scholarly journals Specific type 1 diabetes risk genes underpin age-at-diagnosis and indicate joint defects in immunity, beta-cell fragility and responses to viral infections in early-onset disease

2019 ◽  
Author(s):  
Jamie R.J. Inshaw ◽  
Antony J. Cutler ◽  
Daniel J.M. Crouch ◽  
Linda S. Wicker ◽  
John A. Todd
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Viral Infections ◽  
Multinomial Logistic Regression ◽  
Age At Diagnosis ◽  
Diabetes Diagnosis ◽  
Logistic Regression Models ◽  
Risk Alleles ◽  
Hla Haplotypes

AbstractObjectiveImmunohistological analyses of pancreata from patients with type 1 diabetes suggest a stratification of islet pathology of both B and T lymphocyte islet inflammation common in children diagnosed at <7 years (<7 group), whereas B cells are rare in those diagnosed age ≥13 (≥13 group). Based on these observations, we sought to identify differences in genetic susceptibility between these age-at-diagnosis groups, to inform on the aetiology of the most aggressive form of type 1 diabetes that initiates in the first years of life.Research Design and MethodsUsing multinomial logistic regression models, we tested if known type 1 diabetes loci (17 within the HLA region and 55 non-HLA regions) had significantly stronger effect sizes in the <7 group compared to the ≥13 group, using genotype data from 27,075 individuals (18,488 controls, 3,109 cases diagnosed at <7, 3,754 at 7-13 and 1,724 at ≥13).ResultsSix HLA haplotypes/classical alleles and seven non-HLA regions, one of which functions specifically in beta cells (GLIS3), and the other six likely affecting key T cell (IL2RA, IL10, SIRPG, IKZF3, THEMIS), thymus (THEMIS) and B cell development/functions (IKZF3, IL10) or in both immune and beta cells (CTSH) had stronger effects in the <7 group.ConclusionsIn newborn children with the greatest load of certain risk alleles, dysregulated response of immune and beta cells to environmental stresses such as virus infection, combine to cause a rapid loss of insulin production, driving down the age of type 1 diabetes diagnosis.

scholarly journals Long-Term Occupational Consequences for Families of Children With Type 1 Diabetes: The Mothers Take the Burden

2021 ◽  
Author(s):  
Andrea Dehn-Hindenberg ◽  
Heike Saßmann ◽  
Verena Berndt ◽  
Torben Biester ◽  
Bettina Heidtmann ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Young Children ◽  
Financial Burden ◽  
Working Hours ◽  
Age At Diagnosis ◽  
First Year ◽  
Diabetes Diagnosis ◽  
Negative Consequences

<b>OBJECTIVE</b> <p>To investigate the occupational and financial consequences for parents following the onset of type 1 diabetes in their child. </p> <p><b>RESEARCH DESIGN AND METHODS</b> </p> <p>A questionnaire assessing occupational and financial situations before and in the first year after the onset of diabetes was distributed to all families with a child ≤14 years of age at diagnosis with a diabetes duration of at least 12 months in nine German pediatric diabetes centers. </p> <p><b>RESULTS</b></p> <p>Data of 1,144 children (mean age at diagnosis 6.7 (3.6) years, 46.5% female) and their families were obtained. Mothers’ occupational status reflected in paid working hours was significantly reduced in the first year after their child's diabetes diagnosis (<i>P</i> < 0.001). Overall, 15.1% of mothers stopped working, and 11.5% reduced working hours. Mothers of preschool children were particularly affected. Fathers’ working status hardly changed (<i>P</i> = 0.75). Nearly half of the families (46.4%) reported moderate to severe financial losses. Compared to an earlier similar study in 2003, significant negative occupational consequences for mothers and financial burden on families remain unchanged in 2018 (<i>P</i> = 0.59 & 0.31, respectively).</p> <p><b>CONCLUSIONS</b></p> <p>Mothers of young children with newly diagnosed diabetes experienced negative consequences in their occupational situation. This inequality for mothers can have long-term negative consequences for their mental health and future economic situation. There is an urgent need for action to reduce the burden on families and to provide professional, social, and regulatory support especially for mothers of young children with diabetes. </p>

scholarly journals Article Carer's Attachment Anxiety, Stressful Life Events, and the Risk of Childhood-Onset Type 1 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Anja Turin ◽  
Klemen Dovč ◽  
Simona Klemenčič ◽  
Nataša Bratina ◽  
Tadej Battelino ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Life Events ◽  
Stressful Life Events ◽  
Multinomial Logistic Regression ◽  
Attachment Anxiety ◽  
Stressful Life ◽  
Attachment Representations ◽  
Logistic Regression Models ◽  
Relationship Structures

Background/Objective: Type 1 diabetes (T1D) is among the most common chronic diseases in children/adolescents, and the incidence continues to rise worldwide. Different environmental factors have been evaluated in the etiology. In the present study, we investigated the role of attachment examining whether insecure attachment to carers or carers' own attachment insecurity was related to a higher risk of T1D in children.Methods: We included 101 children with T1D (mean age 11.8 years), 106 healthy controls (11.6 years), and one of their carers. We assessed children's attachment using the Child Attachment Interview and carers' attachment using the Relationship Structures Questionnaire. We constructed binary multinomial logistic regression models using attachment to mothers, carers' attachment representations, and stressful life-events as T1D predictors.Results: Higher carer attachment anxiety was associated with the child's T1D diagnosis (p &lt; 0.05; R2 = 0.0613) while security of attachment to mothers showed no significant association. When mothers' education was included in the model, both attachment anxiety in higher educated mothers and stressful life events showed a significant association with the child's T1D (p &lt; 0.001; R2 = 0.293).Conclusions: Our findings suggest that higher attachment-related anxiety in carers with high education and stressful life events are associated with T1D in children.

scholarly journals Long-Term Occupational Consequences for Families of Children With Type 1 Diabetes: The Mothers Take the Burden

2021 ◽  
Author(s):  
Andrea Dehn-Hindenberg ◽  
Heike Saßmann ◽  
Verena Berndt ◽  
Torben Biester ◽  
Bettina Heidtmann ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Young Children ◽  
Financial Burden ◽  
Working Hours ◽  
Age At Diagnosis ◽  
First Year ◽  
Diabetes Diagnosis ◽  
Negative Consequences

<b>OBJECTIVE</b> <p>To investigate the occupational and financial consequences for parents following the onset of type 1 diabetes in their child. </p> <p><b>RESEARCH DESIGN AND METHODS</b> </p> <p>A questionnaire assessing occupational and financial situations before and in the first year after the onset of diabetes was distributed to all families with a child ≤14 years of age at diagnosis with a diabetes duration of at least 12 months in nine German pediatric diabetes centers. </p> <p><b>RESULTS</b></p> <p>Data of 1,144 children (mean age at diagnosis 6.7 (3.6) years, 46.5% female) and their families were obtained. Mothers’ occupational status reflected in paid working hours was significantly reduced in the first year after their child's diabetes diagnosis (<i>P</i> < 0.001). Overall, 15.1% of mothers stopped working, and 11.5% reduced working hours. Mothers of preschool children were particularly affected. Fathers’ working status hardly changed (<i>P</i> = 0.75). Nearly half of the families (46.4%) reported moderate to severe financial losses. Compared to an earlier similar study in 2003, significant negative occupational consequences for mothers and financial burden on families remain unchanged in 2018 (<i>P</i> = 0.59 & 0.31, respectively).</p> <p><b>CONCLUSIONS</b></p> <p>Mothers of young children with newly diagnosed diabetes experienced negative consequences in their occupational situation. This inequality for mothers can have long-term negative consequences for their mental health and future economic situation. There is an urgent need for action to reduce the burden on families and to provide professional, social, and regulatory support especially for mothers of young children with diabetes. </p>

1316-P: Celiac Disease in Youth with Type 1 Diabetes: Association with Age at Diabetes Diagnosis

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1316-P
Author(s):  
ERIN ALVING ◽  
KRISTEN CARLIN ◽  
DALE LEE ◽  
ALISSA J. ROBERTS ◽  
JANE DICKERSON ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Celiac Disease ◽  
Diabetes Diagnosis

scholarly journals DR15-DQ6 remains dominantly protective against type 1 diabetes throughout the first five decades of life

Diabetologia ◽  
2021 ◽  
Author(s):  
Nicholas J. Thomas ◽  
John M. Dennis ◽  
Seth A. Sharp ◽  
Akaal Kaur ◽  
Shivani Misra ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Major Type ◽  
Diabetes Incidence ◽  
Diabetes Diagnosis ◽  
Risk Haplotype ◽  
Adult Onset ◽  
Uk Biobank ◽  
Onset Type ◽  
Increased Risk

Abstract Aims/hypothesis Among white European children developing type 1 diabetes, the otherwise common HLA haplotype DR15-DQ6 is rare, and highly protective. Adult-onset type 1 diabetes is now known to represent more overall cases than childhood onset, but it is not known whether DR15-DQ6 is protective in older-adult-onset type 1 diabetes. We sought to quantify DR15-DQ6 protection against type 1 diabetes as age of onset increased. Methods In two independent cohorts we assessed the proportion of type 1 diabetes cases presenting through the first 50 years of life with DR15-DQ6, compared with population controls. In the After Diabetes Diagnosis Research Support System-2 (ADDRESS-2) cohort (n = 1458) clinician-diagnosed type 1 diabetes was confirmed by positivity for one or more islet-specific autoantibodies. In UK Biobank (n = 2502), we estimated type 1 diabetes incidence rates relative to baseline HLA risk for each HLA group using Poisson regression. Analyses were restricted to white Europeans and were performed in three groups according to age at type 1 diabetes onset: 0–18 years, 19–30 years and 31–50 years. Results DR15-DQ6 was protective against type 1 diabetes through to age 50 years (OR < 1 for each age group, all p < 0.001). The following ORs for type 1 diabetes, relative to a neutral HLA genotype, were observed in ADDRESS-2: age 5–18 years OR 0.16 (95% CI 0.08, 0.31); age 19–30 years OR 0.10 (0.04, 0.23); and age 31–50 years OR 0.37 (0.21, 0.68). DR15-DQ6 also remained highly protective at all ages in UK Biobank. Without DR15-DQ6, the presence of major type 1 diabetes high-risk haplotype (either DR3-DQ2 or DR4-DQ8) was associated with increased risk of type 1 diabetes. Conclusions/interpretation HLA DR15-DQ6 confers dominant protection from type 1 diabetes across the first five decades of life. Graphical abstract

scholarly journals Viruses and Type 1 Diabetes: From Enteroviruses to the Virome

2021 ◽  
Vol 9 (7) ◽  
pp. 1519
Author(s):  
Sonia R. Isaacs ◽  
Dylan B. Foskett ◽  
Anna J. Maxwell ◽  
Emily J. Ward ◽  
Clare L. Faulkner ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Viral Infections ◽  
Antiviral Drug ◽  
Virus Detection ◽  
Detection Methods ◽  
Islet Autoimmunity ◽  
Comprehensive Overview ◽  
Drug Candidates

For over a century, viruses have left a long trail of evidence implicating them as frequent suspects in the development of type 1 diabetes. Through vigorous interrogation of viral infections in individuals with islet autoimmunity and type 1 diabetes using serological and molecular virus detection methods, as well as mechanistic studies of virus-infected human pancreatic β-cells, the prime suspects have been narrowed down to predominantly human enteroviruses. Here, we provide a comprehensive overview of evidence supporting the hypothesised role of enteroviruses in the development of islet autoimmunity and type 1 diabetes. We also discuss concerns over the historical focus and investigation bias toward enteroviruses and summarise current unbiased efforts aimed at characterising the complete population of viruses (the “virome”) contributing early in life to the development of islet autoimmunity and type 1 diabetes. Finally, we review the range of vaccine and antiviral drug candidates currently being evaluated in clinical trials for the prevention and potential treatment of type 1 diabetes.

Prevalence of autoantibodies in type 1 diabetes mellitus pediatrics in Mazandaran, North of Iran

2020 ◽  
Vol 33 (10) ◽  
pp. 1299-1305
Author(s):  
Daniel Zamanfar ◽  
Mohsen Aarabi ◽  
Monireh Amini ◽  
Mahila Monajati
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Serum Level ◽  
Type 1 Diabetes Mellitus ◽  
Children And Adolescents ◽  
Statistical Significance ◽  
Pancreatic Beta Cell ◽  
Eligible Patient ◽  
Diabetes Diagnosis

AbstractObjectivesType 1 diabetes is an autoimmune disease. Its most important immunologic markers are pancreatic beta-cell autoantibodies. This study aimed to determine diabetes mellitus antibodies frequency among children and adolescents with type 1 diabetes.MethodsThis descriptive study evaluated the frequency of four diabetes autoantibodies (glutamic acid decarboxylase 65 autoantibodies [GADA], islet cell autoantibodies [ICA], insulin autoantibodies [IAA], tyrosine phosphatase–like insulinoma antigen-2 antibodies [IA-2A]) and their serum level in children and adolescents diagnosed with type 1 diabetes mellitus at the diabetes department of Bou-Ali-Sina Hospital and Baghban Clinic, Sari, Iran, from March 2012 to March 2018. The relationship between the level of different antibodies and age, gender, and diabetes duration were determined. A two-sided p value less than 0.05 indicated statistical significance.ResultsOne hundred forty-two eligible patient records were screened. The average age at diabetes diagnosis was 4.2 ± 4.4 years. The median duration of diabetes was 34.0 (12.7–69.7) months. 53.5% of patients were female, and 81.7% of them had at least one positive autoantibody, and ICA in 66.2%, GADA in 56.3%, IA-2A in 40.1%, and IAA in 21.8% were positive. The type of the autoantibodies and their serum level was similar between females and males but there was a higher rate of positive autoantibodies in females. The level of IA-2A and ICA were in positive and weak correlation with age at diagnosis.ConclusionsMore than 80% of pediatric and adolescent patients with type 1 diabetes were autoantibody-positive. ICA and GADA were the most frequently detected autoantibodies. The presence of antibodies was significantly higher in females.

scholarly journals Continuous subcutaneous insulin infusion alters microRNA expression and glycaemic variability in children with type 1 diabetes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emma S. Scott ◽  
Andrzej S. Januszewski ◽  
Luke M. Carroll ◽  
Gregory R. Fulcher ◽  
Mugdha V. Joglekar ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Continuous Subcutaneous Insulin Infusion ◽  
Insulin Infusion ◽  
Diabetes Diagnosis ◽  
Subcutaneous Insulin ◽  
Glycaemic Variability ◽  
Altered Expression ◽  
C Peptide

AbstractTo determine whether continuous subcutaneous insulin infusion (CSII) vs. multiple daily injections (MDI) therapy from near-diagnosis of type 1 diabetes is associated with reduced glycaemic variability (GV) and altered microRNA (miRNAs) expression. Adolescents (74% male) within 3-months of diabetes diagnosis (n = 27) were randomized to CSII (n = 12) or MDI. HbA1c, 1-5-Anhydroglucitol (1,5-AG), high sensitivity C-peptide and a custom TaqMan qPCR panel of 52 miRNAs were measured at baseline and follow-up (median (LQ-UQ); 535 (519–563) days). There were no significant differences between groups in baseline or follow-up HbA1c or C-peptide, nor baseline miRNAs. Mean ± SD 1,5-AG improved with CSII vs. MDI (3.1 ± 4.1 vs. − 2.2 ± − 7.0 mg/ml respectively, P = 0.029). On follow-up 11 miRNAs associated with diabetes vascular complications had altered expression in CSII-users. Early CSII vs. MDI use is associated with lower GV and less adverse vascular-related miRNAs. Relationships with future complications are of interest.

scholarly journals Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

2021 ◽  
Vol 9 (6) ◽  
pp. 1177
Author(s):  
Abdulaziz Alhazmi ◽  
Magloire Pandoua Nekoua ◽  
Hélène Michaux ◽  
Famara Sane ◽  
Aymen Halouani ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Viral Infections ◽  
Lymphoid Organ ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Coxsackievirus B4

The thymus gland is a primary lymphoid organ for T-cell development. Various viral infections can result in disturbance of thymic functions. Medullary thymic epithelial cells (mTECs) are important for the negative selection of self-reactive T-cells to ensure central tolerance. Insulin-like growth factor 2 (IGF2) is the dominant self-peptide of the insulin family expressed in mTECs and plays a crucial role in the intra-thymic programing of central tolerance to insulin-secreting islet β-cells. Coxsackievirus B4 (CVB4) can infect and persist in the thymus of humans and mice, thus hampering the T-cell maturation and differentiation process. The modulation of IGF2 expression and protein synthesis during a CVB4 infection has been observed in vitro and in vivo in mouse models. The effect of CVB4 infections on human and mouse fetal thymus has been studied in vitro. Moreover, following the inoculation of CVB4 in pregnant mice, the thymic function in the fetus and offspring was disturbed. A defect in the intra-thymic expression of self-peptides by mTECs may be triggered by CVB4. The effects of viral infections, especially CVB4 infection, on thymic cells and functions and their possible role in the pathogenesis of type 1 diabetes (T1D) are presented.

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