Coxsackievirus B Type 4 Infection in β Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing

Bernard, H.; Teijeiro, Ana; Perez, Almudena Chaves; Perna, Cristian; Satish, Basanthi; Novials, Anna; Wang, Jennifer; Djouder, Nabil

doi:10.1016/j.xcrm.2020.100125

Cited by 12 publications

(10 citation statements)

References 89 publications

(142 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Demethylating agent procainamide-mediated DNMT1 inhibition has been shown to reinstate PDX1 expression and protects against diabetes in pancreatic URI-depleted mice. 118 Acarbose is a prescribed medicine for the treatment of type 2 diabetes that has been demonstrated to promote the proliferation of islet β-cells and inhibit PDX-1 methylation in islet β-cells from diabetic mice. 119 In addition, it has been shown that the expression of PDX-1 can be induced by various approaches as demonstrated in the study of differentiation of mesenchymal stromal cells (MSC) into β-cells.…”

Section: The Treatment Of T2dm Is Related To the Expression Of Pdx-1mentioning

confidence: 99%

Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus

Liu¹,

Lang²,

Shi³

2021

DMSO

View full text Add to dashboard Cite

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by hyperglycemia which is caused by insufficient insulin secretion or insulin resistance. Interaction of genetic, epigenetic and environmental factors plays a significant role in the development of T2DM. Several environmental factors including diet and lifestyle, as well as age have been associated with an increased risk for T2DM. It has been demonstrated that these environmental factors may affect global epigenetic status, and alter the expression of susceptible genes, thereby contributing to the pathogenesis of T2DM. In recent years, a growing body of molecular and genetic studies in diabetes have been focused on the ways to restore the numbers or function of β-cells in order to reverse a range of metabolic consequences of insulin deficiency. The pancreatic duodenal homeobox 1 (PDX-1) is a transcriptional factor that is essential for the development and function of islet cells. A number of studies have shown that there is a significant increase in the level of DNA methylation of PDX-1 resulting in reduced activity in T2DM islets. The decrease in PDX-1 activity may be a critical mediator causing dysregulation of pancreatic β cells in T2DM. This article reviews the epigenetic mechanisms of PDX-1 involved in T2DM, focusing on diabetes and DNA methylation, and discusses some potential strategies for the application of PDX-1 in the treatment of diabetes.

show abstract

Section: The Treatment Of T2dm Is Related To the Expression Of Pdx-1mentioning

confidence: 99%

Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus

Liu¹,

Lang²,

Shi³

2021

DMSO

View full text Add to dashboard Cite

show abstract

“…22 In a study in which coxsackievirus B type 4 isolated from human islets was inoculated into mice and a rat insulinoma cell line, the repression of the URI and PDX1 genes was observed, which affected the β-cell function and identity. 23 In the mentioned study, the URI gene was depleted, which caused endoplasmic reticulum nuclear translocation and activated DNA methyltransferase 1 (DNMT1), thus causing PDX1 promoter hypermethylation and silencing. When the mice were treated with a demethylating agent called procainamide, the PDX1 expression was restored and protected against diabetes.…”

Section: Viral Infection and Type 1 Diabetes Mellitusmentioning

confidence: 96%

Environmental Triggers’ Involvement in the Development of Type 1 Diabetes Mellitus

Yahaya¹,

Liman²,

Obadiah³

et al. 2022

Explor Res Hypothesis Med

View full text Add to dashboard Cite

The huge burden of type 1 diabetes mellitus (T1DM) has been a source of concern globally since the Industrial Revolution in the 18 th -19 th centuries. To this end, studies have shown that certain environmental changes that accompanied the Revolution may have increased the risk and burden of the disease in genetically predisposed individuals. However, documented studies that synthesize these environmental triggers are scarce. As a result, the current study was conceived to synthesize the environmental triggers of T1DM to boost public awareness. Relevant information was retrieved from reputable academic databases; namely, Scopus, PubMed, SpringerLink, and Embase. The results showed that chemical exposure, viral infection, gut microbiome disruption, vitamin and mineral deficiencies, inadequate or exclusive breastfeeding, as well as early exposure to infant feeding formulas could increase the risk and burden of T1DM in genetically predisposed individuals. As a consequence, these triggers could compromise the expression of certain genes involved in insulin synthesis and immune function, such as the human leukocyte antigen (HLA), insulin (INS), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes. This would result in a dysfunctional immune system in which immune cells, such as T-cells and B-cells and molecules, such as cytokines would attack self-tissues, thus causing autoimmunity of the pancreatic beta cells. Environmental triggers could also induce the T1DM pathophysiology by modifying the epigenome of the mentioned genes. Furthermore, some epigenetic changes could be reversed, which would infer that treatment procedures that would include the pathophysiology of the environmental triggers could be more effective.

show abstract

“…The Ifih1 ΔHel1 mutation delayed T1D development partly due to reduced immune cell infiltration of islets without compromising β-cell function. Since CVB has a tropism for the pancreas and can induce macrophage and T cell infiltration leading to the destruction of infected pancreatic exocrine and endocrine cells (32)(33)(34), we investigated if the Ifih1 ΔHel1 and Ifih1 KO mutations affected pancreatic macrophage and T cell populations. We analyzed pancreatic macrophages from both uninfected and CVB3-infected NOD, ΔHel1, and KO female mice by flow cytometry at 7 days post-injection.…”

Section: Ifih1 Mutations Dampen Islet Infiltration Without Hindering ...mentioning

confidence: 99%

MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance

Blum¹,

Taylor²,

Barra³

et al. 2023

JCI Insight

View full text Add to dashboard Cite

Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β-cell destruction. Coxsackievirus B3 (CVB3) infection and melanoma differentiation-associated protein 5 (MDA5)-dependent antiviral responses are linked with T1D development. Mutations within IFIH1, encoding for MDA5, are correlated with T1D susceptibility, but how these mutations contribute to T1D remains unclear. Utilizing non-obese diabetic (NOD) mice lacking Ifih1 expression (KO) or containing an in-frame deletion within the ATPase site of the helicase 1 domain of MDA5 (ΔHel1), we tested the hypothesis that partial or complete loss-of-function mutations in MDA5 would delay T1D by impairing proinflammatory pancreatic macrophage and T cell responses. Spontaneous T1D developed in female NOD and KO mice similarly, but was significantly delayed in ΔHel1 mice that may be partly due to a concomitant increase in myeloidderived suppressor cells. Interestingly, KO male mice had increased spontaneous T1D compared to NOD mice. While NOD and KO mice developed CVB3-accelerated T1D, ΔHel1 mice were protected partly due to decreased type I interferons, pancreatic-infiltrating TNF + macrophages, IFNγ + CD4 + T cells, and perforin + CD8 + T cells. Furthermore, ΔHel1 MDA5 protein had reduced ATP hydrolysis compared to wild-type MDA5. Our results suggest that dampened MDA5 function delays T1D, yet loss of MDA5 promotes T1D.

show abstract

Coxsackievirus B Type 4 Infection in β Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing

Cited by 12 publications

References 89 publications

Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus

Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus

Environmental Triggers’ Involvement in the Development of Type 1 Diabetes Mellitus

MDA5-dependent responses contribute to autoimmune diabetes progression and hindrance

Contact Info

Product

Resources

About