scholarly journals A20 deficiency sensitizes pancreatic beta cells to cytokine-induced apoptosis in vitro but does not influence type 1 diabetes development in vivo

2015 ◽  
Vol 6 (10) ◽  
pp. e1918-e1918 ◽  
Author(s):  
L Catrysse ◽  
M Fukaya ◽  
M Sze ◽  
K Meyerovich ◽  
R Beyaert ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Diabetes Development ◽  
Induced Apoptosis

scholarly journals BET Proteins Are Required for Transcriptional Activation of the Senescent Islet Cell Secretome in Type 1 Diabetes

2019 ◽  
Vol 20 (19) ◽  
pp. 4776 ◽  
Author(s):  
Peter J. Thompson ◽  
Ajit Shah ◽  
Hara Apostolopolou ◽  
Anil Bhushan
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Transcriptional Activation ◽  
Pancreatic Beta Cells ◽  
Islet Cells ◽  
Disease Onset ◽  
Protein Inhibition ◽  
Bet Protein

Type 1 diabetes (T1D) results from the progressive loss of pancreatic beta cells as a result of autoimmune destruction. We recently reported that during the natural history of T1D in humans and the female nonobese diabetic (NOD) mouse model, beta cells acquire a senescence-associated secretory phenotype (SASP) that is a major driver of disease onset and progression, but the mechanisms that activate SASP in beta cells were not explored. Here, we show that the SASP in islet cells is transcriptionally controlled by Bromodomain ExtraTerminal (BET) proteins, including Bromodomain containing protein 4 (BRD4). A chromatin analysis of key beta cell SASP genes in NOD islets revealed binding of BRD4 at active regulatory regions. BET protein inhibition in NOD islets diminished not only the transcriptional activation and secretion of SASP factors, but also the non-cell autonomous activity. BET protein inhibition also decreased the extent of SASP induction in human islets exposed to DNA damage. The BET protein inhibitor iBET-762 prevented diabetes in NOD mice and also attenuated SASP in islet cells in vivo. Taken together, our findings support a crucial role for BET proteins in the activation of the SASP transcriptional program in islet cells. These studies suggest avenues for preventing T1D by transcriptional inhibition of SASP.

Glucose-dependent expansion of pancreatic beta-cells by the protein p8 in vitro and in vivo

2007 ◽  
Vol 115 (S 1) ◽  
Author(s):  
G Päth ◽  
A Opel ◽  
M Gehlen ◽  
V Rothhammer ◽  
X Niu ◽  
...  
Keyword(s):  
Beta Cells ◽  
Pancreatic Beta Cells

scholarly journals Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

2021 ◽  
Vol 9 (6) ◽  
pp. 1177
Author(s):  
Abdulaziz Alhazmi ◽  
Magloire Pandoua Nekoua ◽  
Hélène Michaux ◽  
Famara Sane ◽  
Aymen Halouani ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Viral Infections ◽  
Lymphoid Organ ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Coxsackievirus B4

The thymus gland is a primary lymphoid organ for T-cell development. Various viral infections can result in disturbance of thymic functions. Medullary thymic epithelial cells (mTECs) are important for the negative selection of self-reactive T-cells to ensure central tolerance. Insulin-like growth factor 2 (IGF2) is the dominant self-peptide of the insulin family expressed in mTECs and plays a crucial role in the intra-thymic programing of central tolerance to insulin-secreting islet β-cells. Coxsackievirus B4 (CVB4) can infect and persist in the thymus of humans and mice, thus hampering the T-cell maturation and differentiation process. The modulation of IGF2 expression and protein synthesis during a CVB4 infection has been observed in vitro and in vivo in mouse models. The effect of CVB4 infections on human and mouse fetal thymus has been studied in vitro. Moreover, following the inoculation of CVB4 in pregnant mice, the thymic function in the fetus and offspring was disturbed. A defect in the intra-thymic expression of self-peptides by mTECs may be triggered by CVB4. The effects of viral infections, especially CVB4 infection, on thymic cells and functions and their possible role in the pathogenesis of type 1 diabetes (T1D) are presented.

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 Modeling Type 1 Diabetes Using Pluripotent Stem Cell Technology

2021 ◽  
Vol 12 ◽  
Author(s):  
Kriti Joshi ◽  
Fergus Cameron ◽  
Swasti Tiwari ◽  
Stuart I. Mannering ◽  
Andrew G. Elefanty ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Stem Cell ◽  
Genetic Variants ◽  
Genetic Background ◽  
Pluripotent Stem Cell ◽  
Cell Types ◽  
Polygenic Inheritance

Induced pluripotent stem cell (iPSC) technology is increasingly being used to create in vitro models of monogenic human disorders. This is possible because, by and large, the phenotypic consequences of such genetic variants are often confined to a specific and known cell type, and the genetic variants themselves can be clearly identified and controlled for using a standardized genetic background. In contrast, complex conditions such as autoimmune Type 1 diabetes (T1D) have a polygenic inheritance and are subject to diverse environmental influences. Moreover, the potential cell types thought to contribute to disease progression are many and varied. Furthermore, as HLA matching is critical for cell-cell interactions in disease pathogenesis, any model that seeks to test the involvement of particular cell types must take this restriction into account. As such, creation of an in vitro model of T1D will require a system that is cognizant of genetic background and enables the interaction of cells representing multiple lineages to be examined in the context of the relevant environmental disease triggers. In addition, as many of the lineages critical to the development of T1D cannot be easily generated from iPSCs, such models will likely require combinations of cell types derived from in vitro and in vivo sources. In this review we imagine what an ideal in vitro model of T1D might look like and discuss how the required elements could be feasibly assembled using existing technologies. We also examine recent advances towards this goal and discuss potential uses of this technology in contributing to our understanding of the mechanisms underlying this autoimmune condition.

scholarly journals Similarities Between Bacterial GAD and Human GAD65: Implications in Gut Mediated Autoimmune Type 1 Diabetes

2021 ◽  
Author(s):  
Monica Westley ◽  
Tiffany Richardson ◽  
Suhana Bedi ◽  
Baofeng Jia ◽  
Fiona S.L. Brinkman ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Gut Microbiome ◽  
Pancreatic Beta Cells ◽  
Acid Decarboxylase ◽  
Host Immune System ◽  
Gamma Aminobutyric Acid ◽  
Human Gut ◽  
Autoimmune Attack

Abstract    A variety of islet autoantibodies (AAbs) can predict and possibly dictate eventual type 1 diabetes (T1D) diagnosis. Upwards of 75% of those with T1D are positive for AAbs against glutamic acid decarboxylase (GAD65), a producer of gamma-aminobutyric acid (GABA) in human pancreatic beta cells. Interestingly, bacterial populations within the human gut also express GAD65 and produce GABA. Evidence suggests that dysbiosis of the microbiome may correlate with T1D pathogenesis and physiology. Therefore, autoimmune linkages between the gut microbiome and islets susceptible to autoimmune attack need to be further elucidated. Utilizing silico analyses, we show here that 25 GAD sequences from different human gut bacterial sources show sequence and motif similarities to human beta cell GAD65. Our motif analyses determined that a majority of gut GAD sequences contain the pyroxical dependent decarboxylase domain of human GAD65 which is important for its enzymatic activity. Additionally, we showed overlap with known human GAD65 T-cell receptor epitopes which may implicate the immune destruction of beta cells. Thus, we propose a physiological hypothesis in which changes in the gut microbiome in those with T1D result in a release of bacterial GAD, thus causing miseducation of the host immune system. Due to the notable similarities, we found between humans and bacterial GAD, these deputized immune cells may then go on to target human beta cells leading to the development of T1D.

scholarly journals Glycosylation of CaV3.2 Channels Contributes to the Hyperalgesia in Peripheral Neuropathy of Type 1 Diabetes

2020 ◽  
Vol 14 ◽  
Author(s):  
Sonja Lj. Joksimovic ◽  
J. Grayson Evans ◽  
William E. McIntire ◽  
Peihan Orestes ◽  
Paula Q. Barrett ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Adult Female ◽  
Molecular Mechanisms ◽  
Sprague Dawley ◽  
Knock Out ◽  
Peripheral Diabetic Neuropathy ◽  
Novel Treatments

Our previous studies implicated glycosylation of the CaV3.2 isoform of T-type Ca2+ channels (T-channels) in the development of Type 2 painful peripheral diabetic neuropathy (PDN). Here we investigated biophysical mechanisms underlying the modulation of recombinant CaV3.2 channel by de-glycosylation enzymes such as neuraminidase (NEU) and PNGase-F (PNG), as well as their behavioral and biochemical effects in painful PDN Type 1. In our in vitro study we used whole-cell recordings of current-voltage relationships to confirm that CaV3.2 current densities were decreased ~2-fold after de-glycosylation. Furthermore, de-glycosylation induced a significant depolarizing shift in the steady-state relationships for activation and inactivation while producing little effects on the kinetics of current deactivation and recovery from inactivation. PDN was induced in vivo by injections of streptozotocin (STZ) in adult female C57Bl/6j wild type (WT) mice, adult female Sprague Dawley rats and CaV3.2 knock-out (KO mice). Either NEU or vehicle (saline) were locally injected into the right hind paws or intrathecally. We found that injections of NEU, but not vehicle, completely reversed thermal and mechanical hyperalgesia in diabetic WT rats and mice. In contrast, NEU did not alter baseline thermal and mechanical sensitivity in the CaV3.2 KO mice which also failed to develop painful PDN. Finally, we used biochemical methods with gel-shift analysis to directly demonstrate that N-terminal fragments of native CaV3.2 channels in the dorsal root ganglia (DRG) are glycosylated in both healthy and diabetic animals. Our results demonstrate that in sensory neurons glycosylation-induced alterations in CaV3.2 channels in vivo directly enhance diabetic hyperalgesia, and that glycosylation inhibitors can be used to ameliorate painful symptoms in Type 1 diabetes. We expect that our studies may lead to a better understanding of the molecular mechanisms underlying painful PDN in an effort to facilitate the discovery of novel treatments for this intractable disease.

scholarly journals Peroxiredoxin 6 Attenuates Alloxan-Induced Type 1 Diabetes Mellitus in Mice and Cytokine-Induced Cytotoxicity in RIN-m5F Beta Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Elena G. Novoselova ◽  
Olga V. Glushkova ◽  
Sergey M. Lunin ◽  
Maxim O. Khrenov ◽  
Svetlana B. Parfenyuk ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Cell Apoptosis ◽  
Pancreatic Beta Cells ◽  
Apoptotic Cell ◽  
Main Idea ◽  
Severe Form ◽  
Peroxiredoxin 6 ◽  
Cells Cultured

Type 1 diabetes is associated with the destruction of pancreatic beta cells, which is mediated via an autoimmune mechanism and consequent inflammatory processes. In this article, we describe a beneficial effect of peroxiredoxin 6 (PRDX6) in a type 1 diabetes mouse model. The main idea of this study was based on the well-known data that oxidative stress plays an important role in pathogenesis of diabetes and its associated complications. We hypothesised that PRDX6, which is well known for its various biological functions, including antioxidant activity, may provide an antidiabetic effect. It was shown that PRDX6 prevented hyperglycemia, lowered the mortality rate, restored the plasma cytokine profile, reversed the splenic cell apoptosis, and reduced the β cell destruction in Langerhans islets in mice with a severe form of alloxan-induced diabetes. In addition, PRDX6 protected rat insulinoma RIN-m5F β cells, cultured with TNF-α and IL-1β, against the cytokine-induced cytotoxicity and reduced the apoptotic cell death and production of ROS. Signal transduction studies showed that PRDX6 prevented the activation of NF-κB and c-Jun N-terminal kinase signaling cascades in RIN-m5F β cells cultured with cytokines. In conclusion, there is a prospect for therapeutic application of PRDX6 to delay or even prevent β cell apoptosis in type 1 diabetes.

scholarly journals High-glucose-induced miR-214-3p inhibits BMSCs osteogenic differentiation in type 1 diabetes mellitus

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Rongze Wang ◽  
Yuanxu Zhang ◽  
Fujun Jin ◽  
Gongchen Li ◽  
Yao Sun ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Osteogenic Differentiation ◽  
High Glucose ◽  
Bone Homeostasis ◽  
Marrow Mesenchymal Stem Cells

Abstract Type 1 diabetes mellitus (T1DM) is an autoimmune insulin-dependent disease associated with destructive bone homeostasis. Accumulating evidence has proven that miRNAs are widely involved in the regulation of bone homeostasis. However, whether miRNAs also regulate osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in T1DM mice is under exploration. In this study, miRNA microarray was utilized to screen the differentially expressed miRNAs, which uncovered that miR-214-3p potentially inhibited BMSCs osteogenic differentiation in T1DM mice. We found that high glucose suppressed BMSCs osteogenic differentiation with significant elevation of the miR-214-3p expression. Further study found that the osteogenic differentiation of BMSCs was inhibited by AgomiR-214-3p while enhanced by AntagomiR-214-3p in BMSCs supplemented with high glucose. Moreover, we found that miR-214-3p knockout T1DM mice were resistant to high-glucose-induced bone loss. These results provide a novel insight into an inhibitory role of high-glucose-induced miR-214-3p in BMSCs osteogenic differentiation both in vitro and in vivo. Molecular studies revealed that miR-214-3p inhibits BMSCs osteogenic differentiation by targeting the 3′-UTR of β-catenin, which was further corroborated in human bone specimens and BMSCs of T1DM patients. Taken together, our study discovered that miR-214-3p is a pivotal regulator of BMSCs osteogenic differentiation in T1DM mice. Our findings also suggest that miR-214-3p could be a potential target in the treatment of bone disorders in patients with T1DM.

scholarly journals Regulated hAAT Expression from a Novel rAAV Vector and Its Application in the Prevention of Type 1 Diabetes

2019 ◽  
Vol 8 (9) ◽  
pp. 1321 ◽  
Author(s):  
Hongxia Ma ◽  
Yuanqing Lu ◽  
Keith Lowe ◽  
Lonneke van der Meijden-Erkelens ◽  
Clive Wasserfall ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Transgene Expression ◽  
Viral Vectors ◽  
Fine Tuning ◽  
Vector System ◽  
Regulation System ◽  
Raav Vector

We, and others, have previously achieved high and sustained levels of transgene expression from viral vectors, such as recombinant adeno-associated virus (rAAV). However, regulatable transgene expression may be preferred in gene therapy for diseases, such as type 1 diabetes (T1D) and rheumatoid arthritis (RA), in which the timing and dosing of the therapeutic gene product play critical roles. In the present study, we generated a positive feedback regulation system for human alpha 1 antitrypsin (hAAT) expression in the rAAV vector. We performed quantitative kinetics studies in vitro and in vivo demonstrating that this vector system can mediate high levels of inducible transgene expression. Transgene induction could be tailored to occur rapidly or gradually, depending on the dose of the inducing drug, doxycycline (Dox). Conversely, after withdrawal of Dox, the silencing of transgene expression occurred slowly over the course of several weeks. Importantly, rAAV delivery of inducible hAAT significantly prevented T1D development in non-obese diabetic (NOD) mice. These results indicate that this Dox-inducible vector system may facilitate the fine-tuning of transgene expression, particularly for hAAT treatment of human autoimmune diseases, including T1D.

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