RETRACTED: Exendin-4 prevented pancreatic beta cells from apoptosis in (Type I) diabetic mouse via keap1-Nrf2 signaling

Abstract Background Type 1 diabetes (T1D) is an autoimmune disease characterized by the progressive destruction of pancreatic beta cells. Interferon-α (IFNα), an antiviral cytokine, is expressed in the pancreatic islets in early T1D, which may be secondary to viral infections. However, not all patients harboring a type I IFN signature present signals of viral infection, suggesting that this response might be initiated by other “danger signals”. Accumulation of mitochondrial double-stranded RNA (mtdsRNA; a danger signal), secondary to silencing of members of the mitochondrial degradosome, PNPT1 and SUV3, has been described to activate the innate immune response. Methods To evaluate whether mtdsRNA represents a “danger signal” for pancreatic beta cells in the context of T1D, we silenced PNPT1 and/or SUV3 in slowly proliferating human insulin-secreting EndoC-βH1 cells and in non-proliferating primary human beta cells and evaluated dsRNA accumulation by immunofluorescence and the type I IFN response by western blotting and RT-qPCR. Results Only the simultaneous silencing of PNPT1/SUV3 induced dsRNA accumulation in EndoC-βH1 cells but not in dispersed human islets, and there was no induction of a type I IFN response. By contrast, silencing of these two genes individually was enough to induce dsRNA accumulation in fibroblasts present in the human islet preparations. Conclusions These data suggest that accumulation of endogenous mtdsRNA following degradosome knockdown depends on the proliferative capacity of the cells and is not a mediator of the type I IFN response in human pancreatic beta cells.

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Pancreatic beta cells cultured from individual preneoplastic foci in a multistage tumorigenesis pathway: a potentially general technique for isolating physiologically representative cell lines.

Molecular and Cellular Biology ◽

10.1128/mcb.13.7.4223 ◽

1993 ◽

Vol 13 (7) ◽

pp. 4223-4232 ◽

Cited By ~ 59

Author(s):

F Radvanyi ◽

S Christgau ◽

S Baekkeskov ◽

C Jolicoeur ◽

D Hanahan

Keyword(s):

Major Histocompatibility Complex ◽

Beta Cell ◽

Beta Cells ◽

Cell Lines ◽

Pancreatic Beta Cells ◽

Type I ◽

Major Histocompatibility ◽

Normal Cells ◽

Histocompatibility Complex ◽

Preneoplastic Foci

Culturing and comparing the discrete stages of tumorigenesis provide a route to defining important components of the cancer phenotype and, in addition, present the opportunity to establish cell cultures more representative of normal cells than the ultimate malignant cancer cells. Herein we report that preneoplastic foci in one multistep tumorigenesis pathway can be cultured in vitro and show that they preserve distinctive characteristics of the normal cells from which they arose, pancreatic beta cells. In the RIP1-Tag2 line of transgenic mice, which express the simian virus 40 T antigen in insulin-producing beta cells, pancreatic islets develop into vascularized tumors in a multistage pathway. We established conditions for reproducible derivation of beta-cell lines from individual hyperplastic islets that have not yet developed into solid tumors. Most of these cell lines, designated beta HC, release insulin at physiological concentrations of glucose. In contrast to tumor-derived lines (beta TC), which are not properly regulated, the ability of the beta HC lines to respond correctly to glucose correlated with maintenance of normally depressed levels of low-Km hexokinases. Glutamic acid decarboxylase (GAD), an early autoantigen in type I diabetes, was detected in most of the beta HC lines. The relative levels of the two forms of this enzyme (GAD65 and GAD67) varied significantly between the different cell lines, suggesting independent regulation. Class I major histocompatibility complex antigens were detected on the beta HC cells, and the levels of surface major histocompatibility complex expression correlated with their capacity to serve as targets in a cytotoxic T-cell killing assay. The beta HC lines will be of value for studies of beta-cell physiology, autoantigenicity, and tumor development. This work suggests the possibility of culturing preneoplastic stages of other cancers, both to address the mechanisms of transformation and to provide a source of cells that maintain important qualities of their normal progenitors.

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A T1D-associated lncRNA modulates the type I interferon signaling and the antiviral response in pancreatic beta cells.

2020 IEEE International Conference on Bioinformatics and Biomedicine (BIBM) ◽

10.1109/bibm49941.2020.9313457 ◽

2020 ◽

Author(s):

Itziar Gonzalez-Moro ◽

Izortze Santin

Keyword(s):

Beta Cells ◽

Pancreatic Beta Cells ◽

Type I Interferon ◽

Antiviral Response ◽

Type I ◽

Interferon Signaling

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Suppressive role of E3 ubiquitin ligase FBW7 in type I diabetes in non-obese diabetic mice through mediation of ubiquitination of EZH2

Cell Death Discovery ◽

10.1038/s41420-021-00605-x ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yingxue Guo ◽

Junfeng Li ◽

Shuang Fan ◽

Qibo Hu

Keyword(s):

Beta Cells ◽

Ubiquitin Ligase ◽

Pancreatic Beta Cells ◽

Type I Diabetes ◽

E3 Ubiquitin Ligase ◽

Nod Mice ◽

Beta Cell Apoptosis ◽

Type I ◽

Immunoprecipitation Assay ◽

The Stability

AbstractThe current study tried to uncover the molecular mechanism of E3 ubiquitin ligase F-box and WD repeat domain-containing 7 (FBW7) in a heritable autoimmune disease, type I diabetes (T1D). After streptozotocin-induced T1D model establishment in non-obese diabetic (NOD) mouse, the protein expression of FBW7, enhancer of zeste homolog 2 (EZH2), and Zinc finger and BTB domain containing 16 (ZBTB16) was quantified. Next, splenocytes and pancreatic beta cells were isolated to measure the production of pro-inflammatory cytokines in splenocytes, as well as islet beta-cell apoptosis. Additionally, the stability of EZH2 induced by FBW7 was analyzed by cycloheximide chase assay. The binding affinity of FBW7 and EZH2 and the consequence of ubiquitination were monitored by co-immunoprecipitation assay. Last, a chromatin immunoprecipitation assay was employed to analyze the accumulation of EZH2 and H3K27me3 at the ZBTB16 promoter region. Our study demonstrated downregulated FBW7 and ZBTB16 and upregulated EZH2 in diabetic NOD mice. Overexpression of FBW7 in the NOD mice inhibited pro-inflammatory cytokine release in the splenocytes and the apoptosis of islets beta cells. FBW7 destabilized EZH2 and accelerated ubiquitin-dependent degradation. EZH2 and H3K27me3 downregulated the ZBTB16 expression by accumulating in the ZBTB16 promoter and methylation. FBW7 upregulates the expression of ZBTB16 by targeting histone methyltransferase EZH2 thus reducing the occurrence of T1D.

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Glucocorticoid receptor expression is altered in pancreatic [beta ] cells of the non-obese diabetic mouse during postnatal development

Metabolism ◽

10.1053/meta.2002.32033 ◽

2002 ◽

Vol 51 (6) ◽

pp. 765-768 ◽

Cited By ~ 3

Author(s):

A. Thompson ◽

E.J. Arany ◽

D.J. Hill ◽

K. Yang

Keyword(s):

Glucocorticoid Receptor ◽

Postnatal Development ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Diabetic Mouse ◽

Receptor Expression

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Pancreatic beta cells cultured from individual preneoplastic foci in a multistage tumorigenesis pathway: a potentially general technique for isolating physiologically representative cell lines

Molecular and Cellular Biology ◽

10.1128/mcb.13.7.4223-4232.1993 ◽

1993 ◽

Vol 13 (7) ◽

pp. 4223-4232

Author(s):

F Radvanyi ◽

S Christgau ◽

S Baekkeskov ◽

C Jolicoeur ◽

D Hanahan

Keyword(s):

Major Histocompatibility Complex ◽

Beta Cell ◽

Beta Cells ◽

Cell Lines ◽

Pancreatic Beta Cells ◽

Type I ◽

Major Histocompatibility ◽

Normal Cells ◽

Histocompatibility Complex ◽

Preneoplastic Foci

Culturing and comparing the discrete stages of tumorigenesis provide a route to defining important components of the cancer phenotype and, in addition, present the opportunity to establish cell cultures more representative of normal cells than the ultimate malignant cancer cells. Herein we report that preneoplastic foci in one multistep tumorigenesis pathway can be cultured in vitro and show that they preserve distinctive characteristics of the normal cells from which they arose, pancreatic beta cells. In the RIP1-Tag2 line of transgenic mice, which express the simian virus 40 T antigen in insulin-producing beta cells, pancreatic islets develop into vascularized tumors in a multistage pathway. We established conditions for reproducible derivation of beta-cell lines from individual hyperplastic islets that have not yet developed into solid tumors. Most of these cell lines, designated beta HC, release insulin at physiological concentrations of glucose. In contrast to tumor-derived lines (beta TC), which are not properly regulated, the ability of the beta HC lines to respond correctly to glucose correlated with maintenance of normally depressed levels of low-Km hexokinases. Glutamic acid decarboxylase (GAD), an early autoantigen in type I diabetes, was detected in most of the beta HC lines. The relative levels of the two forms of this enzyme (GAD65 and GAD67) varied significantly between the different cell lines, suggesting independent regulation. Class I major histocompatibility complex antigens were detected on the beta HC cells, and the levels of surface major histocompatibility complex expression correlated with their capacity to serve as targets in a cytotoxic T-cell killing assay. The beta HC lines will be of value for studies of beta-cell physiology, autoantigenicity, and tumor development. This work suggests the possibility of culturing preneoplastic stages of other cancers, both to address the mechanisms of transformation and to provide a source of cells that maintain important qualities of their normal progenitors.

Download Full-text