Substance P preserves pancreatic β-cells in streptozotocin-induced type 1 diabetic mice

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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A Novel Resolution of Diabetes: C-C Chemokine Motif Ligand 4 Is a Common Target in Different Types of Diabetes by Protecting Pancreatic Islet Cell and Modulating Inflammation

Frontiers in Immunology ◽

10.3389/fimmu.2021.650626 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ting-Ting Chang ◽

Liang-Yu Lin ◽

Jaw-Wen Chen

Keyword(s):

Insulin Resistance ◽

Blood Sugar ◽

Islet Cell ◽

Diabetic Mice ◽

Β Cells ◽

Pancreatic Β Cells ◽

Type 2 Dm ◽

Tnf Α

Systemic inflammation is related to hyperglycemia in diabetes mellitus (DM). C-C chemokine motif ligand (CCL) 4 is upregulated in type 1 & type 2 DM patients. This study aimed to investigate if CCL4 could be a potential target to improve blood sugar control in different experimental DM models. Streptozotocin-induced diabetic mice, Leprdb/JNarl diabetic mice, and C57BL/6 mice fed a high fat diet were used as the type 1 DM, type 2 DM, and metabolic syndrome model individually. Mice were randomly assigned to receive an anti-CCL4 neutralizing monoclonal antibody. The pancreatic β-cells were treated with streptozotocin for in vitro experiments. In streptozotocin-induced diabetic mice, inhibition of CCL4 controlled blood sugar, increased serum insulin levels, increased islet cell proliferation and decreased pancreatic interleukin (IL)-6 expression. In the type 2 diabetes and metabolic syndrome models, CCL4 inhibition retarded the progression of hyperglycemia, reduced serum tumor necrosis factor (TNF)-α and IL-6 levels, and improved insulin resistance via reducing the phosphorylation of insulin receptor substrate-1 in skeletal muscle and liver tissues. CCL4 inhibition directly protected pancreatic β-cells from streptozotocin stimulation. Furthermore, CCL4-induced IL-6 and TNF-α expressions could be abolished by siRNA of CCR2/CCR5. In summary, direct inhibition of CCL4 protected pancreatic islet cells, improved insulin resistance and retarded the progression of hyperglycemia in different experimental models, suggesting the critical role of CCL4-related inflammation in the progression of DM. Future experiments may investigate if CCL4 could be a potential target for blood sugar control in clinical DM.

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

Microorganisms ◽

10.3390/microorganisms9061125 ◽

2021 ◽

Vol 9 (6) ◽

pp. 1125

Author(s):

Magloire Pandoua Nekoua ◽

Antoine Bertin ◽

Famara Sane ◽

Jean-Pascal Gimeno ◽

Isabelle Fournier ◽

...

Keyword(s):

Cell Cultures ◽

Β Cells ◽

Pancreatic Β Cells ◽

Gene Expressions ◽

Insulin Metabolism ◽

Pancreatic Cell ◽

Persistently Infected ◽

Coxsackievirus B4 ◽

Or Gene

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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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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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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