A perfect storm: Genetics and anticommensal antibodies shore up type 1 diabetes

HLA haplotypes in conjunction with serum anticommensal antibody responses are predictive of type 1 diabetes progression. See related Research Article by Paun et al.

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Contrast Enhanced Ultrasound with Submicron-Sized Contrast Agents Detects Diabetes Progression in Mouse Models of Type 1 Diabetes

Diabetes ◽

10.2337/db18-319-or ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 319-OR

Author(s):

DAVID RAMIREZ ◽

RICHARD K. BENNINGER

Keyword(s):

Type 1 Diabetes ◽

Contrast Agents ◽

Mouse Models ◽

Contrast Enhanced Ultrasound ◽

Contrast Enhanced ◽

Diabetes Progression

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Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomised controlled trial

Diabetologia ◽

10.1007/s00125-020-05376-1 ◽

2021 ◽

Author(s):

Robin Assfalg ◽

Jan Knoop ◽

Kristi L. Hoffman ◽

Markus Pfirrmann ◽

Jose Maria Zapardiel-Gonzalo ◽

...

Keyword(s):

Immune Response ◽

Type 1 Diabetes ◽

Randomised Controlled Trial ◽

Primary Outcome ◽

Controlled Trial ◽

Antibody Responses ◽

Oral Insulin ◽

Cell Responses ◽

Randomised Controlled

Abstract Aims/hypothesis Oral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes. Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6 months to assess its safety and immune response actions on immunity and the gut microbiome. Methods A phase I/II randomised controlled trial was performed in a single clinical study centre in Germany. Participants were 44 islet autoantibody-negative children aged 6 months to 2.99 years who had a first-degree relative with type 1 diabetes and a susceptible HLA DR4-DQ8-containing genotype. Children were randomised 1:1 to daily oral insulin (7.5 mg with dose escalation to 67.5 mg) or placebo for 12 months using a web-based computer system. The primary outcome was immune efficacy pre-specified as induction of antibody or T cell responses to insulin and measured in a central treatment-blinded laboratory. Results Randomisation was performed in 44 children. One child in the placebo group was withdrawn after the first study visit and data from 22 insulin-treated and 21 placebo-treated children were analysed. Oral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in children who received both insulin (54.5%) and placebo (66.7%), and the trial did not demonstrate an effect on its primary outcome (p = 0.54). In exploratory analyses, there was preliminary evidence that the immune response and gut microbiome were modified by the INS genotype Among children with the type 1 diabetes-susceptible INS genotype (n = 22), antibody responses to insulin were more frequent in insulin-treated (72.7%) as compared with placebo-treated children (18.2%; p = 0.03). T cell responses to insulin were modified by treatment-independent inflammatory episodes. Conclusions/interpretation The study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe, but was not associated with an immune response as predefined in the trial primary outcome. Exploratory analyses suggested that antibody responses to oral insulin may occur in children with a susceptible INS genotype, and that inflammatory episodes may promote the activation of insulin-responsive T cells. Trial registration Clinicaltrials.gov NCT02547519 Funding The main funding source was the German Center for Diabetes Research (DZD e.V.) Graphical abstract

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Interleukin-12p40 gene (IL-12B) polymorphism and Type 1 diabetes mellitus in Japanese: Possible role in subjects without having high-risk HLA haplotypes

Diabetes Research and Clinical Practice ◽

10.1016/j.diabres.2005.05.005 ◽

2006 ◽

Vol 71 (2) ◽

pp. 164-169 ◽

Cited By ~ 15

Author(s):

Jian Mei Yang ◽

Shoichiro Nagasaka ◽

Toshimitsu Yatagai ◽

Tomoatsu Nakamura ◽

Ikuyo Kusaka ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

High Risk ◽

Type 1 Diabetes Mellitus ◽

Hla Haplotypes

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Time to Peak Glucose and Peak C-Peptide During the Progression to Type 1 Diabetes in the Diabetes Prevention Trial and TrialNet Cohorts

10.2337/figshare.14974563.v2 ◽

2021 ◽

Author(s):

Michael G Voss ◽

David D Cuthbertson ◽

Mario M Cleves ◽

Ping Xu ◽

Carmella Evans-Molina ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetes Prevention ◽

Prevention Trial ◽

Oral Glucose ◽

Z Score ◽

C Peptide ◽

Time To Peak ◽

Diabetes Progression ◽

Diabetes Development

Objective: To assess the progression of type 1 diabetes using time to peak glucose or C-peptide during oral glucose tolerance tests (OGTTs) in autoantibody positive (Ab+) relatives of people with type 1 diabetes. Methods: We examined 2-hour OGTTs of participants in the Diabetes Prevention Trial Type 1 (DPT-1) and TrialNet Pathway to Prevention (PTP) studies. We included 706 DPT-1 participants (Mean±SD age: 13.84±9.53 years; BMI-Z-Score: 0.33±1.07; 56.1% male) and 3,720 PTP participants (age: 16.01±12.33 Years, BMI-Z-Score 0.66±1.3; 49.7% male). Log-rank testing and Cox regression analyses with adjustments (age, sex, race, BMI Z-Score, HOMA-IR and peak Glucose/C-peptide levels, respectively) were performed. Results: In each of DPT-1 and PTP, higher 5-year diabetes progression risk was seen in those with time to peak glucose >30 min and time to peak C-peptide >60 min (p<0.001 for all groups), before and after adjustments. In models examining strength of association with diabetes development, associations were greater for time to peak C-peptide versus peak C-peptide value (DPT-1: X2 = 25.76 vs. X2 = 8.62 and PTP: X2 = 149.19 vs. X2 = 79.98; all p<0.001). Changes in the percentage of individuals with delayed glucose and/or C-peptide peaks were noted over time. Conclusions: In two independent at risk populations, we show that those with delayed OGTT peak times for glucose or C-peptide are at higher risk of diabetes development within 5 years, independent of peak levels. Moreover, time to peak C-peptide appears more predictive than the peak level, suggesting its potential use as a specific biomarker for diabetes progression.

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Association of high-affinity autoantibodies with type 1 diabetes high-risk HLA haplotypes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab853 ◽

2021 ◽

Author(s):

Taylor M Triolo ◽

Laura Pyle ◽

Hali Broncucia ◽

Taylor Armstrong ◽

Liping Yu ◽

...

Keyword(s):

Type 1 Diabetes ◽

High Risk ◽

Islet Autoimmunity ◽

Initial Visit ◽

Prevention Study ◽

High Affinity ◽

Z Scores ◽

Hla Haplotypes ◽

Hla Dr3

Abstract Objective ECL assays are high-affinity autoantibody (Ab) tests that are more specific than Abs detected by traditional radiobinding assays (RBA) for risk screening and prediction of progression to type 1 diabetes. We sought to characterize the association of high-risk HLA haplotypes and genotypes with electrochemiluminescence (ECL) positivity and levels in relatives of individuals with type 1 diabetes. Methods We analyzed 602 participants from the TrialNet Pathway to Prevention Study who were positive for at least one RBA diabetes related Ab (GADA or IAA) and for whom ECL and HLA data were available. ECL and RBA Ab levels were converted to SD units away from mean (Z-scores) for analyses. Results Mean age at initial visit was 19.4+13.7 years; 344 (57.1%) were female and 104 (17.3%) carried the high-risk HLA- DR3/4*0302 genotype. At initial visit 424/602 (70.4%) participants were positive for either ECL-GADA or ECL-IAA, and 178/602 (29.6%) were ECL negative. ECL and RBA-GADA positivity were associated with both HLA-DR3 and DR4 haplotypes (all p<0.05), while ECL and RBA-GADA z-score titers were higher in participants with HLA-DR3 haplotypes only (both p<0.001). ECL-IAA (but not RBA-IAA) positivity was associated with the HLA-DR4 haplotype (p<0.05). Conclusions ECL-GADA positivity is associated with the HLA-DR3 and HLA-DR4 haplotypes and levels are associated with the HLA-DR3 haplotype. ECL-IAA positivity is associated with HLA-DR4 haplotype. These studies further contribute to the understanding of genetic risk and islet autoimmunity endotypes in type 1 diabetes.

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Illuminating the core of adaptive immunity—how the regulatory genome controls Rag chromatin dynamics

Science Immunology ◽

10.1126/sciimmunol.abd6427 ◽

2020 ◽

Vol 5 (51) ◽

pp. eabd6427

Author(s):

Xun Wang ◽

Ellen V. Rothenberg

Keyword(s):

Adaptive Immunity ◽

Large Scale ◽

Chromatin Dynamics ◽

Related Research ◽

The Core ◽

Link Type ◽

Research Article ◽

Super Enhancer ◽

Regulatory Genome ◽

Topological Changes

E2A specifies adaptive immunity by instructing large-scale topological changes for Rag gene super-enhancer formation (see the related Research Article by Miyazaki et al.).

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P2X7R: The Achilles heel of follicular helper memory T cells

Science Immunology ◽

10.1126/sciimmunol.aba8097 ◽

2020 ◽

Vol 5 (45) ◽

pp. eaba8097

Author(s):

Jeffrey C. Nolz

Keyword(s):

T Cells ◽

Cell Death ◽

Memory T Cells ◽

Related Research ◽

Link Type ◽

Follicular Helper ◽

Research Article

Protecting TFH memory CD4+ T cells from NAD-induced cell death reveals both their longevity and plasticity (see related Research Article by Künzli et al.).

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