Interaction of Onset and Duration of Diabetes on the Percent of GAD and IA-2 Antibody–Positive Subjects in the Type 1 Diabetes Genetics Consortium Database

Tridgell, David; Spiekerman, Charles; Wang, Richard S.; Greenbaum, Carla J.

doi:10.2337/dc10-1903

Cited by 36 publications

(29 citation statements)

References 17 publications

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“…We found vast differences in the amplitude and multitude of beta cell-specific T cell proliferation and identified different types of responders. It is generally believed that most immune-mediated beta cell damage has happened before clinical onset of the disease and that the rate of active autoimmunity declines thereafter, in line with isletautoantibody titres [19]. However, we show the opposite, with almost all individuals responding to at least one of the tested beta cell antigens.…”

Section: Discussionsupporting

confidence: 51%

Clinical and genetic correlates of islet-autoimmune signatures in juvenile-onset type 1 diabetes

et al. 2019

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Aims/hypothesis Heterogeneity in individuals with type 1 diabetes has become more generally appreciated, but has not yet been extensively and systematically characterised. Here, we aimed to characterise type 1 diabetes heterogeneity by creating immunological, genetic and clinical profiles for individuals with juvenile-onset type 1 diabetes in a cross-sectional study. Methods Participants were HLA-genotyped to determine HLA-DR-DQ risk, and SNP-genotyped to generate a non-HLA genetic risk score (GRS) based on 93 type 1 diabetes-associated SNP variants outside the MHC region. Islet autoimmunity was assessed as T cell proliferation upon stimulation with the beta cell antigens GAD65, islet antigen-2 (IA-2), preproinsulin (PPI) and defective ribosomal product of the insulin gene (INS-DRIP). Clinical parameters were collected retrospectively. Results Of 80 individuals, 67 had proliferation responses to one or more islet antigens, with vast differences in the extent of proliferation. Based on the multitude and amplitude of the proliferation responses, individuals were clustered into non-, intermediate and high responders. High responders could not be characterised entirely by enrichment for the highest risk HLA-DR3-DQ2/DR4-DQ8 genotype. However, high responders did have a significantly higher non-HLA GRS. Clinically, high T cell responses to beta cell antigens did not reflect in worsened glycaemic control, increased complications, development of associated autoimmunity or younger age at disease onset. The number of beta cell antigens that an individual responded to increased with disease duration, pointing to chronic islet autoimmunity and epitope spreading. Conclusions/interpretation Collectively, these data provide new insights into type 1 diabetes disease heterogeneity and highlight the importance of stratifying patients on the basis of their genetic and autoimmune signatures for immunotherapy and personalised disease management.

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Section: Discussionsupporting

confidence: 51%

Clinical and genetic correlates of islet-autoimmune signatures in juvenile-onset type 1 diabetes

et al. 2019

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“…Still, new trials of DPP-4 inhibitors and vitamin D3 in patients with T1DM should be conducted to confirm their safety and efficacy in these patients. The decrease in antibodies levels in the cases reported here, as well as in others reported in the literature, reinforces this hypothesis since patients with T1DM older than 14 years of age and with positive anti-GAD levels only show a decrease in anti-GAD levels after 5 years (30). Large trials are still needed to confirm this theory.…”

Section: Discussionsupporting

confidence: 90%

Four-year clinical remission of type 1 diabetes mellitus in two patients treated with sitagliptin and vitamin D3

Pinheiro

Torres

2016

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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SummaryType 1 diabetes mellitus (T1DM) is a chronic disease characterized by autoimmune destruction of pancreatic beta cells and inadequate insulin production. Remission criteria in T1DM take into account serum levels of C-peptide and glycosylated hemoglobin, as well as the dose of insulin administered to the patient. However, remission of T1DM lasting longer than 1 year is rare. We describe here the cases of two young women who presented with positive glutamic acid decarboxylase (GAD) antibody and classic clinical manifestations of T1DM. Both patients had a prior history of Hashimoto’s thyroiditis. They were initially treated with a basal-bolus regimen of insulin (glargine and lispro/glulisine). Once their blood glucose levels were controlled, they were started on oral sitagliptin 100 mg and vitamin D3 5000 IU daily. After this therapy, both patients achieved clinical diabetes remission for 4 years, along with a decrease in anti-GAD antibody levels. These benefits were probably associated with immunological effects of these medications. Inhibition of dipeptidyl peptidase 4 (DPP-4) in animal models deregulates Th1 immune response, increases secretion of Th2 cytokines, activates CD4+CD25+FoxP3+ regulatory T-cells and prevents IL-17 production. Vitamin D3 also activates CD4+CD25+FoxP3+ regulatory T-cells, and these medications combined can improve the immune response in patients with new-onset T1DM and probably promote sustained clinical remission.Learning points:The use of sitagliptin and vitamin D3 in patients with new-onset type 1 diabetes mellitus (T1DM) may help decrease the daily insulin requirement by delaying beta cell loss and improving endogenous insulin production.The use of sitagliptin and vitamin D3 in new-onset T1DM could help regulate the imbalance between Th17 and Treg cells.Age 14 years or above, absence of ketoacidosis and positive C-peptide levels in patients with T1DM are good criteria to predict prolonged T1DM remission.The determination of anti-GAD antibodies and C-peptide levels could be helpful in the follow-up of patients in use of sitagliptin and vitamin D3, which could be associated with prolonged T1DM clinical remission.

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“…Among classic T1D patients, their autoantibodies declined significantly during five years after they were diagnosed. The mean age at which a patient was diagnosed with diabetes was 27.6±17.7 years, which was similar to the observation in the report, Tridgell et al (Tridgell, 2011). They found that for individuals who were diagnosed with diabetes at age 14 or older, the prevalence for GADA changed little during the first five years after diagnosis, as we demonstrated.…”

Section: Discussionsupporting

confidence: 80%

The heterogeneity of islet autoantibodies and the progression of islet failure in type 1 diabetic patients

Liu

Bian

et al. 2016

Sci. China Life Sci.

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Type 1 diabetes mellitus is heterogeneous in many facets. The patients suffered from type 1 diabetes present several levels of islet function as well as variable number and type of islet-specific autoantibodies. This study was to investigate prevalence and heterogeneity of the islet autoantibodies and clinical phenotypes of type 1 diabetes mellitus; and also discussed the process of islet failure and its risk factors in Chinese type 1 diabetic patients. A total of 1,291 type 1 diabetic patients were enrolled in this study. Demographic information was collected. Laboratory tests including mixed-meal tolerance test, human leukocyte antigen alleles, hemoglobinA1c, lipids, thyroid function and islet autoantibodies were conducted. The frequency of islet-specific autoantibody in newly diagnosed T1DM patients (duration shorter than half year) was 73% in East China. According to binary logistic regressions, autoantibody positivity, longer duration and lower Body Mass Index were the risk factors of islet failure. As the disease developed, autoantibodies against glutamic acid decarboxylase declined as well as the other two autoantibodies against zinc transporter 8 and islet antigen 2. The decrease of autoantibodies was positively correlated with aggressive beta cell destruction. Autoantibodies can facilitate the identification of classic T1DM from other subtypes and predict the progression of islet failure. As there were obvious heterogeneity in autoantibodies and clinical manifestation in different phenotypes of the disease, we should take more factors into consideration when identifying type 1 diabetes mellitus.autoantibodies, heterogeneity, islet failure, type 1 diabetes Citation:

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Interaction of Onset and Duration of Diabetes on the Percent of GAD and IA-2 Antibody–Positive Subjects in the Type 1 Diabetes Genetics Consortium Database

Cited by 36 publications

References 17 publications

Clinical and genetic correlates of islet-autoimmune signatures in juvenile-onset type 1 diabetes

Clinical and genetic correlates of islet-autoimmune signatures in juvenile-onset type 1 diabetes

Four-year clinical remission of type 1 diabetes mellitus in two patients treated with sitagliptin and vitamin D3

The heterogeneity of islet autoantibodies and the progression of islet failure in type 1 diabetic patients

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