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

2007 ◽  
Vol 27 (6) ◽  
pp. 321-326 ◽  
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.

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

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.

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

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.

scholarly journals Markers for Risk of Type 1 Diabetes in Relatives of Alsacian Patients With Type 1 Diabetes

2002 ◽  
Vol 3 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Jean Claude Ongagna ◽  
Remi Sapin ◽  
Michel Pinget ◽  
Alain Belcourt
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Receptor Protein ◽  
Diabetic Patients ◽  
Control Subjects ◽  
First Degree Relatives ◽  
Hla Dq ◽  
Increased Risk ◽  
Type 1 Diabetic Patients

Background: The cytotoxic T lymphocyteassociated antigen 4 gene (CTLA-4) encode the T cell receptor involved in the control of T cell proliferation and mediates T cell apoptosis. The receptor protein is a specific T lymphocyte surface antigen that is detected on cells only after antigen presentation. Thus, CTLA-4 is directly involved in both immune and autoimmune responses and may be involved in the pathogenesis of multiple T cell-mediated autoimmune disorders. There is polymorphism at position 49 in exon 1 of the CTLA-4 gene, providing an A-G exchange. Moreover, we assessed the CTLA-4 49 (Thr/Ala) polymorphism in diabetic patients and first-degree relatives as compared to control subjects.Research design and methods: Three loci (HLA-DQB1, DQA1 and CTLA-4) were analysed in 62 type 1 diabetic patients, 72 firstdegree relatives and 84 nondiabetic control subjects by means of PCR-RFLP.Results: A significant enrichment in DQB1 alleles encoding for an amino acid different from Asp in position 57 (NA) and DQA1 alleles encoding for Arg in position 52 was observed in diabetic subjects and first-degree relatives as compared to controls. The genotype and allele frequencies of these polymorphisms in type 1 diabetic patients and firstdegree relatives differed significantly from those of controls (p< 0.001 and 0.05 respectively). CTLA-49 Ala alleles frequencies were 75.8% in type 1 diabetic patients and 68.1% in first-degree relatives in comparison to 35.7% in control subjects. The Ala/Ala genotype conferred a relative risk of 18.8 (p < 0.001).Conclusion: The CTLA-4 49 Ala allele confers an increased risk of type 1 diabetes, independent of age and HLA-DQ genetic markers.

Cardiac responses to insulin-induced hypoglycemia in nondiabetic and intensively treated type 1 diabetic patients

2001 ◽  
Vol 281 (5) ◽  
pp. E1029-E1036 ◽  
Author(s):  
Raymond R. Russell ◽  
Deborah Chyun ◽  
Steven Song ◽  
Robert S. Sherwin ◽  
William V. Tamborlane ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Radionuclide Angiography ◽  
Left Ventricular ◽  
Cardiac Response ◽  
Left Ventricular Ejection ◽  
Diabetic Patients ◽  
Plasma Catecholamine ◽  
Ventricular Ejection Fraction ◽  
Type 1 Diabetic Patients

Insulin-induced hypoglycemia occurs commonly in intensively treated patients with type 1 diabetes, but the cardiovascular consequences of hypoglycemia in these patients are not known. We studied left ventricular systolic [left ventricular ejection fraction (LVEF)] and diastolic [peak filling rate (PFR)] function by equilibrium radionuclide angiography during insulin infusion (12 pmol · kg−1 · min−1) under either hypoglycemic (∼2.8 mmol/l) or euglycemic (∼5 mmol/l) conditions in intensively treated patients with type 1 diabetes and healthy nondiabetic subjects ( n = 9 for each). During hypoglycemic hyperinsulinemia, there were significant increases in LVEF (ΔLVEF = 11 ± 2%) and PFR [ΔPFR = 0.88 ± 0.18 end diastolic volume (EDV)/s] in diabetic subjects as well as in the nondiabetic group (ΔLVEF = 13 ± 2%; ΔPFR = 0.79 ± 0.17 EDV/s). The increases in LVEF and PFR were comparable overall but occurred earlier in the nondiabetic group. A blunted increase in plasma catecholamine, cortisol, and glucagon concentrations occurred in response to hypoglycemia in the diabetic subjects. During euglycemic hyperinsulinemia, LVEF also increased in both the diabetic (ΔLVEF = 7 ± 1%) and nondiabetic (ΔLVEF = 4 ± 2%) groups, but PFR increased only in the diabetic group. In the comparison of the responses to hypoglycemic and euglycemic hyperinsulinemia, only the nondiabetic group had greater augmentation of LVEF, PFR, and cardiac output in the hypoglycemic study ( P < 0.05 for each). Thus intensively treated type 1 diabetic patients demonstrate delayed augmentation of ventricular function during moderate insulin-induced hypoglycemia. Although diabetic subjects have a more pronounced cardiac response to hyperinsulinemia per se than nondiabetic subjects, their response to hypoglycemia is blunted.

Use of a systems biology approach to understand pancreatic β-cell death in Type 1 diabetes

2008 ◽  
Vol 36 (3) ◽  
pp. 321-327 ◽  
Author(s):  
Decio L. Eizirik ◽  
Fabrice Moore ◽  
Daisy Flamez ◽  
Fernanda Ortis
Keyword(s):  
Cell Death ◽  
Type 1 Diabetes ◽  
Systems Biology ◽  
Gene Networks ◽  
Nuclear Factor Κb ◽  
Signal Transducer ◽  
Trial And Error ◽  
Β Cells ◽  
Β Cell

Accumulating evidence indicates that β-cells die by apoptosis in T1DM (Type 1 diabetes mellitus). Apoptosis is an active gene-directed process, and recent observations suggest that β-cell apoptosis depends on the parallel and/or sequential up- and down-regulation of hundreds of genes controlled by key transcription factors such as NF-κB (nuclear factor κB) and STAT-1 (signal transducer and activator of transcription 1). Understanding the regulation of these gene networks, and how they modulate β-cell death and the ‘dialogue’ between β-cells and the immune system, will require a systems biology approach to the problem. This will hopefully allow the search for a cure for T1DM to move from a ‘trial-and-error’ approach to one that is really mechanistically driven.

scholarly journals Increased Incidence of Type 1 Diabetes during the COVID-19 Pandemic in Romanian Children

Medicina ◽  
2021 ◽  
Vol 57 (9) ◽  
pp. 973
Author(s):  
Adrian Vlad ◽  
Viorel Serban ◽  
Romulus Timar ◽  
Alexandra Sima ◽  
Veronica Botea ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Background Information ◽  
First Year ◽  
Age Group ◽  
Newly Diagnosed ◽  
Β Cells ◽  
Specific Antibodies ◽  
Autoimmune Destruction ◽  
Geographical Regions

Background and Objective: It is known that several viruses are involved in the pathogenesis of type 1 diabetes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new worldwide spread virus that may act as a trigger for the autoimmune destruction of the β-cells, as well, and thus lead to an increase in the incidence of type 1 diabetes. Material and Methods: The Romanian National Organization for the Protection of Children and Adolescents with Diabetes (ONROCAD) has collected information regarding new cases of type 1 diabetes in children aged 0 to 14 years from all over the country since 1996 and has computed the incidence of type 1 diabetes in this age group. Results: We observed a marked increase in the incidence of type 1 diabetes in the first year of the COVID-19 pandemic, with 16.9%, from 11.4/100,000 in 2019 to 13.3/100,000 in 2020, much higher compared to previous years (mean yearly increase was 5.1% in the period 1996–2015 and 0.8% in the interval 2015–2019). The proportion of newly diagnosed cases was significantly higher in the second half of 2020 compared to the second half of the previous years (57.8 vs. 51%, p < 0.0001). Conclusions: All these aspects suggest the role that SARS-CoV-2 could have in triggering pancreatic autoimmunity. To confirm this, however, collecting information from larger populations from different geographical regions, monitoring the incidence curves over a period of several years, and gathering background information on COVID-19 and/or data on COVID-19 specific antibodies are needed.

scholarly journals The Presence of Thyrogastric Antibodies in First Degree Relatives of Type 1 Diabetic Patients Is Associated with Age and Proband Antibody Status

2001 ◽  
Vol 86 (9) ◽  
pp. 4358-4363 ◽  
Author(s):  
Christophe E. M. De Block ◽  
Ivo H. De Leeuw ◽  
Katelijn Decochez ◽  
Frederic Winnock ◽  
Jan Van Autreve ◽  
...  
Keyword(s):  
Diabetic Patients ◽  
First Degree Relatives ◽  
Type 1 Diabetic Patients

scholarly journals Systemic TNFα correlates with residual β-cell function in children and adolescents newly diagnosed with type 1 diabetes

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Anne Julie Overgaard ◽  
Jens Otto Broby Madsen ◽  
Flemming Pociot ◽  
Jesper Johannesen ◽  
Joachim Størling
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
Disease Onset ◽  
Newly Diagnosed ◽  
Β Cell ◽  
Entire Study ◽  
C Peptide ◽  
Disease Remission ◽  
Β Cell Function

Abstract Background Type 1 diabetes (T1D) is caused by immune-mediated destruction of the β-cells. After initiation of insulin therapy many patients experience a period of improved residual β-cell function leading to partial disease remission. Cytokines are important immune-modulatory molecules and contribute to β-cell damage in T1D. The patterns of systemic circulating cytokines during T1D remission are not clear but may constitute biomarkers of disease status and progression. In this study, we investigated if the plasma levels of various pro- and anti-inflammatory cytokines around time of diagnosis were predictors of remission and residual β-cell function in children with T1D followed for one year after disease onset. Methods In a cohort of 63 newly diagnosed children (33% females) with T1D with a mean age of 11.3 years (3.3–17.7), ten cytokines were measured of which eight were detectable in plasma samples by Mesoscale Discovery multiplex technology at study start and after 6 and 12 months. Linear regression models were used to evaluate association of cytokines with stimulated C-peptide. Results Systemic levels of tumor necrosis factor (TNF)-α, interleukin (IL)-2 and IL-6 inversely correlated with stimulated C-peptide levels over the entire study (P < 0.05). The concentrations of TNFα and IL-10 at study start predicted stimulated C-peptide level at 6 months (P = 0.011 and P = 0.043, respectively, adjusted for sex, age, HbA1c and stage of puberty). Conclusions In recent-onset T1D, systemic cytokine levels, and in particular that of TNFα, correlate with residual β-cell function and may serve as prognostic biomarkers of disease remission and progression to optimize treatment strategies. Trial Registration The study was performed according to the criteria of the Helsinki II Declaration and was approved by the Danish Capital Region Ethics Committee on Biomedical Research Ethics (journal number H-3-2014-052). The parents of all participants gave written consent.

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