scholarly journals Beta Cell Autophagy in the Pathogenesis of Type 1 Diabetes

2021 ◽  
Author(s):  
Charanya Muralidharan ◽  
Amelia K Linnemann
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Potential Role ◽  
Cell Dysfunction ◽  
Unconventional Secretion ◽  
Insulin Dependent

Type 1 diabetes is an insulin-dependent, autoimmune disease where the pancreatic beta cells are destroyed resulting in hyperglycemia. This multi-factorial disease involves multiple environmental and genetic factors, and has no clear etiology. Accumulating evidence suggests that early signaling defects within the beta cells may promote a change in the local immune mileu, contributing to autoimmunity. Therefore, many studies have been focused on intrinsic beta cell mechanisms that aid in restoration of cellular homeostasis under environmental conditions that cause dysfunction. One of these intrinsic mechanisms to promote homeostasis is autophagy, defects in which are clearly linked with beta cell dysfunction in the context of type 2 diabetes. Recent studies have now also pointed towards beta cell autophagy defects in the context of type 1 diabetes. In this perspectives review, we will discuss the evidence supporting a role for beta cell autophagy in the pathogenesis of type 1 diabetes, including a potential role for unconventional secretion of autophagosomes/lysosomes in the changing dialogue between the beta cell and immune cells.

scholarly journals Partners in Crime: Beta-Cells and Autoimmune Responses Complicit in Type 1 Diabetes Pathogenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Eliana Toren ◽  
KaLia S. Burnette ◽  
Ronadip R. Banerjee ◽  
Chad S. Hunter ◽  
Hubert M. Tse
Keyword(s):  
Type 1 Diabetes ◽  
Immune System ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Disease Etiology ◽  
Autoreactive T Cell ◽  
Beta Cell Heterogeneity ◽  
Beta Cell Response

Type 1 diabetes (T1D) is an autoimmune disease characterized by autoreactive T cell-mediated destruction of insulin-producing pancreatic beta-cells. Loss of beta-cells leads to insulin insufficiency and hyperglycemia, with patients eventually requiring lifelong insulin therapy to maintain normal glycemic control. Since T1D has been historically defined as a disease of immune system dysregulation, there has been little focus on the state and response of beta-cells and how they may also contribute to their own demise. Major hurdles to identifying a cure for T1D include a limited understanding of disease etiology and how functional and transcriptional beta-cell heterogeneity may be involved in disease progression. Recent studies indicate that the beta-cell response is not simply a passive aspect of T1D pathogenesis, but rather an interplay between the beta-cell and the immune system actively contributing to disease. Here, we comprehensively review the current literature describing beta-cell vulnerability, heterogeneity, and contributions to pathophysiology of T1D, how these responses are influenced by autoimmunity, and describe pathways that can potentially be exploited to delay T1D.

scholarly journals Mediators and mechanisms of pancreatic beta-cell death in type 1 diabetes

2008 ◽  
Vol 52 (2) ◽  
pp. 156-165 ◽  
Author(s):  
Pierre Pirot ◽  
Alessandra K. Cardozo ◽  
Décio L. Eizirik
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Map Kinases ◽  
Pancreatic Beta Cell ◽  
Insulin Deficiency ◽  
Beta Cell Destruction ◽  
Pro Inflammatory Cytokines

Type 1 diabetes mellitus (T1D) is characterized by severe insulin deficiency resulting from chronic and progressive destruction of pancreatic beta-cells by the immune system. The triggering of autoimmunity against the beta-cells is probably caused by environmental agent(s) acting in the context of a predisposing genetic background. Once activated, the immune cells invade the islets and mediate their deleterious effects on beta-cells via mechanisms such as Fas/FasL, perforin/granzyme, reactive oxygen and nitrogen species and pro-inflammatory cytokines. Binding of cytokines to their receptors on the beta-cells activates MAP-kinases and the transcription factors STAT-1 and NFkappa-B, provoking functional impairment, endoplasmic reticulum stress and ultimately apoptosis. This review discusses the potential mediators and mechanisms leading to beta-cell destruction in T1D.

scholarly journals Amylin under examination. Fibrillogenic potential of the troublesome molecule

2018 ◽  
Vol 72 ◽  
pp. 295-306
Author(s):  
Małgorzata Marszałek
Keyword(s):  
Diabetes Mellitus ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Loss ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Cell Dysfunction ◽  
Insulin Dependent ◽  
Methodological Difficulties

In patients or animals affected by 2 type diabetes mellitus (diabetes mellitus type 2 DM2, non-insulin dependent diabetes mellitus NIDDM) some pathological deposits, called amyloid are observed among cells of islets of Langerhans. Among others constituents deposits consist of insoluble, fibrillar form of polipeptide neurohormone called amylin, produced by pancreatic beta cells.. It is thought that formation of fibrillar deposits of misfolded and aggregated polipeptide is highly toxic to beta cells and leads to cell dysfunction, cell loss, pancreas destruction and progress of the disease. Due to the extreme insolubility of this polipeptide and its instant fibrillation amylin constitutes a methodological problem and there is a need for a special methodology in experiments. This article reviews the most important experiments aimed at discovering fibrillogenic potential of amylin and models of interaction of the polipeptide’s monomers in man and rat. Numerous methodological difficulties in amylin research has been also emphasized.

scholarly journals Beta Cell Therapies for Preventing Type 1 Diabetes: From Bench to Bedside

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1681
Author(s):  
Gabriel Brawerman ◽  
Peter J. Thompson
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Stress Responses ◽  
Pancreatic Beta Cells ◽  
Disease Onset ◽  
Disease Heterogeneity ◽  
Cell Therapies ◽  
Cell Dysfunction ◽  
Open Questions

Type 1 diabetes (T1D) is a chronic metabolic disease characterized by insulin deficiency, generally resulting from progressive autoimmune-mediated destruction of pancreatic beta cells. While the phenomenon of beta cell autoimmunity continues to be an active area of investigation, recent evidence suggests that beta cell stress responses are also important contributors to disease onset. Here we review the pathways driving different kinds of beta cell dysfunction and their respective therapeutic targets in the prevention of T1D. We discuss opportunities and important open questions around the effectiveness of beta cell therapies and challenges for clinical utility. We further evaluate ways in which beta cell drug therapy could be combined with immunotherapy for preventing T1D in light of our growing appreciation of disease heterogeneity and patient endotypes. Ultimately, the emergence of pharmacologic beta cell therapies for T1D have armed us with new tools and closing the knowledge gaps in T1D etiology will be essential for maximizing the potential of these approaches.

scholarly journals Long-RNA Sequencing and Ribosome Profiling of Inflamed Beta-Cells Reveal an Extensive Translatome Landscape

2021 ◽  
Author(s):  
Sofia Thomaidou ◽  
Roderick C. Slieker ◽  
Arno R. van der Slik ◽  
Jasper Boom ◽  
Flip Mulder ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Beta Cells ◽  
Translation Initiation ◽  
Pancreatic Beta Cells ◽  
Ribosome Profiling ◽  
Central Tolerance ◽  
Autoreactive T Cell ◽  
Human Beta Cells

Type 1 diabetes is an autoimmune disease characterized by autoreactive T-cell mediated destruction of the insulin-producing pancreatic beta-cells. Increasing evidence suggest that the beta-cells themselves contribute to their own destruction by generating neo-antigens through the production of aberrant or modified proteins that escape central tolerance. We have recently demonstrated that ribosomal infidelity amplified by stress could lead to the generation of neoantigens in human beta-cells, emphasizing the participation of nonconventional translation events to autoimmunity, as occurring in cancer or virus-infected tissues. Using a transcriptome-wide profiling approach to map translation initiation start sites in human beta-cells under standard and inflammatory conditions, we identify a completely new set of polypeptides derived from non-canonical start sites and translation initiation within lncRNA. Our data underline the extreme diversity of the beta-cell translatome and may reveal new functional biomarkers for beta-cell distress, disease prediction and progression and therapeutic intervention in type 1 diabetes.

scholarly journals Abnormal cannabidiol ameliorates inflammation preserving pancreatic beta cells in mouse models of experimental type 1 diabetes and beta cell damage

2021 ◽  
pp. 112361
Author(s):  
Isabel González-Mariscal ◽  
Macarena Pozo Morales ◽  
Silvana Y. Romero-Zerbo ◽  
Vanesa Espinosa-Jimenez ◽  
Alejandro Escamilla-Sánchez ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Beta Cells ◽  
Mouse Models ◽  
Pancreatic Beta Cells ◽  
Cell Damage ◽  
Experimental Type ◽  
Beta Cell Damage

scholarly journals Long-RNA Sequencing and Ribosome Profiling of Inflamed Beta-Cells Reveal an Extensive Translatome Landscape

2021 ◽  
Author(s):  
Sofia Thomaidou ◽  
Roderick C. Slieker ◽  
Arno R. van der Slik ◽  
Jasper Boom ◽  
Flip Mulder ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Beta Cells ◽  
Translation Initiation ◽  
Pancreatic Beta Cells ◽  
Ribosome Profiling ◽  
Central Tolerance ◽  
Autoreactive T Cell ◽  
Human Beta Cells

Type 1 diabetes is an autoimmune disease characterized by autoreactive T-cell mediated destruction of the insulin-producing pancreatic beta-cells. Increasing evidence suggest that the beta-cells themselves contribute to their own destruction by generating neo-antigens through the production of aberrant or modified proteins that escape central tolerance. We have recently demonstrated that ribosomal infidelity amplified by stress could lead to the generation of neoantigens in human beta-cells, emphasizing the participation of nonconventional translation events to autoimmunity, as occurring in cancer or virus-infected tissues. Using a transcriptome-wide profiling approach to map translation initiation start sites in human beta-cells under standard and inflammatory conditions, we identify a completely new set of polypeptides derived from non-canonical start sites and translation initiation within lncRNA. Our data underline the extreme diversity of the beta-cell translatome and may reveal new functional biomarkers for beta-cell distress, disease prediction and progression and therapeutic intervention in type 1 diabetes.

scholarly journals The role of apoptosis in pathogenesis of type 1 diabetes mellitus

2010 ◽  
Vol 13 (1) ◽  
pp. 45-49
Author(s):  
Elena Vladimirovna Pekareva ◽  
Tatiana Vasil'evna Nikonova ◽  
Olga Mikhailovna Smirnova
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Beta Cell ◽  
Type 1 Diabetes Mellitus ◽  
Beta Cells ◽  
Cell Apoptosis ◽  
Pancreatic Beta Cells ◽  
Beta Cell Apoptosis

Type 1 diabetes mellitus (DM1) is known to be associated with progressive destruction of pancreatic beta-cells. Apoptosis plays the key role in this destructiveprocess. The paper focuses on major mechanisms underlying activation of beta-cell apoptosis and its role in regulation of immune processes inpatients with DM1.

scholarly journals The Endoplasmic Reticulum and Calcium Homeostasis in Pancreatic Beta Cells

Endocrinology ◽  
2019 ◽  
Vol 161 (2) ◽  
Author(s):  
Irina X Zhang ◽  
Malini Raghavan ◽  
Leslie S Satin
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Type 1 Diabetes ◽  
Beta Cell ◽  
Er Stress ◽  
Beta Cells ◽  
Unfolded Protein ◽  
Protein Response

Abstract The endoplasmic reticulum (ER) mediates the first steps of protein assembly within the secretory pathway and is the site where protein folding and quality control are initiated. The storage and release of Ca2+ are critical physiological functions of the ER. Disrupted ER homeostasis activates the unfolded protein response (UPR), a pathway which attempts to restore cellular equilibrium in the face of ER stress. Unremitting ER stress, and insufficient compensation for it results in beta-cell apoptosis, a process that has been linked to both type 1 diabetes (T1D) and type 2 diabetes (T2D). Both types are characterized by progressive beta-cell failure and a loss of beta-cell mass, although the underlying causes are different. The reduction of mass occurs secondary to apoptosis in the case of T2D, while beta cells undergo autoimmune destruction in T1D. In this review, we examine recent findings that link the UPR pathway and ER Ca2+ to beta cell dysfunction. We also discuss how UPR activation in beta cells favors cell survival versus apoptosis and death, and how ER protein chaperones are involved in regulating ER Ca2+ levels. Abbreviations: BiP, Binding immunoglobulin Protein ER; endoplasmic reticulum; ERAD, ER-associated protein degradation; IFN, interferon; IL, interleukin; JNK, c-Jun N-terminal kinase; KHE, proton-K+ exchanger; MODY, maturity-onset diabetes of young; PERK, PRKR-like ER kinase; SERCA, Sarco/Endoplasmic Reticulum Ca2+-ATPases; T1D, type 1 diabetes; T2D, type 2 diabetes; TNF, tumor necrosis factor; UPR, unfolded protein response; WRS, Wolcott–Rallison syndrome.

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