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Screening for islet autoantibodies in children and adolescents identifies individuals who will later develop type 1 diabetes, allowing patient and family education to prevent diabetic ketoacidosis at onset and to enable consideration of preventive therapies. We aimed to assess whether islet autoantibody screening is effective for predicting type 1 diabetes in adolescents aged 10−18 years with an increased risk of developing type 1 diabetes.

ObjectiveINGR1D (INvestigating Genetic Risk for type 1 Diabetes) was a type 1 diabetes (T1D) genetic screening study established to identify participants for a primary prevention trial (POInT, Primary Oral Insulin Trial).MethodsThe majority of participants were recruited by research midwives in antenatal clinics from 18 weeks’ gestation. Using the NHS Newborn Bloodspot Screening Programme (NBSP) infrastructure, participants enrolled in INGR1D had an extra sample taken from their day 5 bloodspot card sent for T1D genetic screening. Those at an increased risk of T1D were informed of the result, given education about T1D and the opportunity to take part in POInT.ResultsBetween April 2018 and November 2020, 66% of women approached about INGR1D chose to participate. 15 660 babies were enrolled into INGR1D and 14 731 blood samples were processed. Of the processed samples, 157 (1%) had confirmed positive results, indicating an increased risk of T1D, of whom a third (n=49) enrolled into POInT (20 families were unable to participate in POInT due to COVID-19 lockdown restrictions).ConclusionThe use of prospective consent to perform personalised genetic testing on samples obtained through the routine NBSP represents a novel mechanism for clinical genetic research in the UK and provides a model for further population-based genetic studies in the newborn.

Women with gestational diabetes mellitus (GDM) have a high risk of developing postpartum type 2 diabetes. Strategies to prevent postpartum type 2 diabetes are important to reduce the epidemic of diabetes and its societal impact. Breastfeeding was reported to improve early postpartum glucose tolerance and reduce the subsequent risk of type 2 diabetes. To investigate whether breastfeeding influences short- and long-term postpartum diabetes outcomes, women with GDM (n = 304) participating in the prospective German GDM study were followed from delivery for up to 19 years postpartum for diabetes development. All participants were recruited between 1989 and 1999. Postpartum diabetes developed in 147 women and was dependent on the treatment received during pregnancy (insulin vs. diet), BMI, and presence/absence of islet autoantibodies. Among islet autoantibody-negative women, breastfeeding was associated with median time to diabetes of 12.3 years compared with 2.3 years in women who did not breastfeed. The lowest postpartum diabetes risk was observed in women who breastfed for >3 months. On the basis of these results, we recommend that breastfeeding should be encouraged among these women because it offers a safe and feasible low-cost intervention to reduce the risk of subsequent diabetes in this high-risk population., Gestational diabetes mellitus (GDM) occurs in around 4% of pregnancies and is defined as glucose intolerance with an onset or first diagnosis during pregnancy (1). GDM is known to increase [...]

OBJECTIVE--The incidence of type 1 diabetes is increasing. Delivery by cesarean section is also more prevalent, and it is suggested that cesarean section is associated with type 1 diabetes risk. We examine associations between cesarean delivery, islet autoimmunity and type 1 diabetes, and genes involved in type 1 diabetes susceptibility. RESEARCH DESIGN AND METHODS--Cesarean section was examined as a risk factor in 1,650 children born to a parent with type 1 diabetes and followed from birth for the development of islet autoantibodies and type 1 diabetes. RESULTS--Children delivered by cesarean section (n = 495) had more than twofold higher risk for type 1 diabetes than children born by vaginal delivery (hazard ratio [HR] 2.5; 95% CI 1.4-4.3; P = 0.001). Cesarean section did not increase the risk for islet autoantibodies (P = 0.6) but was associated with a faster progression to diabetes after the appearance of autoimmunity (P = 0.015). Cesarean section-associated risk was independent of potential confounder variables (adjusted HR 2.7;1.5-5.0; P = 0.001) and observed in children with and without high-risk HLA genotypes. Interestingly, cesarean section appeared to interact with immune response genes, including CD25 and in particular the interferon-induced helicase 1 gene, where increased risk for type 1 diabetes was only seen in children who were delivered by cesarean section and had type 1 diabetes-susceptible IFIH1 genotypes (12-year risk, 9.1 vs. CONCLUSIONS--These findings suggest that type 1 diabetes risk modification by cesarean section may be linked to viral responses in the preclinical autoantibody-positive disease phase., Type 1 diabetes is characterized by autoimmunity and a genetic susceptibility encoded in multiple genes (1). The last decades have seen a marked increase in the incidence of type 1 [...]

OBJECTIVE--Genome-wide association studies have identified gene regions associated with the development of type 1 diabetes. The aim of this study was to determine whether these associations are with the development of autoimmunity and/or progression to diabetes. RESEARCH DESIGN AND METHODS--Children (n = 1,650) of parents with type 1 diabetes were prospectively followed from birth (median follow-up 10.20 years) for the development of islet autoantibodies, thyroid peroxidase antibodies, tissue transglutaminase antibodies, and diabetes. Genotyping for single-nucleotide polymorphisms of the PTPN22, ERBB3, PTPN2, KIAA0350, CD25, and IFIH1 genes was performed using the MassARRAY system with iPLEX chemistry. RESULTS--Islet autoantibodies developed in 137 children and diabetes developed in 47 children. Type 1 diabetes risk was associated with the IFIH1 rs2111485 single-nucleotide polymorphism (hazard ratio 2.08; 95% CI 1.16-3.74; P = 0.014). None of the other genes were significantly associated with diabetes development in this cohort. IFIH1 genotypes did not associate with the development of islet autoantibodies (P = 0.80) or autoantibodies against thyroid peroxidase (P = 0.55) and tissue transglutaminase (P = 0.66). Islet autoantibody-positive children with the IFIH1 rs2111485 GG genotype had a faster progression to diabetes (31% within 5 years) than children with the type 1 diabetes protective GA or AA genotypes (11% within 5 years; P = 0.006). CONCLUSIONS--The findings indicate that IFIH1 genotypes influence progression from autoimmunity to diabetes development, consistent with the notion that protective genotypes down-regulate responses to environmental insults after initiation of autoimmunity., Genome-wide association studies have identified a number of gene regions associated with type 1 diabetes (1). Candidate genes, along with potential mechanisms of action in disease pathogenesis, have been proposed [...]

OBJECTIVE--To determine whether HHEX-IDE and CDKAL1 genes, which are associated with birth weight and susceptibility to type 2 diabetes, continue to influence growth during childhood. RESEARCH DESIGN AND METHODS--BMI, weight, and height at age 8 years expressed as age- and sex-corrected standard deviation scores (SDS) against national reference data and single-nucleotide polymorphism genotyping of HHEX-IDE and CDKAL1 loci were analyzed in 646 prospectively followed children in the German BABYDIAB cohort. All children were singleton full-term births; 386 had mothers with type 1 diabetes, and 260 had fathers with type 1 diabetes and a nondiabetic mother. RESULTS--Type 2 diabetes risk alleles at the HHEX-IDE locus were associated with reduced BMI-SDS at age 8 years (0.17 SDS per allele; P = 0.004). After stratification for birth weight, both HHEX-IDE and CDKAL1 risk alleles were associated with reduced BMI-SDS (0.45 SDS, P = 0.0002; 0.52 SDS, P = 0.0001) and weight-SDS (0.22 SDS, P = 0.04; 0.56 SDS, P = 0.0002) in children born large for gestational age (>90th percentile) but not children born small or appropriate for gestational age. Within children born large for gestational age, BMI and weight decreased with each additional type 2 diabetes risk allele (~ -2 kg per allele; >8 kg overall). Findings were consistent in children of mothers with type 1 diabetes (P < 0.0001) and children of nondiabetic mothers (P = 0.008). CONCLUSIONS--The type 2 diabetes susceptibility alleles at HHEX-IDE and CDKAL1 loci are associated with low BMI at age 8 years in children who were born large for gestational age., Genome-wide association studies have recently identified common, novel type 2 diabetes susceptibility loci that are likely to predispose one to diabetes via impaired pancreatic β-cell function, impaired insulin secretion, and/or [...]

US-amerikanische Schwarze Feminist*innen entwickelten den Begriff Birth Justice, um strukturell verankerte Ungleichheits- und Gewaltverhältnisse rund um Schwangerschaft, Geburt und frühe Elternschaft sichtbar zu machen (Oparah 2015). Birth Justice verortet sich im Kontext des Konzeptes von Reproductive Justice und ist durch eine menschenrechtsbasierte, intersektionale Analyse reproduktiver Ungleichheitsverhältnisse gekennzeichnet (Oparah 2015; Ross und Solinger 2017).

Type 1 diabetes is the most common chronic metabolic disease in childhood. Often diagnosis comes with acutely life-threatening ketoacidosis and requires hospitalization. To avoid this, early detection of children at a pre-symptomatic stage is worthwhile. This task is met by a population-based screening in Bavaria, Germany – the Fr1da study. Here, we aim to evaluate the study concept, feasibility and medical evidence of the Fr1da study. 308 pediatricians, 16 diabetes care centers and participating families were asked to evaluate the Fr1da study by completing questionnaires assessing study concept and feasibility, educational program and study organization. The assessment was done anonymously. In order to evaluate the effectiveness of the training the parents had to answer questionnaires to assess their knowledge about diabetes. 48% of pediatricians and 56% of pediatric diabetes care centers filled out the questionnaire. The majority positively judged the collaboration with the Fr1da coordinating center and the feasibility to integrate the project into daily routine. Medical evidence of the screening was recognized and most of the respondents endorsed the screening to be permanently integrated into standard care-program. The majority of parents would recommend the study to other parents with young children since they were satisfied with the collaboration with pediatricians, diabetes care centers and the coordinating center. Quality control of the educational program revealed good understanding of the teaching content. The Fr1da study received high acceptance and recognition by both, health care providers and participating families, and demonstrated sustainable success with the developed educational program.

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.

Activation of G-protein-coupled receptors is the first step of the signaling cascade triggered by binding of an agonist. Here we compare the activation kinetics of the Gq-coupled M3acetylcholine receptor (M3-AChR) with that of a constitutively active mutant receptor (M3-AChR-N514Y) using M3-AChR constructs that report receptor activation by changes in the fluorescence resonance energy transfer (FRET) signal. We observed a leftward shift in the concentration-dependent FRET response for acetylcholine and carbachol with M3-AChR-N514Y. Consistent with this result, at submaximal agonist concentrations, the activation kinetics of M3-AChR-N514Y were significantly faster, whereas at maximal agonist concentrations the kinetics of receptor activation were identical. Receptor deactivation was significantly faster with carbachol than with acetylcholine and was significantly delayed by the N514Y mutation. Receptor-G-protein interaction was measured by FRET between M3-AChR-yellow fluorescent protein (YFP) and cyan fluorescent protein (CFP)-Gγ2. Agonist-induced receptor-G-protein coupling was of a time scale similar to that of receptor activation. As observed for receptor deactivation, receptor-G-protein dissociation was slower for acetylcholine than that for carbachol. Acetylcholine-stimulated increases in receptor-G-protein coupling of M3-AChR-N514Y reached only 12% of that of M3-AChR and thus cannot be kinetically analyzed. G-protein activation was measured using YFP-tagged Gαqand CFP-tagged Gγ2. Activation of Gqwas significantly slower than receptor activation and indistinguishable for the two agonists. However, Gqdeactivation was significantly prolonged for acetylcholine compared with that for carbachol. Consistent with decreased agonist-stimulated coupling to Gq, agonist-stimulated Gqactivation by M3-AChR-N514Y was not detected. Taken together, these results indicate that the N514Y mutation produces constitutive activation of M3-AChR by decreasing the rate of receptor deactivation, while having minimal effect on receptor activation.

Mitochondria consist of four compartments–outer membrane, intermembrane space, inner membrane, and matrix—with crucial but distinct functions for numerous cellular processes. A comprehensive characterization of the proteome of an individual mitochondrial compartment has not been reported so far. We used a eukaryotic model organism, the yeast Saccharomyces cerevisiae, to determine the proteome of highly purified mitochondrial outer membranes. We obtained a coverage of ∼85% based on the known outer membrane proteins. The proteome represents a rich source for the analysis of new functions of the outer membrane, including the yeast homologue (Hfd1/Ymr110c) of the human protein causing Sjögren–Larsson syndrome. Surprisingly, a subclass of proteins known to reside in internal mitochondrial compartments were found in the outer membrane proteome. These seemingly mislocalized proteins included most top scorers of a recent genome-wide analysis for mRNAs that were targeted to mitochondria and coded for proteins of prokaryotic origin. Together with the enrichment of the precursor form of a matrix protein in the outer membrane, we conclude that the mitochondrial outer membrane not only contains resident proteins but also accumulates a conserved subclass of preproteins destined for internal mitochondrial compartments.

CONTEXT: The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion also reduce birth weight, and an association of low birth weight and the type 2 diabetes risk alleles at the HHEX-IDE and CDKAL1 loci were recently reported. OBJECTIVE: Here, we examined the relationship between type 2 diabetes risk alleles and birth weight in a diabetic environment presented in children of mothers with type 1 diabetes. Research Design and Methods: Birth weight and genotyping of single nucleotide polymorphisms (SNPs) at the CDKAL1, HHEX-IDE, and SLC30A8 loci was obtained and analyzed in 729 singleton full-term children of mothers with type 1 diabetes born in Germany. RESULTS: The fetal risk alleles of HHEX-IDE SNP rs5015480 and SNP rs10882102 were associated with reduced birth weight: 81g (95% confidence interval, 20–140 g; P = 0.009) and 85 g (95% confidence interval, 25–145 g; P = 0.005) lower birth weight per risk allele, respectively. The association remained significant after adjusting for maternal pregnancy-glycosylated hemoglobin. Fetal genotypes at the CDKAL1 and SLC30A8 loci were not associated with birth weight in this cohort. CONCLUSIONS: The association of low birth weight and type 2 diabetes risk alleles of the HHEX-IDE locus is confirmed in children of mothers with type 1 diabetes.

Background/aimExposure to the intrauterine hyperglycemic environment has been suggested to increase the offspring’s later overweight and metabolic risk, but conclusive evidence for pregnancies affected by maternal type 1 diabetes (T1D) is still lacking. Further, it is unknown whether changes in the offspring’s metabolome are in the potential pathway.MethodsWe analysed data from 610 and 2169 offspring having a first-degree relative with T1D from the TEENDIAB and BABYDIAB/BABYDIET cohorts, respectively. Associations of maternal T1D with anthropometric and metabolic outcomes in the offspring, assessed longitudinally at 0.3–18 years of age, were investigated using mixed regression models. Non-targeted metabolomics measurements were carried out in 500 fasting serum samples from TEENDIAB and associated with maternal T1D and offspring overweight.ResultsOffspring of T1D mothers had a higher body mass index standard deviation score (SDS) and an increased risk for overweight than offspring of non-diabetic mothers (e.g. odds ratio for overweight in TEENDIAB: 2.40 (95% confidence interval: 1.41; 4.06)). Further, waist circumference SDS, fasting levels of insulin and C-peptide, as well as insulin resistance and abdominal obesity were significantly increased in offspring of T1D mothers, even when adjusted for potential confounders and birth weight. Metabolite patterns related to androgenic steroids and branched-chain amino acids were found to be associated with offspring’s overweight, but no significant associations were observed between maternal T1D and metabolite concentrations in the offspring.ConclusionMaternal T1D is associated with offspring’s overweight and metabolic health in later life, but this is not likely due to alterations in the offspring’s metabolome.