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (1 April 2021) | Viewed by 14689

Special Issue Editor

Dr. Joachim Størling

E-Mail Website1 Website2
Guest Editor
Steno Diabetes Center Copenhagen & University of Copenhagen, 1165 København, Denmark
Interests: type 1 diabetes pathogenesis; β-cell and islet biology; cytokines and inflammation; signal transduction; genetics; incretins; apoptosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Type 1 diabetes (T1D) is a multifactorial metabolic disease characterized by immune-mediated destruction of the insulin-producing β-cells leading to a collapse of blood glucose regulation. Although research over the last decades in the field of immune-mediated β-cell destruction has provided insights into the mechanisms underlying β-cell loss in T1D, our understanding of the immune factors and signaling pathways leading to β-cell dysfunction and death is still incomplete. Interestingly, recent studies have suggested that part of the genetic predisposition to T1D involves risk genes that modulate the sensitivity of the β-cells to undergo immune-mediated apoptosis. Moreover, the β-cells seem ‘to talk’ to the immune system via the production of cytokines and chemokines under stress conditions. These factors may accelerate β-cell death via autocrine signaling mechanisms and/or by increasing immune cell infiltration of the islets. Better insight into the pathways and processes that regulate immune-mediated β-cell death may pave the way for the development of new therapeutic strategies to halt β-cell destruction in T1D.

This Special Issue of the International Journal of Molecular Sciences welcomes mechanistic studies investigating β-cell destruction in the context of T1D. Such studies include, but are not limited to, investigations of cytokine-mediated β-cell apoptosis, T-cell mechanisms of β-cell killing, β-cell pro- and antiapoptotic signaling pathways, the dialog between β-cells and the immune system, T1D risk genes, and genetic variants affecting β-cell death and survival.

Dr. Joachim Storling
Guest Editor

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Keywords

  • β-cell death
  • Cytokines
  • Apoptosis
  • Immune-mediated β-cell killing
  • Proapoptotic signaling

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Published Papers (4 papers)

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Research

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18 pages, 3472 KiB  
Article
Long, Noncoding RNA SRA Induces Apoptosis of β-Cells by Promoting the IRAK1/LDHA/Lactate Pathway
by Yu-Nan Huang, Shang-Lun Chiang, Yu-Jung Lin, Su-Ching Liu, Yen-Hsien Li, Yu-Chen Liao, Maw-Rong Lee, Pen-Hua Su, Fuu-Jen Tsai, Hui-Chih Hung and Chung-Hsing Wang
Int. J. Mol. Sci. 2021, 22(4), 1720; https://doi.org/10.3390/ijms22041720 - 9 Feb 2021
Cited by 13 | Viewed by 2799
Abstract
Long non-coding RNA steroid receptor RNA activators (LncRNA SRAs) are implicated in the β-cell destruction of Type 1 diabetes mellitus (T1D), but functional association remains poorly understood. Here, we aimed to verify the role of LncRNA SRA regulation in β-cells. LncRNA SRAs were [...] Read more.
Long non-coding RNA steroid receptor RNA activators (LncRNA SRAs) are implicated in the β-cell destruction of Type 1 diabetes mellitus (T1D), but functional association remains poorly understood. Here, we aimed to verify the role of LncRNA SRA regulation in β-cells. LncRNA SRAs were highly expressed in plasma samples and peripheral blood mononuclear cells (PBMCs) from T1D patients. LncRNA SRA was strongly upregulated by high-glucose treatment. LncRNA SRA acts as a microRNA (miR)-146b sponge through direct sequence–structure interactions. Silencing of lncRNA SRA increased the functional genes of Tregs, resulting in metabolic reprogramming, such as decreased lactate levels, repressed lactate dehydrogenase A (LDHA)/phosphorylated LDHA (pLDHA at Tyr10) expression, decreased reactive oxygen species (ROS) production, increased ATP production, and finally, decreased β-cell apoptosis in vitro. There was a positive association between lactate level and hemoglobin A1c (HbA1c) level in the plasma from patients with T1D. Recombinant human interleukin (IL)-2 treatment repressed lncRNA SRA expression and activity in β-cells. Higher levels of lncRNA-SRA/lactate in the plasma are associated with poor regulation in T1D patients. LncRNA SRA contributed to T1D pathogenesis through the inhibition of miR-146b in β-cells, with activating signaling transduction of interleukin-1 receptor-associated kinase 1 (IRAK1)/LDHA/pLDHA. Taken together, LncRNA SRA plays a critical role in the function of β-cells. Full article
(This article belongs to the Special Issue Mechanisms of β-Cell Destruction in Type 1 Diabetes)
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25 pages, 5634 KiB  
Article
Proinflammatory Cytokines Perturb Mouse and Human Pancreatic Islet Circadian Rhythmicity and Induce Uncoordinated β-Cell Clock Gene Expression via Nitric Oxide, Lysine Deacetylases, and Immunoproteasomal Activity
by Phillip Alexander Keller Andersen, Volodymyr Petrenko, Peter Horskjær Rose, Melissa Koomen, Nico Fischer, Seyed Mojtaba Ghiasi, Tina Dahlby, Charna Dibner and Thomas Mandrup-Poulsen
Int. J. Mol. Sci. 2021, 22(1), 83; https://doi.org/10.3390/ijms22010083 - 23 Dec 2020
Cited by 8 | Viewed by 4227
Abstract
Pancreatic β-cell-specific clock knockout mice develop β-cell oxidative-stress and failure, as well as glucose-intolerance. How inflammatory stress affects the cellular clock is under-investigated. Real-time recording of Per2:luciferase reporter activity in murine and human pancreatic islets demonstrated that the proinflammatory cytokine interleukin-1β (IL-1β) lengthened [...] Read more.
Pancreatic β-cell-specific clock knockout mice develop β-cell oxidative-stress and failure, as well as glucose-intolerance. How inflammatory stress affects the cellular clock is under-investigated. Real-time recording of Per2:luciferase reporter activity in murine and human pancreatic islets demonstrated that the proinflammatory cytokine interleukin-1β (IL-1β) lengthened the circadian period. qPCR-profiling of core clock gene expression in insulin-producing cells suggested that the combination of the proinflammatory cytokines IL-1β and interferon-γ (IFN-γ) caused pronounced but uncoordinated increases in mRNA levels of multiple core clock genes, in particular of reverse-erythroblastosis virus α (Rev-erbα), in a dose- and time-dependent manner. The REV-ERBα/β agonist SR9009, used to mimic cytokine-mediated Rev-erbα induction, reduced constitutive and cytokine-induced brain and muscle arnt-like 1 (Bmal1) mRNA levels in INS-1 cells as expected. SR9009 induced reactive oxygen species (ROS), reduced insulin-1/2 (Ins-1/2) mRNA and accumulated- and glucose-stimulated insulin secretion, reduced cell viability, and increased apoptosis levels, reminiscent of cytokine toxicity. In contrast, low (<5,0 μM) concentrations of SR9009 increased Ins-1 mRNA and accumulated insulin-secretion without affecting INS-1 cell viability, mirroring low-concentration IL-1β mediated β-cell stimulation. Inhibiting nitric oxide (NO) synthesis, the lysine deacetylase HDAC3 and the immunoproteasome reduced cytokine-mediated increases in clock gene expression. In conclusion, the cytokine-combination perturbed the intrinsic clocks operative in mouse and human pancreatic islets and induced uncoordinated clock gene expression in INS-1 cells, the latter effect associated with NO, HDAC3, and immunoproteasome activity. Full article
(This article belongs to the Special Issue Mechanisms of β-Cell Destruction in Type 1 Diabetes)
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15 pages, 2016 KiB  
Article
The Connexin 43 Regulator Rotigaptide Reduces Cytokine-Induced Cell Death in Human Islets
by Seyed Mojtaba Ghiasi, Jakob Bondo Hansen, Dan Ploug Christensen, Björn Tyrberg and Thomas Mandrup-Poulsen
Int. J. Mol. Sci. 2020, 21(12), 4311; https://doi.org/10.3390/ijms21124311 - 17 Jun 2020
Cited by 4 | Viewed by 3184
Abstract
Background: Intercellular communication mediated by cationic fluxes through the Connexin family of gap junctions regulates glucose-stimulated insulin secretion and beta cell defense against inflammatory stress. Rotigaptide (RG, ZP123) is a peptide analog that increases intercellular conductance in cardiac muscle cells by the prevention [...] Read more.
Background: Intercellular communication mediated by cationic fluxes through the Connexin family of gap junctions regulates glucose-stimulated insulin secretion and beta cell defense against inflammatory stress. Rotigaptide (RG, ZP123) is a peptide analog that increases intercellular conductance in cardiac muscle cells by the prevention of dephosphorylation and thereby uncoupling of Connexin-43 (Cx43), possibly via action on unidentified protein phosphatases. For this reason, it is being studied in human arrhythmias. It is unknown if RG protects islet cell function and viability against inflammatory or metabolic stress, a question of considerable translational interest for the treatment of diabetes. Methods: Apoptosis was measured in human islets shown to express Cx43, treated with RG or the control peptide ZP119 and exposed to glucolipotoxicity or IL-1β + IFNɣ. INS-1 cells shown to lack Cx43 were used to examine if RG protected human islet cells via Cx43 coupling. To study the mechanisms of action of Cx43-independent effects of RG, NO, IkBα degradation, mitochondrial activity, ROS, and insulin mRNA levels were determined. Results: RG reduced cytokine-induced apoptosis ~40% in human islets. In Cx43-deficient INS-1 cells, this protective effect was markedly blunted as expected, but unexpectedly, RG still modestly reduced apoptosis, and improved mitochondrial function, insulin-2 gene levels, and accumulated insulin release. RG reduced NO production in Cx43-deficient INS-1 cells associated with reduced iNOS expression, suggesting that RG blunts cytokine-induced NF-κB signaling in insulin-producing cells in a Cx43-independent manner. Conclusion: RG reduces cytokine-induced cell death in human islets. The protective action in Cx43-deficient INS-1 cells suggests a novel inhibitory mechanism of action of RG on NF-κB signaling. Full article
(This article belongs to the Special Issue Mechanisms of β-Cell Destruction in Type 1 Diabetes)
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Review

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13 pages, 916 KiB  
Review
Apolipoprotein CIII Is an Important Piece in the Type-1 Diabetes Jigsaw Puzzle
by Ismael Valladolid-Acebes, Per-Olof Berggren and Lisa Juntti-Berggren
Int. J. Mol. Sci. 2021, 22(2), 932; https://doi.org/10.3390/ijms22020932 - 19 Jan 2021
Cited by 10 | Viewed by 3308
Abstract
It is well known that type-2 diabetes mellitus (T2D) is increasing worldwide, but also the autoimmune form, type-1 diabetes (T1D), is affecting more people. The latest estimation from the International Diabetes Federation (IDF) is that 1.1 million children and adolescents below 20 years [...] Read more.
It is well known that type-2 diabetes mellitus (T2D) is increasing worldwide, but also the autoimmune form, type-1 diabetes (T1D), is affecting more people. The latest estimation from the International Diabetes Federation (IDF) is that 1.1 million children and adolescents below 20 years of age have T1D. At present, we have no primary, secondary or tertiary prevention or treatment available, although many efforts testing different strategies have been made. This review is based on the findings that apolipoprotein CIII (apoCIII) is increased in T1D and that in vitro studies revealed that healthy β-cells exposed to apoCIII became apoptotic, together with the observation that humans with higher levels of the apolipoprotein, due to mutations in the gene, are more susceptible to developing T1D. We have summarized what is known about apoCIII in relation to inflammation and autoimmunity in in vitro and in vivo studies of T1D. The aim is to highlight the need for exploring this field as we still are only seeing the top of the iceberg. Full article
(This article belongs to the Special Issue Mechanisms of β-Cell Destruction in Type 1 Diabetes)
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