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

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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Potential Mimicry of Viral and Pancreatic β Cell Antigens Through Non-Spliced and cis-Spliced Zwitter Epitope Candidates in Type 1 Diabetes

Frontiers in Immunology ◽

10.3389/fimmu.2021.656451 ◽

2021 ◽

Vol 12 ◽

Author(s):

Michele Mishto ◽

Artem Mansurkhodzhaev ◽

Teresa Rodriguez-Calvo ◽

Juliane Liepe

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Viral Infections ◽

Hla Class I ◽

Class I ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells

Increasing evidence suggests that post-translational peptide splicing can play a role in the immune response under pathological conditions. This seems to be particularly relevant in Type 1 Diabetes (T1D) since post-translationally spliced epitopes derived from T1D-associated antigens have been identified among those peptides bound to Human Leucocyte Antigen (HLA) class I and II complexes. Their immunogenicity has been confirmed through CD4+ and CD8+ T cell-mediated responses in T1D patients. Spliced peptides theoretically have a large sequence variability. This might increase the frequency of viral-human zwitter peptides, i.e. peptides that share a complete sequence homology irrespective of whether they originate from human or viral antigens, thereby impinging upon the discrimination between self and non-self antigens by T cells. This might increase the risk of autoimmune responses triggered by viral infections. Since enteroviruses and other viral infections have historically been associated with T1D, we investigated whether cis-spliced peptides derived from selected viruses might be able to trigger CD8+ T cell-mediated autoimmunity. We computed in silico viral-human non-spliced and cis-spliced zwitter epitope candidates, and prioritized peptide candidates based on: (i) their binding affinity to HLA class I complexes, (ii) human pancreatic β cell and medullary thymic epithelial cell (mTEC) antigens’ mRNA expression, (iii) antigen association with T1D, and (iv) potential hotspot regions in those antigens. Neglecting potential T cell receptor (TCR) degeneracy, no viral-human zwitter non-spliced peptide was found to be an optimal candidate to trigger a virus-induced CD8+ T cell response against human pancreatic β cells. Conversely, we identified some zwitter peptide candidates, which may be produced by proteasome-catalyzed peptide splicing, and might increase the likelihood of pancreatic β cells recognition by virus-specific CD8+ T cell clones, therefore promoting β cell destruction in the context of viral infections.

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

10.2337/figshare.12245363.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Geming Lu ◽

Francisco Rausell-Palamos ◽

Jiamin Zhang ◽

Zihan Zheng ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Heparan Sulfate ◽

Dextran Sulfate ◽

Nod Mice ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells

A failure in self-tolerance leads to autoimmune destruction of pancreatic β-cells and type 1 diabetes (T1D). Low molecular weight dextran sulfate (DS) is a sulfated semi-synthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties in vitro. However, whether DS can protect pancreatic β-cells, reduce autoimmunity and ameliorate T1D is unknown. Here we report that DS, but not dextran, protects human β-cells against cytokine-mediated cytotoxicity in vitro. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a pro-inflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in pre-diabetic non-obese diabetic (NOD) mice, and most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG) expression and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory co-stimulatory molecule programmed death-1 (PD-1) in T-cells, reduces interferon-γ+ CD4+ and CD8+ T-cells and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on β-cell protection, extracellular matrix preservation and immunomodulation can reverse diabetes in NOD mice highlighting its therapeutic potential for the treatment of T1D.

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

10.2337/figshare.12245363 ◽

2020 ◽

Author(s):

Ada Admin ◽

Geming Lu ◽

Francisco Rausell-Palamos ◽

Jiamin Zhang ◽

Zihan Zheng ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Heparan Sulfate ◽

Dextran Sulfate ◽

Nod Mice ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells

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Expression of the B7.1 Costimulatory Molecule on Pancreatic β Cells Abrogates the Requirement for CD4 T Cells in the Development of Type 1 Diabetes

The Journal of Immunology ◽

10.4049/jimmunol.173.2.787 ◽

2004 ◽

Vol 173 (2) ◽

pp. 787-796 ◽

Cited By ~ 12

Author(s):

Evis Havari ◽

Ana Maria Lennon-Dumenil ◽

Ludger Klein ◽

Devon Neely ◽

Jacqueline A. Taylor ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Cd4 T Cells ◽

Costimulatory Molecule ◽

Β Cells ◽

Pancreatic Β Cells

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Type 1 Diabetic Serum Interferes with Pancreatic β-cell Ca2+ -Handling

Bioscience Reports ◽

10.1007/s10540-007-9055-y ◽

2007 ◽

Vol 27 (6) ◽

pp. 321-326 ◽

Cited By ~ 2

Author(s):

N. Dekki ◽

R. Nilsson ◽

S. Norgren ◽

S. M. Rössner ◽

I. Appelskog ◽

...

Keyword(s):

Type 1 Diabetes ◽

Ethnic Background ◽

Diabetic Patients ◽

Pancreatic Β Cell ◽

Newly Diagnosed ◽

Β Cells ◽

Β Cell ◽

First Degree Relatives ◽

Type 1 Diabetic Patients

The aim of this study was to clarify the frequency of patients with type 1 diabetes that have serum that increases pancreatic β-cell cytoplasmic free Ca2+ concentration, [Ca2+]i, and if such an effect is also present in serum from first-degree relatives. We also studied a possible link between the serum effect and ethnic background as well as presence of autoantibodies. Sera obtained from three different countries were investigated as follows: 82 Swedish Caucasians with newly diagnosed type 1 diabetes, 56 Americans with different duration of type 1 diabetes, 117 American first-degree relatives of type 1 diabetic patients with a mixed ethnic background and 31 Caucasian Finnish children with newly diagnosed type 1 diabetes. Changes in [Ca2+]i, upon depolarization, were measured in β-cells incubated overnight with sera from type 1 diabetic patients, first-degree relatives or healthy controls. Our data show that there is a group constituting approximately 30% of type 1 diabetic patients of different gender, age, ethnic background and duration of the disease, as well as first-degree relatives of type 1 diabetic patients, that have sera that interfere with pancreatic β-cell Ca2+-handling. This effect on β-cell [Ca2+]i could not be correlated to the presence of autoantibodies. In a defined subgroup of patients with type 1 diabetes and first-degree relatives a defect Ca2+-handling may aggravate development of β-cell destruction.

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Immune interventions to preserve β cell function in type 1 diabetes

Journal of Investigative Medicine ◽

10.1097/jim.0000000000000227 ◽

2016 ◽

Vol 64 (1) ◽

pp. 7-13 ◽

Cited By ~ 11

Author(s):

Mario R Ehlers

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Regulatory T Cells ◽

Immune Modulation ◽

Cell Function ◽

Cell Mass ◽

Β Cells ◽

Β Cell

Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to destruction of pancreatic β cells, lifelong dependence on insulin, and increased morbidity and mortality from diabetes-related complications. Preservation of residual β cells at diagnosis is a major goal because higher levels of endogenous insulin secretion are associated with better short- and long-term outcomes. For the past 3 decades, a variety of immune interventions have been evaluated in the setting of new-onset T1D, including nonspecific immunosuppression, pathway-specific immune modulation, antigen-specific therapies, and cellular therapies. To date, no single intervention has produced durable remission off therapy in most treated patients, but the field has gained valuable insights into disease mechanisms and potential immunologic correlates of success. In particular, T-cell–directed therapies, including therapies that lead to partial depletion or modulation of effector T cells and preservation or augmentation of regulatory T cells, have shown the most success and will likely form the backbone of future approaches. The next phase will see evaluation of rational combinations, comprising one or more of the following: an effector T-depleting or -modulating drug, a cytokine-based tolerogenic (regulatory T-cells–promoting) agent, and an antigen-specific component. The long term goal is to reestablish immunologic tolerance to β cells, thereby preserving residual β cells early after diagnosis or enabling restoration of β-cell mass from autologous stem cells or induced neogenesis in patients with established T1D.

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Effective Destruction of Fas-deficient Insulin-producing β Cells in Type 1 Diabetes

Journal of Experimental Medicine ◽

10.1084/jem.20030698 ◽

2003 ◽

Vol 198 (7) ◽

pp. 1103-1106 ◽

Cited By ~ 52

Author(s):

Irina Apostolou ◽

Zhenyue Hao ◽

Klaus Rajewsky ◽

Harald von Boehmer

Keyword(s):

T Cells ◽

Cell Death ◽

Type 1 Diabetes ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Β Cells ◽

Β Cell ◽

Influenza Hemagglutinin ◽

Insulin Promoter

In type 1 diabetes, autoimmune T cells cause destruction of pancreatic β cells by largely unknown mechanism. Previous analyses have shown that β cell destruction is delayed but can occur in perforin-deficient nonobese diabetic (NOD) mice and that Fas-deficient NOD mice do not develop diabetes. However, because of possible pleiotropic functions of Fas, it was not clear whether the Fas receptor was an essential mediator of β cell death in type 1 diabetes. To directly test this hypothesis, we have generated a β cell–specific knockout of the Fas gene in a transgenic model of type 1 autoimmune diabetes in which CD4+ T cells with a transgenic TCR specific for influenza hemagglutinin (HA) are causing diabetes in mice that express HA under control of the rat insulin promoter. Here we show that the Fas-deficient mice develop autoimmune diabetes with slightly accelerated kinetics indicating that Fas-dependent apoptosis of β cells is a dispensable mode of cell death in this disease.

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Inhibition of the Keap1/Nrf2 Signaling Pathway Significantly Promotes the Progression of Type 1 Diabetes Mellitus

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/7866720 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Yanmei Lou ◽

Muyan Kong ◽

Leyan Li ◽

Yu Hu ◽

Wenjun Zhai ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathway ◽

Cell Damage ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Min6 Cells ◽

Nrf2 Signaling Pathway

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insulin deficiency due to pancreatic β-cell damage and leads to hyperglycemia. The precise molecular mechanisms of the etiology of T1DM are not completely understood. Oxidative stress and the antioxidant status of pancreatic β-cells play a vital role in the pathogenesis and progression of T1DM. The Keap1/Nrf2 signaling pathway plays a critical role in cellular resistance to oxidative stress. This study is aimed at investigating the role of the Keap1/Nrf2 signaling pathway in the progression of T1DM. An alloxan- (ALX-) stimulated T1DM animal model in wild-type (WT) and Nrf2 knockout (Nrf2-/-) C57BL/6J mice and a mouse pancreatic β-cell line (MIN6) were established. Compared with the tolerant (ALX exposure, nondiabetic) WT mice, the sensitive (ALX exposure, diabetic) WT mice exhibited higher blood glucose levels and lower plasma insulin levels. The Keap1/Nrf2 signaling pathway was significantly inhibited in the sensitive WT mice, which was reflected by overexpression of Keap1 and low expression of Nrf2, accompanied by a marked decrease in the expression of the antioxidative enzymes. Compared with WT mice, the Nrf2-/- mice had an increased incidence of T1DM and exhibited more severe pancreatic β-cell damage. The results of in vitro experiments showed that ALX significantly inhibited the viability and proliferation and promoted the apoptosis of MIN6 cells. ALX also markedly increased intracellular ROS production and caused DNA damage in MIN6 cells. In addition, the Keap1/Nrf2 signaling pathway was significantly inhibited in the damaged MIN6 cells. Moreover, Nrf2 silencing by transfection with Nrf2 siRNA markedly exacerbated ALX-induced MIN6 cell injury. Conclusively, this study demonstrates that inhibition of the Keap1/Nrf2 signaling pathway could significantly promote the incidence of T1DM. This study indicates that activation of Keap1/Nrf2 signaling in pancreatic β-cells may be a useful pharmacological strategy for the clinical prevention and treatment of T1DM.

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Generation of Pancreatic β-cells From iPSCs and their Potential for Type 1 Diabetes Mellitus Replacement Therapy and Modelling

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-0661-5873 ◽

2018 ◽

Vol 128 (05) ◽

pp. 339-346 ◽

Cited By ~ 1

Author(s):

Maria Csobonyeiova ◽

Stefan Polak ◽

Lubos Danisovic

Keyword(s):

Type 1 Diabetes ◽

Blood Glucose ◽

Replacement Therapy ◽

Cell Physiology ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

High Blood Glucose ◽

Cell Based Therapy

AbstractDiabetes type 1 (T1D) is a common autoimmune disease characterized by permanent destruction of the insulin-secreting β-cells in pancreatic islets, resulting in a deficiency of the glucose-lowering hormone insulin and persisting high blood glucose levels. Insulin has to be replaced by regular subcutaneous injections, and blood glucose level must be monitored due to the risk of hyperglycemia. Recently, transplantation of new pancreatic β-cells into T1D patients has come to be considered one of the most potentially effective treatments for this disease. Therefore, much effort has focused on understanding the regulation of β-cells. Induced pluripotent stem cells (iPSCs) represent a valuable source for T1D modelling and cell replacement therapy because of their ability to differentiate into all cell types in vitro. Recent advances in stem cell-based therapy and gene-editing tools have enabled the generation of functionally adult pancreatic β-cells derived from iPSCs. Although animal and human pancreatic development and β-cell physiology have significant differences, animal models represent an important tool in evaluating the therapeutic potential of iPSC-derived β-cells on type 1 diabetes treatment. This review outlines the recent progress in iPSC-derived β-cell differentiation methods, disease modelling, and future perspectives.

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Peptides derived from insulin granule proteins are targeted by CD8+ T cells across MHC Class I restrictions in humans and NOD mice

10.2337/figshare.12899315 ◽

2020 ◽

Author(s):

Ada Admin ◽

Marie Eliane Azoury ◽

Mahmoud Tarayrah ◽

Georgia Afonso ◽

Aurore Pais ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Nod Mice ◽

Class I ◽

Β Cells ◽

Β Cell ◽

Urocortin 3 ◽

Insulin Granule ◽

Granule Proteins

The antigenic peptides processed by β cells and presented through surface HLA Class I molecules are poorly characterized. Each HLA variant, e.g. the most common HLA-A2 and HLA-A3, carries some peptide-binding specificity. Hence, features that, despite these specificities, remain shared across variants may reveal factors favoring β-cell immunogenicity. Building on our previous description of the HLA-A2/A3 peptidome of β cells, we analyzed the HLA-A3-restricted peptides targeted by circulating CD8+ T cells. Several peptides were recognized by CD8+ T cells within a narrow frequency (1-50/106), which was similar in donors with and without type 1 diabetes and harbored variable effector/memory fractions. These epitopes could be classified as conventional peptides or neo-epitopes, generated either via peptide cis-splicing or mRNA splicing, e.g. secretogranin-5 (SCG5)-009. As reported for HLA-A2-restricted peptides, several epitopes originated from β-cell granule proteins, e.g. SCG3, SCG5 and urocortin-3. Similarly, H-2Kd-restricted CD8+ T cells recognizing the murine orthologues of SCG5, urocortin-3, and proconvertase-2 infiltrated the islets of NOD mice and transferred diabetes into NOD/scid recipients. The finding of granule proteins targeted in both humans and NOD mice supports their disease relevance and identifies the insulin granule as a rich source of epitopes, possibly reflecting its impaired processing in type 1 diabetes.

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