Islet Autoantibodies, Assay Specificity and Disease Specificity

Objective. Islet autoimmunity develops prior to clinical type 1 diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for pre-symptomatic type 1 diabetes. Research Design and Methods. The Environmental Determinants of Diabetes in the Young study prospectively followed 8,556 genetically at-risk children at 3–6-month intervals from birth for the development of islet autoantibodies and type 1 diabetes. The age-related change in the risk of developing islet autoantibodies was determined using landmark and regression models. Results. The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% confidence interval, 3.8–4.7) at 7.5 months of age and declined to 1.1% (95% confidence interval, 0.8–1.3) at a landmark age of 6.25 years (P<0.0001). Risk decline was slight or absent in single insulin- and GAD-autoantibody phenotypes. The influence of sex, HLA and other susceptibility genes on risk subsided with increasing age and was abrogated by age six years. Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for type 1 diabetes was achieved by autoantibody screening at 2 years and again at 5–7 years of age. Conclusions. The risk of developing islet autoimmunity declines exponentially with age and the influence of major genetic factors on this risk is limited to the first few years of life.

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miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes

Nature Communications ◽

10.1038/s41467-019-13587-3 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 6

Author(s):

Martin G. Scherm ◽

Isabelle Serr ◽

Adam M. Zahm ◽

Jonathan Schug ◽

Saverio Bellusci ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Cell Activation ◽

Pancreatic Beta Cells ◽

Cell Activation ◽

Clinical Symptoms ◽

Mechanistic Model ◽

Treg Cells ◽

Islet Autoimmunity ◽

Molecular Approaches

AbstractIn type 1 diabetes, the appearance of islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. While T cells play a major role in the destruction of pancreatic beta cells, molecular underpinnings promoting aberrant T cell activation remain poorly understood. Here, we show that during islet autoimmunity an miR142-3p/Tet2/Foxp3 axis interferes with the efficient induction of regulatory T (Treg) cells, resulting in impaired Treg stability in mouse and human. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity and that its inhibition enhances Treg induction and stability, leading to reduced islet autoimmunity in non-obese diabetic mice. Using various cellular and molecular approaches we identify Tet2 as a direct target of miR142-3p, thereby linking high miR142-3p levels to epigenetic remodeling in Tregs. These findings offer a mechanistic model where during islet autoimmunity miR142-3p/Tet2-mediated Treg instability contributes to autoimmune activation and progression.

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Type 1 Diabetes in the Young: Organization of two National Centers in Israel and Slovenia / Sladkorna Bolezen Tipa 1 Pri Otrocih in Mladostnikih: Organizacija Dela V Dveh Nacionalnih Centrih V Izraelu in Sloveniji

Slovenian Journal of Public Health ◽

10.1515/sjph-2015-0021 ◽

2015 ◽

Vol 54 (2) ◽

pp. 139-145 ◽

Cited By ~ 1

Author(s):

Nataša Bratina ◽

Shlomit Shalitin ◽

Moshe Phillip ◽

Tadej Battelino

Keyword(s):

Type 1 Diabetes ◽

Glycated Hemoglobin ◽

Severe Hypoglycemia ◽

Modern Technology ◽

Steady Increase ◽

Chronic Complications ◽

The Mean ◽

Chronic Autoimmune Disease

Abstract Type 1 diabetes is a chronic autoimmune disease that affects mainly young people. In the last 50 years, a steady increase of the T1D incidence in the young is reported worldwide, with an average 4 % increase annually. In addition, the mean age at the diagnosis is decreasing. Studies show that good metabolic control is important not only for delaying the chronic complications of diabetes but also for improving the quality of life of patients and their families. Continuous education, together with modern technology, is crucial in achieving these goals. Longitudinal data on glycated hemoglobin (HbA1c), along with the data on severe hypoglycemia and severe diabetic ketoacidosis, can describe the quality of care in a defined population. Two national reference diabetes centres taking care of children, adolescents and young adults with diabetes in Israel and Slovenia are described.

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Pathogenesis of Type 1 Diabetes Mellitus: A Brief Overview

Romanian Journal of Diabetes Nutrition and Metabolic Diseases ◽

10.2478/v10255-012-0009-1 ◽

2012 ◽

Vol 19 (1) ◽

pp. 67-72 ◽

Cited By ~ 1

Author(s):

Adrian Vlad ◽

Romulus Timar

Keyword(s):

Quality Of Life ◽

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Insulin Therapy ◽

Type 1 Diabetes Mellitus ◽

Chronic Complications ◽

Type 1 Dm ◽

Preventive Methods

Pathogenesis of Type 1 Diabetes Mellitus: A Brief OverviewBefore the discovery of insulin, type 1 diabetes mellitus (DM) was a disease with acute evolution, leading to death shortly after diagnosis. During the first years of insulin therapy, the medical world was optimistic, even enthusiastic, considering that the therapeutic solution for the malady was found. Unfortunately this was only an illusion, because the patients started to develop chronic complications that shortened their lifespan and impaired their quality of life. In other words, insulin therapy transformed type 1 DM into a chronic disease. The prevention or the delay of the onset of hyperglycemia emerged as a new solution for the patients and, consequently, the understanding of the pathogenesis of the disease (a prerequisite for developing efficient preventive methods) became a priority for all the diabetologists involved in research. Almost 40 years have passed since the autoimmune theory regarding the pathogenesis of type 1 DM was imagined but, despite the tremendous research performed in this field since then, the prevention could not be obtained. The aim of this paper is to present the most important theoretic notions regarding the mechanisms that underlie the development of type 1 DM, in the way they are understood today.

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Autoimmune Thyroid Disease Correlates to Islet Autoimmunity on Zinc Transporter 8 Autoantibody: A Cross-Section Study

10.21203/rs.3.rs-60065/v1 ◽

2020 ◽

Author(s):

Yun Cai ◽

Jieni Yan ◽

Yong Gu ◽

Heng Chen ◽

Qingfang Hu ◽

...

Keyword(s):

Diabetes Mellitus ◽

Thyroid Disease ◽

Autoimmune Thyroid Disease ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Thyroid Autoantibodies ◽

Healthy Controls ◽

Autoimmune Thyroid ◽

Relative Value

Abstract Background The most common coexisting organ-specific autoimmune disease in patients with Type 1 diabetes mellitus (T1DM) is autoimmune thyroid disease (AITD). Many studies have showed prevalence rate of thyroid autoantibodies range from 3.7-35% in T1DM patients, while some of them suggested the associations between thyroid autoantibodies and islet autoantibodies. However, little work has been done about the anti-islet autoimmune status in patients with autoimmune thyroid disease (AITD), and so far there have been no clinical report based on large population about zinc transporter 8 autoantibody (ZnT8A) in patients with AITD. We aimed to explore the presence of islet autoantibodies, ZnT8A, glutamic acid decarboxylase autoantibodies (GADA) and tyrosine phosphatase autoantibodies (IA-2A) compared with thyroid autoantibodies, thyroid peroxidase autoantibodies (TPOAb) and thyroglobulin autoantibodies (TGAb) and thyrotropin receptor autoantibodies (TRAb) in AITD patients. Methods In total 740 AITD patients, 108 type 1 diabetes mellitus (T1DM) patients with AITD, 172 non-autoimmune thyroid disease (nAITD) patients and 115 healthy controls were recruited in the cross-sectional study. Islet autoantibodies, ZnT8A, GADA, IA-2A and thyroid autoantibodies, TPOAb, TGAb, TRAb were detected with Radioimmunoassay and Chemiluminescence. Islet autoantibody relative value was established to compare the distribution of the three islet autoantibodies. Results The prevalence of ZnT8A and GADA in AITD group was significantly higher than that in healthy controls (ZnT8A: 15.00% vs 1.74%, GADA: 7.97% vs 0.87%, both P<0.05). Similarly, the prevalence of IA-2A in AITD group was higher than that in healthy controls (4.19% vs 0%, P<0.05). However, any islet autoantibodies positive rate in AITD group was significantly lower than that in T1DM with AITD group. Analysis of multivariable linear regression suggested that ZnT8A relative value was positively related with GADA relative value (β=0.352, P<0.01) and TPOAb titer (β=0.002, P<0.01), and GADA relative value was also positively related with ZnT8A relative value (β=0.183, P<0.01). Conclusions An increased prevalence of ZnT8A as well as a relatively high prevalence of islet autoimmunity was found in AITD patients, indicating that there is a potential link between thyroid autoimmunity and islet autoimmunity. Trial registration Retrospectively registered.

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An Age-Related Exponential Decline in the Risk of Multiple Islet Autoantibody Seroconversion During Childhood

10.2337/figshare.13643756.v1 ◽

2021 ◽

Author(s):

Ezio Bonifacio ◽

Andreas Weiß ◽

Christiane Winkler ◽

Markus Hippich ◽

Marian J. Rewers ◽

...

Keyword(s):

Type 1 Diabetes ◽

Confidence Interval ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Islet Autoantibody ◽

Age Related ◽

At Risk Children ◽

Exponential Decline ◽

Design And Methods

Objective. Islet autoimmunity develops prior to clinical type 1 diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for pre-symptomatic type 1 diabetes. Research Design and Methods. The Environmental Determinants of Diabetes in the Young study prospectively followed 8,556 genetically at-risk children at 3–6-month intervals from birth for the development of islet autoantibodies and type 1 diabetes. The age-related change in the risk of developing islet autoantibodies was determined using landmark and regression models. Results. The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% confidence interval, 3.8–4.7) at 7.5 months of age and declined to 1.1% (95% confidence interval, 0.8–1.3) at a landmark age of 6.25 years (P<0.0001). Risk decline was slight or absent in single insulin- and GAD-autoantibody phenotypes. The influence of sex, HLA and other susceptibility genes on risk subsided with increasing age and was abrogated by age six years. Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for type 1 diabetes was achieved by autoantibody screening at 2 years and again at 5–7 years of age. Conclusions. The risk of developing islet autoimmunity declines exponentially with age and the influence of major genetic factors on this risk is limited to the first few years of life.

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Dynamics of Islet Autoantibodies During Prospective Follow-Up From Birth to Age 15 Years

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa624 ◽

2020 ◽

Vol 105 (12) ◽

pp. e4638-e4651 ◽

Cited By ~ 1

Author(s):

Petra M Pöllänen ◽

Samppa J Ryhänen ◽

Jorma Toppari ◽

Jorma Ilonen ◽

Paula Vähäsalo ◽

...

Keyword(s):

Glutamate Decarboxylase ◽

Seroconversion Rate ◽

Disease Process ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Prolonged Delay ◽

Islet Antigen

Abstract Context We set out to characterize the dynamics of islet autoantibodies over the first 15 years of life in children carrying genetic susceptibility to type 1 diabetes (T1D). We also assessed systematically the role of zinc transporter 8 autoantibodies (ZnT8A) in this context. Design HLA-predisposed children (N = 1006, 53.0% boys) recruited from the general population during 1994 to 1997 were observed from birth over a median time of 14.9 years (range, 1.9-15.5 years) for ZnT8A, islet cell (ICA), insulin (IAA), glutamate decarboxylase (GADA), and islet antigen-2 (IA-2A) antibodies, and for T1D. Results By age 15.5 years, 35 (3.5%) children had progressed to T1D. Islet autoimmunity developed in 275 (27.3%) children at a median age of 7.4 years (range, 0.3-15.1 years). The ICA seroconversion rate increased toward puberty, but the biochemically defined autoantibodies peaked at a young age. Before age 2 years, ZnT8A and IAA appeared commonly as the first autoantibody, but in the preschool years IA-2A– and especially GADA-initiated autoimmunity increased. Thereafter, GADA-positive seroconversions continued to appear steadily until ages 10 to 15 years. Inverse IAA seroconversions occurred frequently (49.3% turned negative) and marked a prolonged delay from seroconversion to diagnosis compared to persistent IAA (8.2 vs 3.4 years; P = .01). Conclusions In HLA-predisposed children, the primary autoantibody is characteristic of age and might reflect the events driving the disease process toward clinical T1D. Autoantibody persistence affects the risk of T1D. These findings provide a framework for identifying disease subpopulations and for personalizing the efforts to predict and prevent T1D.

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Class II HLA Genotype Association With First-Phase Insulin Response Is Explained by Islet Autoantibodies

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-02040 ◽

2017 ◽

Vol 103 (8) ◽

pp. 2870-2878 ◽

Cited By ~ 3

Author(s):

Maarit K Koskinen ◽

Johanna Lempainen ◽

Eliisa Löyttyniemi ◽

Olli Helminen ◽

Anne Hekkala ◽

...

Keyword(s):

Type 1 Diabetes ◽

Insulin Response ◽

Class Ii ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Intravenous Glucose ◽

Hla Dr ◽

Hla Genotype ◽

First Phase Insulin Response

Abstract Context A declining first-phase insulin response (FPIR) is characteristic of the disease process leading to clinical type 1 diabetes. It is not known whether reduced FPIR depends on class II human leukocyte antigen (HLA) genotype, islet autoimmunity, or both. Objective To dissect the role of class II HLA DR-DQ genotypes and biochemical islet autoantibodies in the compromised FPIR. Design, Setting, Participants A total of 438 children with defined HLA DR-DQ genotype in the prospective Finnish Type 1 Diabetes Prediction and Prevention Study were analyzed for FPIR in a total of 1149 intravenous glucose tolerance tests and were categorized by their HLA DR-DQ genotype and the number of biochemical islet autoantibodies at the time of the first FPIR. Age-adjusted hierarchical linear mixed models were used to analyze repeated measurements of FPIR. Main Outcome Measure The associations between class II HLA DR-DQ genotype, islet autoantibody status, and FPIR. Results A strong association between the degree of risk conferred by HLA DR-DQ genotype and positivity for islet autoantibodies existed (P < 0.0001). FPIR was inversely associated with the number of biochemical autoantibodies (P < 0.0001) irrespective of HLA DR-DQ risk group. FPIR decreased over time in children with multiple autoantibodies and increased in children with no biochemical autoantibodies (P < 0.0001 and P = 0.0013, respectively). Conclusions The class II HLA DR-DQ genotype association with FPIR was secondary to the association between HLA and islet autoimmunity. Declining FPIR was associated with positivity for multiple islet autoantibodies irrespective of class II HLA DR-DQ genotype.

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Circulating Metabolites in Progression to Islet Autoimmunity and Type 1 Diabetes

10.1101/496943 ◽

2018 ◽

Cited By ~ 1

Author(s):

Santosh Lamichhane ◽

Esko Kemppainen ◽

Kajetan Trost ◽

Heli Siljander ◽

Heikki Hyoty ◽

...

Keyword(s):

Type 1 Diabetes ◽

Study Groups ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Islet Autoantibody ◽

Metabolic Disturbances ◽

Longitudinal Plasma ◽

Sugar Derivatives ◽

Negative Controls

Previous studies suggest that metabolic dysregulation precedes the onset of type 1 diabetes (T1D). However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. Here we analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to T1D (PT1D), who seroconverted to one islet autoantibody (Ab) but not to T1D (P1Ab), and Ab-negative controls (CTR). In early infancy, PT1D associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, as compared to CTR. Methionine remained persistently upregulated in PT1D as compared to CTR and P1Ab. Appearance of islet autoantibodies associated with decreased glutamic and aspartic acids. Our findings suggest that children who progress to T1D have a unique metabolic profile, which is however altered with the onset of islet autoantibodies. Our findings may assist in early prediction of T1D.

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Islet Autoimmunity and HLA Markers of Presymptomatic and Clinical Type 1 Diabetes: Joint Analyses of Prospective Cohort Studies in Finland, Germany, Sweden, and the U.S.

10.2337/figshare.14384324 ◽

2021 ◽

Author(s):

Vibha Anand ◽

Ying Li ◽

Bin Liu ◽

Mohamed Ghalwash ◽

Eileen Koski ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cohort Studies ◽

Prospective Cohort ◽

Diabetes Risk ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Diabetes Incidence ◽

Prospective Cohort Studies ◽

Hla Dr

OBJECTIVE: To combine prospective cohort studies, by including HLA harmonization, and to estimate risk of islet autoimmunity and progression to clinical diabetes. RESEARCH DESIGN AND METHODS: Prospective cohorts in Finland, Germany, Sweden and the US have followed 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years. RESULTS: In the infant-toddler cohort, 1413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two or three autoantibodies at seroconversion: 45% (95% CI 40-52%), 85% (78-90%), and 92% (85-97%), respectively. Among those with single autoantibody, their status two years after seroconversion predicted diabetes risk: 12% (10-25%) if reverting to autoantibody negative, 30% (20-40%) if retaining single autoantibody, and 82% (80-95%) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single autoantibody. Their 15-year diabetes incidence for higher vs. lower risk genotypes was 40% (28-50%) vs. 12% (5-38%). The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies ranging from 20%/year to 6%/year in children developing multi-positivity ≤2 years or >7.4 years, respectively. CONCLUSIONS: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.

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