scholarly journals Identification of infants with increased type 1 diabetes genetic risk for enrollment into Primary Prevention Trials—GPPAD‐02 study design and first results

2019 ◽  
Vol 20 (6) ◽  
pp. 720-727 ◽  
Author(s):  
Christiane Winkler ◽  
Florian Haupt ◽  
Martin Heigermoser ◽  
Jose Zapardiel‐Gonzalo ◽  
Jasmin Ohli ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Primary Prevention ◽  
Study Design ◽  
Genetic Risk ◽  
First Results ◽  
Prevention Trials

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 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 Risk Factors and Primary Prevention Trials for Type 1 Diabetes

2013 ◽  
Vol 9 (7) ◽  
pp. 666-679 ◽  
Author(s):  
Yan-Ling Wu ◽  
Yan-Ping Ding ◽  
Jian Gao ◽  
Yoshimasa Tanaka ◽  
Wen Zhang
Keyword(s):  
Risk Factors ◽  
Type 1 Diabetes ◽  
Primary Prevention ◽  
Prevention Trials

Genetic Risk for Type 1 Diabetes Profoundly Influences the Core Gut Microbiome in Children

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 209-LB ◽  
Author(s):  
JORDAN RUSSELL ◽  
LUIZ ROESCH ◽  
MARK A. ATKINSON ◽  
DESMOND SCHATZ ◽  
ERIC W. TRIPLETT ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gut Microbiome ◽  
Genetic Risk ◽  
The Core

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

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.

scholarly journals De‐ coding genetic risk variants in type 1 diabetes

2021 ◽  
Author(s):  
Melanie R Shapiro ◽  
Puchong Thirawatananond ◽  
Leeana Peters ◽  
Robert C Sharp ◽  
Similoluwa Ogundare ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Genetic Risk ◽  
Risk Variants ◽  
Genetic Risk Variants

243-OR: Integrating Genetic Risk Score and Islet Autoantibody Characteristics in the Predictive Model for Type 1 Diabetes in the TrialNet Study

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 243-OR
Author(s):  
LAURIC A. FERRAT ◽  
ANDREA STECK ◽  
HEMANG M. PARIKH ◽  
LU YOU ◽  
SUNA ONENGUT-GUMUSCU ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Predictive Model ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Islet Autoantibody

scholarly journals Prediction of type 1 diabetes at birth: cord blood metabolites versus genetic risk score in the MoBa cohort

2021 ◽  
Author(s):  
German Tapia ◽  
Tommi Suvitaival ◽  
Linda Ahonen ◽  
Nicolai A Lund-Blix ◽  
Pål R Njølstad ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cord Blood ◽  
Bile Acids ◽  
Risk Score ◽  
Genetic Risk ◽  
Risk Group ◽  
Genetic Risk Score ◽  
Blood Concentrations ◽  
Polar Metabolites

Abstract Background and aim Genetic markers are established as predictive of type 1 diabetes, but unknown early life environment is believed to be involved. Umbilical cord blood may reflect perinatal metabolism and exposures. We studied whether selected polar metabolites in cord blood contribute to prediction of type 1 diabetes. Methods Using a targeted UHPLC-QQQ-MS platform, we quantified 27 low molecular weight metabolites (including amino acids, small organic acids and bile acids) in 166 children, who later developed type 1 diabetes, and 177 random control children in the Norwegian Mother, Father and Child (MoBa) cohort. We analysed the data using logistic regression (estimating odds ratios per standard deviation [aOR]), area under the receiver operating characteristic curve (AUC) and k-means clustering. Metabolites were compared to a genetic risk score based on 51 established non-HLA SNPs, and a four-category HLA risk group. Results The strongest associations for metabolites were aminoadipic acid (aOR=1.23,95%CI:0.97–1.55), indoxyl sulfate (aOR=1.15,95%CI:0.87–1.51), and tryptophan (aOR=0.84,95%CI:0.65–1.10), with other aORs close to 1.0, and none significantly associated with type 1 diabetes. K-means clustering identified six clusters, none of which were associated with type 1 diabetes. Cross-validated AUC showed no predictive value of metabolites (AUC 0.49), while the non-HLA genetic risk score AUC was 0.56 and the HLA risk group AUC was 0.78. Conclusions In this large study, we found no support of a predictive role of cord blood concentrations of selected bile acids and other small polar metabolites in the development of type 1 diabetes.

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