Persistence of Coxsackievirus B4 in Pancreatic β Cells Disturbs Insulin Maturation, Pattern of Cellular Proteins, and DNA Methylation

Coxsackievirus-B4 (CV-B4) can persist in pancreatic cell lines and impair the phenoytpe and/or gene expressions in these cells; however, the models used to study this phenomenon did not produce insulin. Therefore, we investigated CV-B4 persistence and its consequences in insulin-producing pancreatic β cells. The insulin-secreting rat β cell line, INS-1, was infected with CV-B4. After lysis of a large part of the cell layer, the culture was still maintained and no additional cytopathic effect was observed. The amount of insulin in supernatants of cell cultures persistently infected with CV-B4 was not affected by the infection; in fact, a larger quantity of proinsulin was found. The mRNA expression of pro-hormone convertase 2, an enzyme involved in the maturation of proinsulin into insulin and studied using real-time reverse transcription-polymerase chain reaction, was inhibited in infected cultures. Further, the pattern of 47 cell proteins analyzed using Shotgun mass spectrometry was significantly modified. The DNA of persistently infected cell cultures was hypermethylated unlike that of controls. The persistent infection of INS-1 cells with CV-B4 had a deep impact on these cells, especially on insulin metabolism. Cellular changes caused by persistent CV-B4 infection of β cells can play a role in type 1 diabetes pathogenesis.

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Insulin promoter in human pancreatic β cells contacts diabetes susceptibility loci and regulates genes affecting insulin metabolism

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1803146115 ◽

2018 ◽

Vol 115 (20) ◽

pp. E4633-E4641 ◽

Cited By ~ 11

Author(s):

Xing Jian ◽

Gary Felsenfeld

Keyword(s):

Type 2 Diabetes ◽

Physical Contact ◽

Susceptibility Loci ◽

Chromosome 11 ◽

Β Cells ◽

Pancreatic Β Cells ◽

Diabetes Susceptibility ◽

Insulin Metabolism

Both type 1 and type 2 diabetes involve a complex interplay between genetic, epigenetic, and environmental factors. Our laboratory has been interested in the physical interactions, in nuclei of human pancreatic β cells, between the insulin (INS) gene and other genes that are involved in insulin metabolism. We have identified, using Circularized Chromosome Conformation Capture (4C), many physical contacts in a human pancreatic β cell line between the INS promoter on chromosome 11 and sites on most other chromosomes. Many of these contacts are associated with type 1 or type 2 diabetes susceptibility loci. To determine whether physical contact is correlated with an ability of the INS locus to affect expression of these genes, we knock down INS expression by targeting the promoter; 259 genes are either up or down-regulated. Of these, 46 make physical contact with INS. We analyze a subset of the contacted genes and show that all are associated with acetylation of histone H3 lysine 27, a marker of actively expressed genes. To demonstrate the usefulness of this approach in revealing regulatory pathways, we identify from among the contacted sites the previously uncharacterized gene SSTR5-AS1 and show that it plays an important role in controlling the effect of somatostatin-28 on insulin secretion. These results are consistent with models in which clustering of genes supports transcriptional activity. This may be a particularly important mechanism in pancreatic β cells and in other cells where a small subset of genes is expressed at high levels.

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Emergence of Fluoxetine-Resistant Variants during Treatment of Human Pancreatic Cell Cultures Persistently Infected with Coxsackievirus B4

Viruses ◽

10.3390/v11060486 ◽

2019 ◽

Vol 11 (6) ◽

pp. 486 ◽

Cited By ~ 1

Author(s):

Enagnon Kazali Alidjinou ◽

Antoine Bertin ◽

Famara Sane ◽

Delphine Caloone ◽

Ilka Engelmann ◽

...

Keyword(s):

Antiviral Activity ◽

Cell Cultures ◽

Acute Infection ◽

Infection Model ◽

Pancreatic Cell ◽

Persistently Infected ◽

Coxsackievirus B4 ◽

Persistent Infections ◽

Fluoxetine Treatment ◽

Putative Target

This study reports the antiviral activity of the drug fluoxetine against some enteroviruses (EV). We had previously established a model of persistent coxsackievirus B4 (CVB4) infection in pancreatic cell cultures and demonstrated that fluoxetine could clear the virus from these cultures. We further report the emergence of resistant variants during the treatment with fluoxetine in this model. Four independent persistent CVB4 infections in Panc-1 cells were treated with fluoxetine. The resistance to fluoxetine was investigated in an acute infection model. The 2C region, the putative target of fluoxetine antiviral activity, was sequenced. However, Fluoxetine treatment failed to clear CVB4 in two persistent infections. The resistance to fluoxetine was later confirmed in HEp-2 cells. The decrease in viral titer was significantly lower when cells were inoculated with the virus obtained from persistently infected cultures treated with fluoxetine than those from susceptible mock-treated cultures (0.6 log TCID50/mL versus 4.2 log TCID50/mL, p < 0.0001). Some previously described mutations and additional ones within the 2C protein were found in the fluoxetine-resistant isolates. The model of persistent infection is an interesting tool for assessing the emergence of variants resistant to anti-EV molecules. The resistance of EV strains to fluoxetine and its mechanisms require further investigation.

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Formation of pancreatic β-cells from precursor cells contributes to the reversal of established type 1 diabetes

Cellular Immunology ◽

10.1016/j.cellimm.2021.104360 ◽

2021 ◽

pp. 104360

Author(s):

Tobechukwu K. Ukah ◽

Alexis N. Cattin-Roy ◽

George E. Davis ◽

Habib Zaghouani

Keyword(s):

Type 1 Diabetes ◽

Precursor Cells ◽

Β Cells ◽

Pancreatic Β Cells

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Substance P preserves pancreatic β-cells in type 1 and type 2 diabetic mice

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2018.04.028 ◽

2018 ◽

Vol 499 (4) ◽

pp. 960-966 ◽

Cited By ~ 2

Author(s):

Jihyun Um ◽

Nunggum Jung ◽

Dongjin Kim ◽

Sanghyuk Choi ◽

Sang-Ho Lee ◽

...

Keyword(s):

Substance P ◽

Diabetic Mice ◽

Β Cells ◽

Pancreatic Β Cells ◽

Type 2 Diabetic

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Nonlinear Analysis for a Type-1 Diabetes Model with Focus on T-Cells and Pancreatic β-Cells Behavior

Mathematical and Computational Applications ◽

10.3390/mca25020023 ◽

2020 ◽

Vol 25 (2) ◽

pp. 23

Author(s):

Diana Gamboa ◽

Carlos E. Vázquez ◽

Paul J. Campos

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Cell Population ◽

Closed Loop ◽

Pancreatic Β Cell ◽

Activated Macrophages ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells

Type-1 diabetes mellitus (T1DM) is an autoimmune disease that has an impact on mortality due to the destruction of insulin-producing pancreatic β -cells in the islets of Langerhans. Over the past few years, the interest in analyzing this type of disease, either in a biological or mathematical sense, has relied on the search for a treatment that guarantees full control of glucose levels. Mathematical models inspired by natural phenomena, are proposed under the prey–predator scheme. T1DM fits in this scheme due to the complicated relationship between pancreatic β -cell population growth and leukocyte population growth via the immune response. In this scenario, β -cells represent the prey, and leukocytes the predator. This paper studies the global dynamics of T1DM reported by Magombedze et al. in 2010. This model describes the interaction of resting macrophages, activated macrophages, antigen cells, autolytic T-cells, and β -cells. Therefore, the localization of compact invariant sets is applied to provide a bounded positive invariant domain in which one can ensure that once the dynamics of the T1DM enter into this domain, they will remain bounded with a maximum and minimum value. Furthermore, we analyzed this model in a closed-loop scenario based on nonlinear control theory, and proposed bases for possible control inputs, complementing the model with them. These entries are based on the existing relationship between cell–cell interaction and the role that they play in the unchaining of a diabetic condition. The closed-loop analysis aims to give a deeper understanding of the impact of autolytic T-cells and the nature of the β -cell population interaction with the innate immune system response. This analysis strengthens the proposal, providing a system free of this illness—that is, a condition wherein the pancreatic β -cell population holds and there are no antigen cells labeled by the activated macrophages.

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Dextran Sulfate Protects Pancreatic β-Cells, Reduces Autoimmunity, and Ameliorates Type 1 Diabetes

Diabetes ◽

10.2337/db19-0725 ◽

2020 ◽

Vol 69 (8) ◽

pp. 1692-1707

Author(s):

Geming Lu ◽

Francisco Rausell-Palamos ◽

Jiamin Zhang ◽

Zihan Zheng ◽

Tuo Zhang ◽

...

Keyword(s):

Type 1 Diabetes ◽

Dextran Sulfate ◽

Β Cells ◽

Pancreatic Β Cells

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Bile acid-polymer-probucol microparticles: protective effect on pancreatic β-cells and decrease in type 1 diabetes development in a murine model

Pharmaceutical Development and Technology ◽

10.1080/10837450.2019.1665069 ◽

2019 ◽

Vol 24 (10) ◽

pp. 1272-1277 ◽

Cited By ~ 1

Author(s):

Armin Mooranian ◽

Nassim Zamani ◽

Giuseppe Luna ◽

Hesham Al-Sallami ◽

Momir Mikov ◽

...

Keyword(s):

Type 1 Diabetes ◽

Bile Acid ◽

Protective Effect ◽

Murine Model ◽

Β Cells ◽

Pancreatic Β Cells ◽

Diabetes Development

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Treatment with Mammalian Ste-20-like Kinase 1/2 (MST1/2) Inhibitor XMU-MP-1 Improves Glucose Tolerance in Streptozotocin-Induced Diabetes Mice

Molecules ◽

10.3390/molecules25194381 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4381

Author(s):

Zakiyatul Faizah ◽

Bella Amanda ◽

Faisal Yusuf Ashari ◽

Efta Triastuti ◽

Rebecca Oxtoby ◽

...

Keyword(s):

Diabetes Mellitus ◽

Glucose Tolerance ◽

Diabetic Mice ◽

Β Cells ◽

Pancreatic Β Cells ◽

In Vivo Models ◽

Type 2 Dm ◽

Type 1 Dm

Diabetes mellitus (DM) is one of the major causes of death in the world. There are two types of DM—type 1 DM and type 2 DM. Type 1 DM can only be treated by insulin injection whereas type 2 DM is commonly treated using anti-hyperglycemic agents. Despite its effectiveness in controlling blood glucose level, this therapeutic approach is not able to reduce the decline in the number of functional pancreatic β cells. MST1 is a strong pro-apoptotic kinase that is expressed in pancreatic β cells. It induces β cell death and impairs insulin secretion. Recently, a potent and specific inhibitor for MST1, called XMU-MP-1, was identified and characterized. We hypothesized that treatment with XMU-MP-1 would produce beneficial effects by improving the survival and function of the pancreatic β cells. We used INS-1 cells and STZ-induced diabetic mice as in vitro and in vivo models to test the effect of XMU-MP-1 treatment. We found that XMU-MP-1 inhibited MST1/2 activity in INS-1 cells. Moreover, treatment with XMU-MP-1 produced a beneficial effect in improving glucose tolerance in the STZ-induced diabetic mouse model. Histological analysis indicated that XMU-MP-1 increased the number of pancreatic β cells and enhanced Langerhans islet area in the severe diabetic mice. Overall, this study showed that MST1 could become a promising therapeutic target for diabetes mellitus.

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