scholarly journals What Have Slow Progressors Taught Us About T1D—Mind the Gap!

2019 ◽  
Vol 19 (10) ◽  
Author(s):  
Kathleen M. Gillespie ◽  
Anna E. Long
Keyword(s):  
At Risk ◽  
Clinical Symptoms ◽  
Adult Population ◽  
Islet Autoimmunity ◽  
Islet Autoantibody ◽  
Progression Rate ◽  
Adult Onset ◽  
Genetic Studies ◽  
Slow Progressors

Abstract Purpose of Review Progression rate from islet autoimmunity to clinical diabetes is unpredictable. In this review, we focus on an intriguing group of slow progressors who have high-risk islet autoantibody profiles but some remain diabetes free for decades. Recent Findings Birth cohort studies show that islet autoimmunity presents early in life and approximately 70% of individuals with multiple islet autoantibodies develop clinical symptoms of diabetes within 10 years. Some “at risk” individuals however progress very slowly. Recent genetic studies confirm that approximately half of type 1 diabetes (T1D) is diagnosed in adulthood. This creates a conundrum; slow progressors cannot account for the number of cases diagnosed in the adult population. Summary There is a large “gap” in our understanding of the pathogenesis of adult onset T1D and a need for longitudinal studies to determine whether there are “at risk” adults in the general population; some of whom are rapid and some slow adult progressors.

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

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

<b>Objective</b>. 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. <p><b>Research Design and Methods</b>. 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. </p> <p><b>Results</b>. 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 (<i>P</i><0.0001). Risk decline was slight or absent in single insulin- and GAD-autoantibody phenotypes. The influence of sex, <i>HLA</i> 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. </p> <p><b>Conclusions</b>. 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. </p>

scholarly journals Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: results from the prospective TEDDY study

2018 ◽  
Vol 56 (9) ◽  
pp. 602-605 ◽  
Author(s):  
Andreas Beyerlein ◽  
Ezio Bonifacio ◽  
Kendra Vehik ◽  
Markus Hippich ◽  
Christiane Winkler ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Factors ◽  
Genetic Risk Score ◽  
Risk Scores ◽  
Islet Autoimmunity ◽  
Islet Autoantibody ◽  
Clinical Type

BackgroundProgression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown.MethodsIn 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression.ResultsIslet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95% CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95% CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95% CI 1.28 to 2.93).ConclusionsGenetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes.

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

2019 ◽  
Vol 10 (1) ◽  
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.

scholarly journals A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk

Diabetes Care ◽  
2018 ◽  
Vol 41 (9) ◽  
pp. 1887-1894 ◽  
Author(s):  
Maria J. Redondo ◽  
Susan Geyer ◽  
Andrea K. Steck ◽  
Seth Sharp ◽  
John M. Wentworth ◽  
...  
Keyword(s):  
At Risk ◽  
Type 1 Diabetes ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Islet Autoimmunity

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

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

<b>Objective</b>. 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. <p><b>Research Design and Methods</b>. 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. </p> <p><b>Results</b>. 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 (<i>P</i><0.0001). Risk decline was slight or absent in single insulin- and GAD-autoantibody phenotypes. The influence of sex, <i>HLA</i> 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. </p> <p><b>Conclusions</b>. 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. </p>

Cytotoxicity-related gene expression and chromatin accessibility define a subset of CD4+ T cells that mark progression to type 1 diabetes

Diabetes ◽  
2022 ◽  
Author(s):  
Naiara G. Bediaga ◽  
Alexandra L. Garnham ◽  
Gaetano Naselli ◽  
Esther Bandala-Sanchez ◽  
Natalie L. Stone ◽  
...  
Keyword(s):  
Gene Expression ◽  
At Risk ◽  
T Cells ◽  
Type 1 Diabetes ◽  
Cd4 T Cells ◽  
Chromatin Accessibility ◽  
Differentially Expressed ◽  
Islet Autoimmunity ◽  
At Risk Children

Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has reported gene expression in specific immune cells of at-risk children, associated with progression to islet autoimmunity. We analysed gene expression by RNAseq in CD4+ and CD8+ T cells, NK cells and B cells, and chromatin accessibility by ATACseq in CD4+ T cells, in five genetically at-risk children with islet autoantibodies who progressed to diabetes over a median of 3 years (‘Progressors’) compared to five children matched for sex, age and HLA-DR who had not progressed (‘Non-progressors). In Progressors, differentially expressed genes (DEGs) were largely confined to CD4+ T cells and enriched for cytotoxicity-related genes/pathways. Several top-ranked DEGs were validated in a semi-independent cohort of 13 Progressors and 11 Non-progressors. Flow cytometry confirmed progression was associated with expansion of CD4+ cells with a cytotoxic phenotype. By ATAC-seq, progression was associated with reconfiguration of regulatory chromatin regions in CD4+ T cells, some linked to differentially expressed cytotoxicity-related genes. Our findings suggest that cytotoxic CD4+ T cells play a role in promoting progression to type 1 diabetes.

Cytotoxicity-related Gene Expression and Chromatin Accessibility Define a Subset of CD4+ T Cells that Mark Progression to Type 1 Diabetes

2022 ◽  
Author(s):  
Naiara G. Bediaga ◽  
Alexandra L. Garnham ◽  
Gaetano Naselli ◽  
Esther Bandala-Sanchez ◽  
Natalie L. Stone ◽  
...  
Keyword(s):  
Gene Expression ◽  
At Risk ◽  
T Cells ◽  
Type 1 Diabetes ◽  
Chromatin Accessibility ◽  
Differentially Expressed ◽  
Islet Autoimmunity ◽  
Preclinical Phase ◽  
At Risk Children

Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has reported gene expression in specific immune cells of at-risk children, associated with progression to islet autoimmunity. We analysed gene expression by RNAseq in CD4<sup>+</sup> and CD8<sup>+</sup> T cells, NK cells and B cells, and chromatin accessibility by ATACseq in CD4<sup>+</sup> T cells, in five genetically at-risk children with islet autoantibodies who progressed to diabetes over a median of 3 years (‘Progressors’) compared to five children matched for sex, age and HLA-DR who had not progressed (‘Non-progressors). In Progressors, differentially expressed genes (DEGs) were largely confined to CD4<sup>+</sup> T cells and enriched for cytotoxicity-related genes/pathways. Several top-ranked DEGs were validated in a semi-independent cohort of 13 Progressors and 11 Non-progressors. Flow cytometry confirmed progression was associated with expansion of CD4<sup>+ </sup>cells with a cytotoxic phenotype. By ATAC-seq, progression was associated with reconfiguration of regulatory chromatin regions in CD4<sup>+ </sup>cells, some linked to differentially expressed cytotoxicity-related genes. Our findings suggest that cytotoxic CD4<sup>+ </sup>T cells play a role in promoting progression to type 1 diabetes.

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