scholarly journals Tolerogenic insulin peptide therapy precipitates type 1 diabetes

2017 ◽  
Vol 214 (7) ◽  
pp. 2153-2156 ◽  
Author(s):  
Marie-Louise Bergman ◽  
Thiago Lopes-Carvalho ◽  
Ana-Catarina Martins ◽  
Fabio A. Grieco ◽  
Décio L. Eizirik ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Disease Onset ◽  
Osmotic Pump ◽  
Preventive Effect ◽  
Peptide Therapy ◽  
Pump Delivery

Daniel et al. (https://doi.org/10.1084/jem.20110574) have previously published in JEM a study on the preventive effect of tolerogenic vaccination with a strong agonist insulin mimetope in type 1 diabetes. Our study now challenges these results and shows that osmotic pump delivery of the modified insulin peptide R22E did not prevent hyperglycemia, accelerated disease onset, increased its incidence, and worsened insulitis.

scholarly journals Reply to “Tolerogenic insulin peptide therapy precipitates type 1 diabetes”

2017 ◽  
Vol 214 (7) ◽  
pp. 2157-2159
Author(s):  
Carolin Daniel ◽  
Benno Weigmann ◽  
Harald von Boehmer
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Regulatory T Cell ◽  
Preventive Effect ◽  
Peptide Therapy ◽  
Cell Conversion

In this issue of JEM, Bergman et al. (https://doi.org/10.1084/jem.20160471) challenge the data published in our previous JEM paper on the preventive effect of tolerogenic vaccination with a strong agonist insulin mimetope in type 1 diabetes. Here, we provide a response to these data and suggest that appropriate subimmunogenic conditions are required to induce Foxp3+ regulatory T cell conversion.

scholarly journals Clinical and demographic features among patients with type 1 diabetes mellitus in Henan, China

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Liguo Yang ◽  
Guangxing Yang ◽  
Xialian Li
Keyword(s):  
Type 1 Diabetes ◽  
Diabetic Retinopathy ◽  
Blood Glucose Control ◽  
Disease Onset ◽  
Overweight And Obesity ◽  
Adult Onset ◽  
C Peptide ◽  
Young Onset ◽  
Onset Group

Abstract Background The hallmark of type 1 diabetes (T1D) is an absolute lack of insulin. However, many studies showed a tendency to heterogeneity in TID. We aimed to investigate the demographic and clinical characteristics in T1D and the differences in young-onset and adult-onset patients. Methods This retrospective study was conducted among 1943 patients with clinically diagnosed T1D. Medical records on patients’ demographics, anthropometric measurements, and clinical manifestation were collected. According to the age at onset, the newly diagnosed patients were divided into the young-onset group (< 18 years, 234 patients, mean age 11 years) and adult-onset group (≥ 18 years, 219 patients, mean age 27 years). Pancreatic β-cell function was assessed by fasting C-peptide (FCP) and 2-h C-peptide (2-h CP). Results The median age of patients at disease onset was 22 years. The median duration of patients was 3 years. The overall median glycated hemoglobin (HbA1c) value was 10.3 % [89(mmol/mol)]. The prevalence of diabetic retinopathy was 25.1 %. The overall rate of DKA at onset in the new-onset patients was 59.6 %. The frequency of overall dyslipidemia was 37.8 %. The most frequent dyslipidemia was low high-density lipoprotein-cholesterol (HDL) (29 %). The proportion of patients with anti-glutamic acid decarboxylase (GADA), insulin antibody (IAA) and islet cell antibody (ICA) were 28.1 %, 6.4 % and 21.6 %, respectively. The mean HbA1c showed a downward trend with age. Increasing or decreasing trends of overweight and obesity in this population during the period 2012 to 2018 was not found. Compared with young-onset T1D, adult-onset patients comprised better islet function (FCP: 0.4 vs. 0.3 ng/ml, P < 0.001; 2-h CP: 0.9 vs. 0.7 ng/ml P < 0.001, respectively) and glycemic control [12.9 % (117mmol/mol) vs. 11.7 % (104mmol/mol), P < 0.001], higher prevalence of diabetes condition in the male gender (64.4 % vs. 51.3 %, P = 0.006), higher proportion of obesity or overweight (24.6 % vs. 9.5 %, P = 0.002), higher frequency of GADA (33.7 % vs. 23.3 %, P = 0.025), and lower frequency of diabetic ketoacidosis at disease onset (64.5 % vs. 43.5 %, P < 0.001). Conclusions This population was characterized by poor overall blood glucose control, high prevalence of DKA, dyslipidemia and diabetic retinopathy, and low prevalence of islet-related antibodies, and overweight or obesity. Adult-onset patients with T1D were not uncommon and had better clinical manifestations than young-onset patients. Any findings related to body mass index (BMI) and autoantibodies should be considered strictly exploratory due to excessive missing data.

scholarly journals Gender-Specific Risk Factors for the Development of Retinal Changes in Children with Type 1 Diabetes

2021 ◽  
Vol 11 (6) ◽  
pp. 588
Author(s):  
Marta Wysocka-Mincewicz ◽  
Joanna Gołębiewska ◽  
Marta Baszyńska-Wilk ◽  
Andrzej Olechowski
Keyword(s):  
Risk Factors ◽  
Type 1 Diabetes ◽  
Uric Acid ◽  
Serum Creatinine ◽  
Regression Models ◽  
Retinal Thickness ◽  
Disease Onset ◽  
Specific Risk ◽  
Gender Specific

The aim of the study was to determine gender-specific risk factor sets which could influence optical coherence tomography (OCT) results in children with type 1 diabetes (T1D). Material and Methods: 175 children with T1D without symptoms of diabetic retinopathy were enrolled, but 330 eyes were used for the final analysis (168 children, mean age 12.81 ± 3.63 years, diabetes duration 4.59 ± 3.71 years). The multivariate regression models for retinal thickness (foveal FT, and parafoveal PFT) and vascular densities (superficial and deep) were carried out separately for both genders using all metabolic and demographic parameters. Results: In the statistically significant multiple regression models for all analyzed OCT parameters for both genders, pH at the onset of diabetes were in existence, as well as for retinal thickness current HbA1c. Duration of continuous insulin infusion (CSII) was an important factor in all parameters, except PFT. For the girls, the most significant factors were daily insulin dose, uric acid, and triglycerides, but for the boys, it was serum creatinine, systolic pressure, and free thyroxine level. Conclusions: We detected significant risk factors set for development of OCT parameters changes, and they were not identical for both genders. Current metabolic control, diabetic ketoacidosis at the disease onset, serum creatinine and longer use of CSII are the most important factors for retinal thickness and vessel densities in both genders in children with type 1 diabetes. For the girls, elements of metabolic syndrome (uric acid and triglycerides) and parameters of insulin amount were more pronounced.

scholarly journals Neuropsychological Profiles of Children With Type 1 Diabetes 6 Years After Disease Onset

Diabetes Care ◽  
2001 ◽  
Vol 24 (9) ◽  
pp. 1541-1546 ◽  
Author(s):  
E. A. Northam ◽  
P. J. Anderson ◽  
R. Jacobs ◽  
M. Hughes ◽  
G. L Warne ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Disease Onset

scholarly journals Pancreas Volume Declines During the First Year After Diagnosis of Type 1 Diabetes and Exhibits Altered Diffusion at Disease Onset

Diabetes Care ◽  
2018 ◽  
Vol 42 (2) ◽  
pp. 248-257 ◽  
Author(s):  
John Virostko ◽  
Jon Williams ◽  
Melissa Hilmes ◽  
Chris Bowman ◽  
Jordan J. Wright ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Disease Onset ◽  
First Year ◽  
Pancreas Volume

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.

scholarly journals Position β57 of I-Ag7 controls early anti-insulin responses in NOD mice, linking an MHC susceptibility allele to type 1 diabetes onset

2019 ◽  
Vol 4 (38) ◽  
pp. eaaw6329 ◽  
Author(s):  
Louis Gioia ◽  
Marie Holt ◽  
Anne Costanzo ◽  
Siddhartha Sharma ◽  
Brian Abe ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Disease Onset ◽  
Insulin Response ◽  
Nod Mice ◽  
Class Ii ◽  
Single Amino Acid ◽  
Specific Gene ◽  
Single Amino Acid Change

The class II region of the major histocompatibility complex (MHC) locus is the main contributor to the genetic susceptibility to type 1 diabetes (T1D). The loss of an aspartic acid at position 57 of diabetogenic HLA-DQβ chains supports this association; this single amino acid change influences how TCRs recognize peptides in the context of HLA-DQ8 and I-Ag7 using a mechanism termed the P9 switch. Here, we built register-specific insulin peptide MHC tetramers to examine CD4+ T cell responses to Ins12–20 and Ins13–21 peptides during the early prediabetic phase of disease in nonobese diabetic (NOD) mice. A single-cell analysis of anti-insulin CD4+ T cells performed in 6- and 12-week-old NOD mice revealed tissue-specific gene expression signatures. TCR signaling and clonal expansion were found only in the islets of Langerhans and produced either classical TH1 differentiation or an unusual Treg phenotype, independent of TCR usage. The early phase of the anti-insulin response was dominated by T cells specific for Ins12–20, the register that supports a P9 switch mode of recognition. The presence of the P9 switch was demonstrated by TCR sequencing, reexpression, mutagenesis, and functional testing of TCRαβ pairs in vitro. Genetic correction of the I-Aβ57 mutation in NOD mice resulted in the disappearance of D/E residues in the CDR3β of anti-Ins12–20 T cells. These results provide a mechanistic molecular explanation that links the characteristic MHC class II polymorphism of T1D with the recognition of islet autoantigens and disease onset.

scholarly journals Human Leukocyte Antigen (HLA) and Islet Autoantibodies Are Tools to Characterize Type 1 Diabetes in Arab Countries: Emphasis on Kuwait

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Mohamed Jahromi ◽  
Ebaa Al-Ozairi
Keyword(s):  
Type 1 Diabetes ◽  
Human Leukocyte Antigen ◽  
Incidence Rate ◽  
Disease Onset ◽  
Human Leukocyte ◽  
Arab Countries ◽  
World Health ◽  
Leukocyte Antigen ◽  
Prospective Longitudinal

The incidence rate of type 1 diabetes in Kuwait had been increasing exponentially and has doubled in children≤14 years old within almost two decades. Therefore, there is a dire need for a careful systematic familial cohort study. Several immunogenetic factors affect the pathogenesis of the disease. The human leukocyte antigen (HLA) accounts for the major genetic susceptibility to the disease. The triggering agents initiate disease onset by type 1 destruction of pancreatic β-cells. Both HLA and anti-islet antibodies can be used to characterize, predict susceptibility to the disease, innovate, or delay the β-cell destruction. Evidence from prospective longitudinal studies suggested that the underlying disease process represents a continuum that begins before the symptoms are clinically evident. Autoimmunity of the functional pancreatic β-cells results in symptomatic type 1 diabetes and lifelong insulin dependence. The autoantibodies against glutamic acid decarboxylase (GADA), insulinoma antigen-2 (IA-2A), insulin (IAA), and zinc transporter-8 (ZnT-8A) comprise the most reliable biomarkers for type 1 diabetes in both children and adults. Although Kuwait is the second among the top 10 countries with a high incidence rate of type 1 diabetes, there have been no proper diagnostic and prediction tools as per the World Health Organization. The Kuwaiti Type 1 Diabetes Study (KADS) was initiated to understand the disease pathogenesis as well as the HLA and anti-islet autoantibody profile of type 1 diabetes in Kuwait. Understanding the disease sequela in a homogenous gene pool and highly consanguineous population of Kuwaitis could help solve the challenges and pathogenesis, as well as hasten the prevention, of type 1 diabetes.

scholarly journals Blood Co-Circulating Extracellular microRNAs and Immune Cell Subsets Associate with Type 1 Diabetes Severity

2020 ◽  
Vol 21 (2) ◽  
pp. 477 ◽  
Author(s):  
Silvia Garavelli ◽  
Sara Bruzzaniti ◽  
Elena Tagliabue ◽  
Francesco Prattichizzo ◽  
Dario Di Silvestre ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune Cell ◽  
Disease Onset ◽  
Cell Subset ◽  
Healthy Controls ◽  
Cell Frequency ◽  
Logistic Regression Models ◽  
Immune Cell Subsets ◽  
Diabetes Severity

Immune cell subsets and microRNAs have been independently proposed as type 1 diabetes (T1D) diagnostic and/or prognostic biomarkers. Here, we aimed to analyze the relationships between peripheral blood circulating immune cell subsets, plasmatic microRNAs, and T1D. Blood samples were obtained from both children with T1D at diagnosis and age-sex matched healthy controls. Then, immunophenotype assessed by flow cytometry was coupled with the quantification of 60 plasmatic microRNAs by quantitative RT-PCR. The associations between immune cell frequency, plasmatic microRNAs, and the parameters of pancreatic loss, glycemic control, and diabetic ketoacidosis were assessed by logistic regression models and correlation analyses. We found that the increase in specific plasmatic microRNAs was associated with T1D disease onset (let-7c-5p, let-7d-5p, let-7f-5p, let-7i-5p, miR-146a-5p, miR-423-3p, and miR-423-5p), serum C-peptide concentration (miR-142-5p and miR-29c-3p), glycated hemoglobin (miR-26a-5p and miR-223-3p) and the presence of ketoacidosis (miR-29c-3p) more strongly than the evaluated immune cell subset frequency. Some of these plasmatic microRNAs were shown to positively correlate with numbers of blood circulating B lymphocytes (miR-142-5p) and CD4+CD45RO+ (miR-146a-5p and miR-223-3p) and CD4+CD25+ cells (miR-423-3p and miR-223-3p) in children with T1D but not in healthy controls, suggesting a disease-specific microRNA association with immune dysregulation in T1D. In conclusion, our results suggest that, while blood co-circulating extracellular microRNAs and immune cell subsets may be biologically linked, microRNAs may better provide powerful information about T1D onset and severity.

scholarly journals Children with type 1 diabetes of early age at onset – immune and metabolic phenotypes

2019 ◽  
Vol 32 (9) ◽  
pp. 935-941
Author(s):  
Madalena Sales Luis ◽  
Margarida Alcafache ◽  
Sara Ferreira ◽  
Ana Laura Fitas ◽  
Joana Simões Pereira ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Age At Onset ◽  
Disease Onset ◽  
Inverse Correlation ◽  
Early Age ◽  
Insulin Requirements ◽  
Age Related ◽  
One Year ◽  
Immune Imbalance

Abstract Objectives We aimed to evaluate children with type 1 diabetes (T1D) with early age at onset (EAO) for clinical, immune and metabolic features in order to identify age-related disease phenotypes. Methods Comparative study of two groups of T1D children: EAO (≤5 years) and later age at onset (LAO; >5 years), regarding the presence of other autoimmune (AI) diseases, diabetes ketoacidosis and immunologic profile at onset and metabolic data 1 year after diagnosis. Statistical analysis was performed with significance set for p < 0.05. Results The study included 137 children (EAO = 52, mean age 3.6 ± 1.5 [mean ± standard deviation (SD)] and LAO = 85, mean age 10.4 ± 2.9). EAO was more associated with concomitant AI diseases (p = 0.032). Despite no differences in disease onset, EAO presented with lower C-peptide levels (p = 0.01) and higher absolute lymphocyte number (p < 0.0001), with an inverse correlation between these two variables (p = 0.028). Additionally, the EAO group had a higher frequency of serum detection of three antibodies (Abs) (p = 0.0008), specifically insulin Abs (p = 0.0001). One year after diagnosis, EAO had higher total daily insulin (TDI) dose (p = 0.008), despite similar hemoglobin A1c (HbA1c). Conclusions Our data show an association of EAO T1D with more AI diseases, higher number of Abs, lower initial insulin reservoir and higher insulin requirements 1 year after diagnosis. In this group, immune imbalance seems more evident and disease progression faster, probably reflecting distinct “immune environment” with different ages at disease onset. Further studies in the field of immunogenetics and immune tolerance are required, to improve patient stratification and find novel targets for therapeutic intervention.

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