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 Replacing murine insulin 1 with human insulin protects NOD mice from diabetes

2019 ◽  
Author(s):  
Colleen M. Elso ◽  
Nicholas A. Scott ◽  
Lina Mariana ◽  
Emma I. Masterman ◽  
Andrew P.R. Sutherland ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Mouse Models ◽  
Human Insulin ◽  
Murine Model ◽  
Pancreatic Beta Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Human Type 1 Diabetes

AbstractType 1, or autoimmune, diabetes is caused by the T-cell mediated destruction of the insulin-producing pancreatic beta cells. Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes akin to human type 1 diabetes. For this reason, the NOD mouse has been the preeminent murine model for human type 1 diabetes research for several decades. However, humanized mouse models are highly sought after because they offer both the experimental tractability of a mouse model and the clinical relevance of human-based research. Autoimmune T-cell responses against insulin, and its precursor proinsulin, play central roles in the autoimmune responses against pancreatic beta cells in both humans and NOD mice. As a first step towards developing a murine model of the human autoimmune response against pancreatic beta cells we set out to replace the murine insulin 1 gene (Ins1) with the human insulin gene (INS) using CRISPR/Cas9. Here we describe a NOD mouse strain that expresses human insulin in place of murine insulin 1, referred to as HuPI. HuPI mice express human insulin, and C-peptide, in their serum and pancreata and have normal glucose tolerance. Compared with wild type NOD mice, the incidence of diabetes is much lower in HuPI mice. Only 15-20% of HuPI mice developed diabetes after 300 days, compared to more than 60% of unmodified NOD mice. Immune-cell infiltration into the pancreatic islets of HuPI mice was not detectable at 100 days but was clearly evident by 300 days. This work highlights the feasibility of using CRISPR/Cas9 to create mouse models of human diseases that express proteins pivotal to the human disease. Furthermore, it reveals that even subtle changes in proinsulin protect NOD mice from diabetes.

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 Type 1 diabetes onset triggered by COVID-19

2020 ◽  
Author(s):  
Lucien Marchand ◽  
Matthieu Pecquet ◽  
Cédric Luyton
Keyword(s):  
Type 1 Diabetes ◽  
Pancreatic Beta Cells ◽  
Autoimmune Diabetes ◽  
Cell Damage ◽  
Short Delay ◽  
Angiotensin Converting Enzyme 2 ◽  
Diabetes Onset ◽  
Environmental Trigger ◽  
Beta Cell Damage

Abstract The epidemic of coronavirus disease-2019 (COVID-19) is caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) virus. Some data describing characteristics and prognosis of patients with COVID-19 and diabetes are now available, for example for hospitalized patients in the CORONADO study. Potential links between diabetes and COVID-19 infection were already described. Indeed Angiotensin-converting-enzyme 2 (ACE2) has been identified as the receptor for the coronavirus spike protein, and ACE is expressed on pancreatic beta cells. It was suggested that SARS-CoV2 could induce beta cell damage and new onset diabetes, but the phenotype of these new cases of diabetes has not been described.This observation presented in that paper highlights the fact that COVID-19 infection may also trigger type 1 diabetes onset. Viral infection, in particular by enteroviruses but also by coronaviruses, is a well-known environmental trigger for the development of type 1 diabetes. In the case presented herein, there was a short delay between COVID-19 infection and diabetes onset. It remains to determine if the hyperinflammation/cytokine storm described with this infection could accelerate the onset of type 1 diabetes in genetically susceptible individuals.The relationship between SARS-CoV2 exposition and autoimmune diabetes development must be further studied, and incidence of type 1 diabetes will be carefully observed in the next months.

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 LncRNA LEGLTBC Functions as a ceRNA to Antagonize the Effects of miR-34a on the Downregulation of SIRT1 in Glucolipotoxicity-Induced INS-1 Beta Cell Oxidative Stress and Apoptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Xiang Kong ◽  
Chong-xiao Liu ◽  
Guo-dong Wang ◽  
Hui Yang ◽  
Xin-ming Yao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Injury ◽  
Cell Damage ◽  
High Serum ◽  
Cell Dysfunction ◽  
Beta Cell Damage

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by elevated blood glucose and/or high serum free fatty acids. Chronic hyperlipidemia causes the dysfunction of pancreatic beta cells, which is aggravated in the presence of hyperglycemia (glucolipotoxicity). Long noncoding RNAs (lncRNAs) have been suggested to play key roles in type 1 diabetes mellitus development. However, their roles in glucolipotoxicity-induced beta cell dysfunction are not fully understood. In the present study, we identified the differentially expressed lncRNAs in INS-1 cells exposed to high glucose and palmitate (HG/PA). Among the dysregulated lncRNAs, NONRATT003679.2 (low expression in glucolipotoxicity-treated beta cells (LEGLTBC)) was involved in glucolipotoxicity-evoked rat islet beta cell damage. LEGLTBC functioned as a molecular sponge of miR-34a in INS-1 cells. Additionally, SIRT1 was identified as a target of miR-34a and LEGLTBC promoted SIRT1 expression by sponging miR-34a. The upregulation of LEGLTBC attenuated HG/PA-induced INS-1 cell injury through the promotion of SIRT1-mediated suppression of ROS accumulation and apoptosis. This is the first study to comprehensively identify the lncRNA expression profiling of HG/PA-treated INS-1 beta cells and to demonstrate that LEGLTBC functions as a competing endogenous RNA and regulates miR-34a/SIRT1-mediated oxidative stress and apoptosis in INS-1 cells undergoing glucolipotoxicity.

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 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.

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