scholarly journals Oral insulin therapy for primary prevention of type 1 diabetes in infants with high genetic risk: the GPPAD-POInT (global platform for the prevention of autoimmune diabetes primary oral insulin trial) study protocol

BMJ Open ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. e028578 ◽  
Author(s):  
Anette-Gabriele Ziegler ◽  
Peter Achenbach ◽  
Reinhard Berner ◽  
Kristina Casteels ◽  
Thomas Danne ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Primary Prevention ◽  
Beta Cell ◽  
Genetic Risk ◽  
Autoimmune Diabetes ◽  
Genetic Risk Score ◽  
Acid Decarboxylase ◽  
Oral Insulin ◽  
Double Blind

IntroductionThe POInT study, an investigator initiated, randomised, placebo-controlled, double-blind, multicentre primary prevention trial is conducted to determine whether daily administration of oral insulin, from age 4.0 months to 7.0 months until age 36.0 months to children with elevated genetic risk for type 1 diabetes, reduces the incidence of beta-cell autoantibodies and diabetes.Methods and analysisInfants aged 4.0 to 7.0 months from Germany, Poland, Belgium, UK and Sweden are eligible if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies as determined by genetic risk score or family history and human leucocyte antigen genotype. Infants are randomised 1:1 to daily oral insulin (7.5 mg for 2 months, 22.5 mg for 2 months, 67.5 mg until age 36.0 months) or placebo, and followed for a maximum of 7 years. Treatment and follow-up is stopped if a child develops diabetes. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies or diabetes. Other outcomes are: (1) Any persistent confirmed beta-cell autoantibody (glutamic acid decarboxylase (GADA), IA-2A, autoantibodies to insulin (IAA) and zinc transporter 8 or tetraspanin 7), or diabetes, (2) Persistent confirmed IAA, (3) Persistent confirmed GADA and (4) Abnormal glucose tolerance or diabetes.Ethics and disseminationThe study is approved by the ethical committees of all participating clinical sites. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the trial.Trial registration numberNCT03364868.

scholarly journals Supplementation with Bifidobacterium longum subspecies infantis EVC001 for mitigation of type 1 diabetes autoimmunity: the GPPAD-SINT1A randomised controlled trial protocol

BMJ Open ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. e052449
Author(s):  
Anette-Gabriele Ziegler ◽  
Stefanie Arnolds ◽  
Annika Kölln ◽  
Peter Achenbach ◽  
Reinhard Berner ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Genetic Risk ◽  
Autoimmune Diabetes ◽  
Genetic Risk Score ◽  
Bifidobacterium Longum ◽  
Daily Administration ◽  
Ethical Review ◽  
Acid Decarboxylase

IntroductionThe Global Platform for the Prevention of Autoimmune Diabetes-SINT1A Study is designed as a randomised, placebo-controlled, double-blind, multicentre, multinational, primary prevention study aiming to assess whether daily administration of Bifidobacterium infantis from age 7 days to 6 weeks until age 12 months to children with elevated genetic risk for type 1 diabetes reduces the cumulative incidence of beta-cell autoantibodies in childhood.Methods and analysisInfants aged 7 days to 6 weeks from Germany, Poland, Belgium, UK and Sweden are eligible for study participation if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies by age 6 years as determined by genetic risk score or family history and HLA genotype. Infants are randomised 1:1 to daily administration of B. infantis EVC001 or placebo until age 12 months and followed for a maximum of 5.5 years thereafter. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies. Secondary outcomes are (1) Any persistent confirmed beta-cell autoantibody, defined as at least one confirmed autoantibody in two consecutive samples, including insulin autoantibodies, glutamic acid decarboxylase, islet tyrosine phosphatase 2 or zinc transporter 8, (2) Diabetes, (3) Transglutaminase autoantibodies associated with coeliac disease, (4) Respiratory infection rate in first year of life during supplementation and (5) Safety. Exploratory outcomes include allergy, antibody response to vaccines, alterations of the gut microbiome or blood metabolome, stool pH and calprotectin.Ethics and disseminationThe study was approved by the local ethical committees of the Technical University Munich, Medical Faculty, the Technische Universität Dresden, the Medizinische Hochschule Hannover, the Medical University of Warsaw, EC Research UZ Leuven and the Swedish ethical review authority. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the study.Trial registration numberNCT04769037.

scholarly journals Immune outcomes and safety of high-dose oral insulin as a primary prevention immunotherapy in young autoantibody-negative children at high genetic risk for type 1 diabetes

2020 ◽  
Author(s):  
Robin Assfalg ◽  
Jan Knoop ◽  
Kristi L. Hoffman ◽  
Markus Pfirrmann ◽  
Jose Maria Zapardiel-Gonzalo ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune System ◽  
Primary Prevention ◽  
Genetic Risk ◽  
Adaptive Immune System ◽  
Oral Insulin ◽  
Dependent Manner ◽  
Cell Responses ◽  
Adaptive Immune

AbstractBackgroundOral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes with insulin autoimmunity often appearing in the first years of life. The aim of this study was to assess the safety and immunological effects of oral insulin immunotherapy as a primary prevention.MethodsA phase I/II randomized controlled trial (Clinicaltrials.govNCT02547519) was performed in 44 islet autoantibody-negative children aged 6 months to 2 years with familial and additional genetic risk for type 1 diabetes. Children were randomized 1:1 to daily insulin (7.5 mg with dose escalation to 67.5 mg) or placebo for 12 months. Hypoglycemia was a major safety measure. The primary immune efficacy outcome was an induction of antibody or T cell responses to oral insulin.ResultsOral insulin was well tolerated with no changes in metabolic variables. The primary immune outcome did not differ between treatment groups and responses were observed in both children who received insulin (55%) or placebo (67%). Responses were, however, modified by the type 1 diabetes INSULIN gene. Among children with a susceptible genotype, antibody responses to insulin were more frequent in insulin-treated (cumulative response, 75.8%) as compared to placebo-treated children (18.2%; P = 0.0085). Mechanistic studies identified microbiome changes that were related to INSULIN genotype and frequent treatment-independent inflammatory episodes that modified the in vitro T cell responses to insulin in children with susceptible INSULIN genotypes.ConclusionThe study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe and engaged the adaptive immune system in an INSULIN genotype-dependent manner, and linked inflammatory episodes to the activation of insulin-responsive T cells.One Sentence SummaryOral insulin given daily to very young children was safe and may engage the adaptive immune system in an INSULIN genotype-dependent manner.

scholarly journals Next steps in the identification of gene targets for type 1 diabetes

Diabetologia ◽  
2020 ◽  
Vol 63 (11) ◽  
pp. 2260-2269 ◽  
Author(s):  
Struan F. A. Grant ◽  
Andrew D. Wells ◽  
Stephen S. Rich
Keyword(s):  
Type 2 Diabetes ◽  
Type 1 Diabetes ◽  
Beta Cell ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Cell Types ◽  
Total Risk ◽  
Chromosome Conformation

Abstract The purpose of this review is to provide a view of the future of genomics and other omics approaches in defining the genetic contribution to all stages of risk of type 1 diabetes and the functional impact and clinical implementations of the associated variants. From the recognition nearly 50 years ago that genetics (in the form of HLA) distinguishes risk of type 1 diabetes from type 2 diabetes, advances in technology and sample acquisition through collaboration have identified over 60 loci harbouring SNPs associated with type 1 diabetes risk. Coupled with HLA region genes, these variants account for the majority of the genetic risk (~50% of the total risk); however, relatively few variants are located in coding regions of genes exerting a predicted protein change. The vast majority of genetic risk in type 1 diabetes appears to be attributed to regions of the genome involved in gene regulation, but the target effectors of those genetic variants are not readily identifiable. Although past genetic studies clearly implicated immune-relevant cell types involved in risk, the target organ (the beta cell) was left untouched. Through emergent technologies, using combinations of genetics, gene expression, epigenetics, chromosome conformation and gene editing, novel landscapes of how SNPs regulate genes have emerged. Furthermore, both the immune system and the beta cell and their biological pathways have been implicated in a context-specific manner. The use of variants from immune and beta cell studies distinguish type 1 diabetes from type 2 diabetes and, when they are combined in a genetic risk score, open new avenues for prediction and treatment.

1535-P: An Insulin Resistance Genetic Risk Score (IR_GRS) Is Associated with Mortality in Type 1 Diabetes (T1D)

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1535-P
Author(s):  
RACHEL G. MILLER ◽  
TINA COSTACOU ◽  
SUNA ONENGUT-GUMUSCU ◽  
WEI-MIN CHEN ◽  
STEPHEN S. RICH ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 1 Diabetes ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score

Type 1 Diabetes-related Autoantibodies in Different Forms of Diabetes

2019 ◽  
Vol 15 (3) ◽  
pp. 199-204 ◽  
Author(s):  
Elin Pettersen Sørgjerd
Keyword(s):  
Type 2 Diabetes ◽  
Type 1 Diabetes ◽  
Autoimmune Diabetes ◽  
Acid Decarboxylase ◽  
Adult Onset ◽  
Latent Autoimmune Diabetes ◽  
Childhood Type 1 Diabetes ◽  
Childhood Type

Autoantibodies against Glutamic Acid Decarboxylase (GADA), insulinoma antigen-2 (IA- 2A), insulin (IAA) and the most recently Zinc Transporter 8 (ZnT8A) are one of the most reliable biomarkers for autoimmune diabetes in both children and adults. They are today the only biomarkers that can distinguish Latent Autoimmune Diabetes in Adults (LADA) from phenotypically type 2 diabetes. As the frequency of autoantibodies at diagnosis in childhood type 1 diabetes depends on age, GADA is by far the most common in adult onset autoimmune diabetes, especially LADA. Being multiple autoantibody positive have also shown to be more common in childhood diabetes compared to adult onset diabetes, and multiple autoantibody positivity have a high predictive value of childhood type 1 diabetes. Autoantibodies have shown inconsistent results to predict diabetes in adults. Levels of autoantibodies are reported to cause heterogeneity in LADA. Reports indicate that individuals with high levels of autoantibodies have a more type 1 diabetes like phenotype and individuals with low levels of autoantibody positivity have a more type 2 diabetes like phenotype. It is also well known that autoantibody levels can fluctuate and transient autoantibody positivity in adult onset autoimmune diabetes have been reported to affect the phenotype.

scholarly journals Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route

2020 ◽  
Vol 21 (5) ◽  
pp. 1598 ◽  
Author(s):  
Johnny Ludvigsson
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Human Subjects ◽  
Subcutaneous Administration ◽  
Acid Decarboxylase ◽  
Recent Onset ◽  
Prevention Trials

Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the disease. In experimental animal models, efficacy was good, but was insufficient in human subjects. Besides the possible minor efficacy of peroral insulin in high-risk individuals to prevent T1D, autoantigen prevention trials have failed. Other studies on autoantigen prevention and intervention at diagnosis are ongoing. One problem is to select autoantigen/s; others are dose and route. Oral administration may be improved by using different vehicles. Proinsulin peptide therapy in patients with T1D has shown possible minor efficacy. In patients with newly diagnosed T1D, subcutaneous injection of glutamic acid decarboxylase (GAD) bound to alum hydroxide (GAD-alum) can likely preserve beta-cell function, but the therapeutic effect needs to be improved. Intra-lymphatic administration may be a better alternative than subcutaneous administration, and combination therapy might improve efficacy. This review elucidates some actual problems of autoantigen therapy in the prevention and/or early intervention of type 1 diabetes.

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