AIM:Pancreatic islet δ-cells produce somatostatin, a paracrine regulator of insulin and glucagon secretion within islets. Although adaptive changes in α- and β-cell populations during pregnancy have been described in both animals and humans, data on δ-cell plasticity are sparse and entirely lacking in human pregnancy. We aimed to determine whether pancreatic islet δ-cell mass undergoes morphological adaptation during human pregnancy. METHODS AND RESULTS:Formalin-fixed paraffin-embedded pancreatic tissue from pregnant (n = 7) and non-pregnant (n = 7) donors was analysed. Sections were immunolabelled for somatostatin to identify δ cells, and whole-slide quantitative analysis was performed using an unbiased automated imaging pipeline. δ-cell area was measured across the entire pancreatic sections and compared between groups. In contrast to previously reported expansion of α- and β-cell populations in pregnancy, δ-cell area was not significantly different between pregnant and non-pregnant donors. No quantitative architectural alterations in δ-cell distribution within islets were observed. CONCLUSION:Pancreatic δ-cell area does not increase during human pregnancy. These findings demonstrate that endocrine cell plasticity within the maternal pancreas is selective and does not uniformly involve all islet cell subtypes.

Type 1 diabetes (T1D) is a chronic condition caused by the immune destruction of the pancreatic beta cells. T1D has recognised asymptomatic pre-clinical stages, providing an opportunity for early diagnosis, education and treatment which may delay the onset of symptoms. The oral glucose tolerance test (OGTT) is the gold standard method to stage and monitor early-stage T1D, which can be poorly tolerated and may contribute to marked loss to follow-up. Our study aims to test the accuracy, feasibility, and acceptability of a capillary alternative (‘GTT@home’ test kit) to the gold standard OGTT. We will invite 45 children and young people (CYP) across the spectrum of glycaemia with or without diabetes, from established research platforms or clinical care, to have a standard 2-hour OGTT, with capillary samples collected alongside their venous samples, at 0 and 120 minutes. A subgroup (n=20) will also have 60-minute capillary and venous samples collected. We will also invite 45 CYP from established research platforms, who are known to have two or more islet autoantibodies and are not on insulin, to undergo a capillary OGTT at home, using the GTT@home kit. We will assess the agreement of capillary and venous glucose and measure diagnostic accuracy by calculating the sensitivity and specificity of capillary measures at established diagnostic thresholds (fasting [5.6 mmol/L, 7.0 mmol/L], 60 minutes post glucose load [11.1 mmol/L] and 120 minutes post glucose load [7.8 mmol/L and 11.1 mmol/L]), using venous glucose as the gold standard. These studies will inform our understanding of whether the GTT@home device can be used in CYP in routine clinical care.

Type 1 diabetes (T1D) is a chronic condition caused by the immune destruction of the pancreatic beta cells. T1D has recognised asymptomatic pre-clinical stages, providing an opportunity for early diagnosis, education and treatment which may delay the onset of symptoms. The oral glucose tolerance test (OGTT) is the gold standard method to stage and monitor early-stage T1D, which can be poorly tolerated and may contribute to marked loss to follow-up. Our study aims to test the accuracy, feasibility, and acceptability of a capillary alternative (‘GTT@home’ test kit) to the gold standard OGTT. We will invite 45 children and young people (CYP) across the spectrum of glycaemia with or without diabetes, from established research platforms or clinical care, to have a standard 2-hour OGTT, with capillary samples collected alongside their venous samples, at 0 and 120 minutes. A subgroup (n=20) will also have 60-minute capillary and venous samples collected. We will also invite 45 CYP from established research platforms, who are known to have two or more islet autoantibodies and are not on insulin, to undergo a capillary OGTT at home, using the GTT@home kit. We will assess the agreement of capillary and venous glucose and measure diagnostic accuracy by calculating the sensitivity and specificity of capillary measures at established diagnostic thresholds (fasting [5.6 mmol/L, 7.0 mmol/L], 60 minutes post glucose load [11.1 mmol/L] and 120 minutes post glucose load [7.8 mmol/L and 11.1 mmol/L]), using venous glucose as the gold standard. These studies will inform our understanding of whether the GTT@home device can be used in CYP in routine clinical care.

Physiological changes during pregnancy support foetal growth, including adaptations in pancreatic islets to maintain glucose homeostasis. We investigate these adaptations using rare, high-quality pancreatic tissue from pregnant human donors and matched controls. We profile islets from pregnant donors using proteomics and assess α- and β-cell characteristics, as well as prolactin receptor and serotonin 2B receptor expression. Proteomic profiling of microdissected human islets identifies 7546 proteins but shows minimal differences in protein expression. In pregnancy, we show that islet area increases 1.9-fold, α- and β-cell areas increase 4.3- and 1.9-fold, driven by an increase in cell number rather than hypertrophy. Prolactin receptor expression is higher in α but not β cells, and serotonin 2B receptor is undetectable in β cells. Glucagon-like peptide-1 abundance increases 2.9-fold in α cells. These findings indicate that the molecular mechanisms driving pregnancy-induced islet adaptations in humans differ from those in mice, highlighting the need for human-based studies.

Type 1 diabetes (T1D) results from the autoimmune destruction of the insulin-producing β cells. Genetic factors account for approximately 50% of the risk for T1D but, by the late 1990s, the genetic basis was limited. The Type 1 Diabetes Genetics Consortium (T1DGC) was formed in 2002 to accelerate discovery of genes contributing to T1D risk through a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to assemble existing data and samples from affected sib-pair families and to establish new collections. In recognition of the 75th anniversary of the NIDDK, this manuscript highlights the contributions made by the T1DGC to understanding the genetic basis of T1D using both family (for linkage) and case-control (for genome-wide association) designs. The T1DGC conducted large-scale genetic research and used fine mapping to define risk regions. The T1DGC data, results, and samples have been made available to the scientific community, leading to the discovery of more than 100 loci associated with T1D risk, many with small effects and relevant to autoimmune pathways. The T1DGC not only expanded the list of genes contributing to disease risk but also identified noncoding genetic variation in disease-relevant cell types that contribute to the etiology of T1D. The success of the T1DGC and the NIDDK investment in the global consortium is highlighted in its continuing effect on mapping genetic variants to their function and identifying pathways that provide new targets for the prediction, prevention, and treatment of T1D.

Biological datasets often consist of thousands or millions of variables, e.g. genetic variants or biomarkers, and when sample sizes are large it is common to find many associated with an outcome of interest, for example, disease risk in a GWAS, at high levels of statistical significance, but with very small effects. The False Discovery Rate (FDR) is used to identify effects of interest based on ranking variables according to their statistical significance. Here, we develop a complementary measure to the FDR, the priorityFDR, that ranks variables by a combination of effect size and significance, allowing further prioritisation among a set of variables that pass a significance or FDR threshold. Applying to the largest GWAS of type 1 diabetes to date (15,573 cases and 158,408 controls), we identified 26 independent genetic associations, including two newly-reported loci, with qualitatively lower priorityFDRs than the remaining 175 signals. We detected putatively causal type 1 diabetes risk genes using Mendelian Randomisation, and found that these were located disproportionately close to low priorityFDR signals (p = 0.005), as were genes in the IL-2 pathway (p = 0.003). Selecting variables on both effect size and significance can lead to improved prioritisation for mechanistic follow-up studies from genetic and other large biological datasets.

Over 1,000 genetic variants have been associated with diabetes by genome-wide association studies (GWASs), but for most, their functional impact is unknown; only 7% alter gene expression in pancreatic islets in expression quantitative trait locus (eQTL) studies. To fill this gap, we developed a co-localization pipeline, colocRedRibbon, that prefilters eQTLs by the direction of effect on gene expression and shortlists overlapping eQTL and GWAS variants prior to co-localization. Applying colocRedRibbon to recent diabetes and glycemic trait GWASs, we identified 292 co-localizing gene regions, including 24 co-localizations for type 1 diabetes and 268 for type 2 diabetes and glycemic traits, representing a 4-fold increase. A low-frequency type 2 diabetes protective variant increases islet MYO5C expression, and a type 1 diabetes protective variant increases FUT2 expression. These novel co-localizations advance the understanding of diabetes genetics and its impact on human islet biology. colocRedRibbon has broad applicability to co-localize GWASs and various QTLs.

BACKGROUND:Viral infections, including COVID-19, are associated with an increased risk for type 1 diabetes (T1D), but potential underlying mechanisms remain unexplored. We evaluated whether COVID-19 or influenza A infection is characterized by differential DNA methylation at immune and T1D susceptibility genes in young children at risk for T1D. METHODS:Epigenome-wide association analysis using the Illumina MethylationEPIC microarray was performed in blood taken at age 1.5 years (IQR, 1.49-1.52 y) from 740 prospectively followed children with increased risk of T1D. SARS-CoV-2 and influenza A H1N1 antibodies were monitored at 2-4-month intervals from age 6 months to identify infection. RESULTS:COVID-19 and influenza infection occurred prior to the DNA methylation sample in 81 and 74 children, respectively. Of these, infection occurred within 3 months of the DNA methylation sample (recent infection) in 43 and 22 children. Compared to children without COVID-19 or influenza A infection, children with recent COVID-19 infection showed differential methylation at key immune- and antiviral genes, including ADAR, IFI44L, MX1 and OASL. In addition to ADAR, six further T1D susceptibility genes, including the SARS-CoV-2 cell entry receptor neuropilin-1, had differential methylation at nearby CpGs in children infected by SARS-CoV-2. A quantitatively less differential methylation was also observed in children with an earlier COVID-19 infection at some of these CpG sites. Infections with influenza showed no associations. CONCLUSION:Children with SARS-CoV-2 infection showed sustained DNA methylation changes at genes critical for antiviral response and T1D susceptibility, potentially contributing to immune dysregulation and promotion of the autoimmune process underlying T1D.

The immune–epithelial–stromal interactions underpinning intestinal damage in celiac disease (CD) are incompletely understood. To address this, we performed single-cell transcriptomics (RNA sequencing; 86,442 immune, parenchymal and epithelial cells; 35 participants) and spatial transcriptomics (20 participants) on CD intestinal biopsy samples. Here we show that in CD, epithelial populations shifted toward a progenitor state, with interferon-driven transcriptional responses, and perturbation of secretory and enteroendocrine populations. Mucosal T cells showed numeric and functional changes in regulatory and follicular helper-like CD4 + T cells, intraepithelial lymphocytes, CD8 + and γδ T cell subsets, with skewed T cell antigen receptor repertoires. Mucosal changes remained detectable despite treatment, representing a persistent immune–epithelial ‘scar’. Spatial transcriptomics defined transcriptional niches beyond those captured in conventional histological scores, including CD-specific lymphoid aggregates containing T cell–B cell interactions. Receptor–ligand spatial analyses integrated with disease susceptibility gene expression defined networks of altered chemokine and morphogen signaling, and provide potential therapeutic targets for CD prevention and treatment.

BACKGROUND:Type 1 diabetes begins with autoimmunity against pancreatic islet antigens, including insulin. The aim of the Primary Oral Insulin Trial (POInT) was to evaluate the efficacy and safety of daily high-dose oral insulin to prevent the development of islet autoantibodies and diabetes. METHODS:In this randomised, controlled, primary prevention trial, genetic screening in seven obstetric and paediatric clinics in Germany, Poland, Sweden, Belgium, and the UK identified newborns with a greater than 10% risk of developing islet autoimmunity. Eligible infants aged 4-7 months were randomly assigned in a 1:1 ratio to receive insulin manufactured from human zinc-insulin crystals administered orally at a once-daily dose of 7·5 mg for 2 months, increasing to 22·5 mg for 2 months and 67·5 mg until age 3 years, or placebo. Participants were randomly assigned via a web-based application and were stratified by site. The primary outcome was the development of two or more islet autoantibodies or diabetes assessed throughout follow-up until a maximum age of 6·5 years. A secondary outcome was the development of dysglycaemia or diabetes. Islet autoantibodies were measured in samples collected at baseline and during study visits conducted at outpatient clinics at 2, 4, and 8 months after randomisation, at age 18 months, and every 6 months thereafter. All participants and their family members, investigators of the study, and laboratory personnel remained masked to treatment allocation during the whole study. All randomly assigned participants who correctly fulfilled eligibility criteria and had not reached the primary outcome at the baseline visit (modified intention-to-treat) were included in the primary analysis. All participants who received at least one dose of study drug were included in the safety analysis. POInT is registered with ClinicalTrials.gov (NCT03364868) and is complete. FINDINGS:Of 241 977 screened newborns, 2750 (1·14%) had an elevated genetic risk of developing islet autoimmunity and 1050 (38·2%) of the eligible infants (531 males [51%], 519 females [49%]), were assigned to oral insulin or placebo between Feb 7, 2018, and March 24, 2021. Two participants in the oral insulin group and none in the placebo group were excluded from the modified intention-to-treat analysis. The primary outcome developed in 52 (10%) participants in the insulin group and 46 (9%) in the placebo group (hazard ratio 1·12 [95% CI 0·76-1·67], p=0·57). An interaction between treatment and the INS rs1004446 genotype was observed, with an increase in the primary outcome in participants in the insulin group carrying non-susceptible INS genotypes compared with the placebo group (2·10 [1·08-4·09]) and protection against diabetes or dysglycaemia in participants in the insulin group carrying susceptible INS genotypes compared with the placebo group (0·38 [0·17-0·86]). Blood glucose values less than 50 mg/dL were observed in two (0·03%) of 7210 measurements in the insulin group and six (0·08%) of 7070 measurements in the placebo group. Of 10 252 reported adverse events, 5076 (49·5%) occurred in 507 (96·0%) of 528 participants in the oral insulin group and 5176 (50·5%) occurred in 500 (95·8%) of 522 participants in the placebo group. One death occurred in the oral insulin group and was unrelated to the study drug following independent review. INTERPRETATION:There was no evidence that high-dose, daily oral insulin prevents the development of islet autoantibodies. Further studies are needed to assess the benefit of primary oral insulin therapy for preventing diabetes in INS genotype-selected infants. FUNDING:Leona M and Harry B Helmsley Charitable Trust.

Objective: C-peptide and islet autoantibodies are key type 1 diabetes biomarkers, typically requiring venous sampling, which limit their utility. We assessed transdermal capillary blood (TCB) collection as a practical alternative. Research Design and methods: Ninety-one individuals (71 type 1 diabetes, 20 controls; type 1 diabetes: aged median 14.8 years[interquartile range 9.1-17.1]; diabetes duration 4.0 years[1.5-7.7]; controls 42.2 years[38.0-52.1]) underwent contemporaneous venous and TCB sampling for measurement of plasma C-peptide. Type 1 diabetes participants also provided venous serum and plasma, and TCB plasma for measurement of autoantibodies to glutamate decarboxylase, islet antigen-2, and zinc transporter 8. The ability of TCB plasma to detect significant endogenous insulin secretion (venous C-peptide ≥200pmol/L) was compared along with agreement in levels using Bland-Altman. Venous serum was compared with venous and TCB plasma for detection of autoantibodies using established thresholds. Acceptability was assessed by age-appropriate questionnaire. Results: Transdermal sampling took a mean of 2.35minutes (SD 1.49). Median sample volume was 50 µl(IQR 40-50) with 3/91(3.3%) failures, and 13/88(14.7%) <35 µL). TCB C-peptide showed good agreement to venous plasma (mean venous ln(C-peptide) – TCB ln(C-peptide) = 0.008, 95% CI(-0.23, 0.29), with 100%(36/36) sensitivity/100%(50/50) specificity to detect venous C-peptide ≥ 200pmol/L. Where venous serum in multiple autoantibody positive TCB plasma agreed in 22/32 (sensitivity 69%), comparative specificity was 35/36 (97%). TCB was preferred to venous sampling (type 1 diabetes: 63% vs 7%; 30% undecided). Conclusions: Transdermal capillary testing for C-peptide is a sensitive, specific, and acceptable alternative to venous sampling, TCB sampling for islet autoantibodies needs further assessment.

Insulin secretion increases progressively during pregnancy to maintain normal maternal blood glucose levels. The placenta plays a crucial role in this process by releasing hormones and extracellular vesicles into the maternal circulation, which drive significant changes in pregnancy physiology. Placental extracellular vesicles, which are detectable in the plasma of pregnant women, have been shown to signal peripheral tissues and contribute to pregnancy-related conditions. While studies using murine models have demonstrated that extracellular vesicles can modulate insulin secretion in pancreatic islets, it remains unclear whether these effects translate to human biology. Understanding how placental signals enhance insulin synthesis and secretion from β cells could be pivotal in developing new therapies for diabetes. In our study, we isolated placental small extracellular vesicles from human placentae and utilised the human β cell line, EndoC-βH3, to investigate their effects on β-cell function in vitro. Our results indicate that human β cells internalise placental small extracellular vesicles, leading to enhanced insulin gene expression and increased insulin content within the β cells. Moreover, these vesicles up-regulated the expression of Annexin A1, a protein known to increase insulin content. This up-regulation of Annexin A1 holds promise as a potential mechanism by which placental small extracellular vesicles enhance insulin biosynthesis.

Type 1 diabetes is an heterogenous condition. Characterising factors explaining differences in an individual’s clinical course and treatment response will have important clinical and research implications. Our aim was to explore type 1 diabetes heterogeneity, as assessed by clinical characteristics, autoantibodies, beta cell function and glycaemic outcomes, during the first 12 months from diagnosis, and how it relates to age at diagnosis. Data were collected from the large INNODIA cohort of individuals (aged 1.0–45.0 years) newly diagnosed with type 1 diabetes, followed 3 monthly, to assess clinical characteristics, C-peptide, HbA1c and diabetes-associated antibodies, and their changes, during the first 12 months from diagnosis, across three age groups: <10 years; 10–17 years; and ≥18 years. The study population included 649 individuals (57.3

OBJECTIVE:Type 1 diabetes (T1D) screening programmes testing islet autoantibodies (IAbs) in childhood can reduce life-threatening diabetic ketoacidosis. General population screening is required to detect the majority of children with T1D, since in >85% there is no family history. Age 3-5 years has been proposed as an optimal age for a single screen approach. DESIGN:Capillary samples were collected from children attending their preschool vaccination and analysed for IAbs to insulin, glutamic acid decarboxylase, islet antigen-2 and zinc transporter 8 using radiobinding/luciferase immunoprecipitation system assays. Acceptability was assessed using semistructured interviews and open-ended postcard questionnaires with parents. SETTING:Two primary care practices in Oxfordshire, UK. MAIN OUTCOME MEASURES:The ability to collect capillary blood to test IAbs in children at the routine preschool vaccination (3.5-4 years). RESULTS:Of 134 parents invited, 66 (49%) were recruited (median age 3.5 years (IQR 3.4-3.6), 26 (39.4%) male); 63 provided a sample (97% successfully), and one participant was identified with a single positive IAb. Parents (n=15 interviews, n=29 postcards) were uniformly positive about screening aligned to vaccination and stated they would have been less likely to take part had screening been a separate visit. Themes identified included preparedness for T1D and the long-term benefit outweighing short-term upset. The perceived volume of the capillary sample was a potential concern and needs optimising. CONCLUSIONS:Capillary IAb testing is a possible method to screen children for T1D. Aligning collection to the preschool vaccination visit can be convenient for families without the need for an additional visit.

Background Vitamin D insufficiency (VDI) may be a factor in the development of type 1 diabetes (T1D). The aim of this study is to investigate the presence and persistence of VDI in a large cohort of infants with increased risk of developing T1D, in light of the differences in local supplementation guidelines.Methods In the POInT Study, a multicentre primary prevention study between February 2018 and March 2021 in Germany, Poland, Belgium, England and Sweden, including infants aged 4–7 months at high genetic risk of developing β-cell autoantibodies, vitamin D levels were analysed at each study visit from inclusion (4–7 months) until 3 years, with an interval of 2 months (first three visits) or 4–6 months (visits 4–8). The protocol actively promotes vitamin D sufficiency to optimise immune tolerance. VDI was defined as a concentration below 30 ng/mL and was treated according to local guidelines of participating centres. Recovery from VDI was defined as a concentration above or equal to 30 ng/mL on the subsequent visit after VDI.Results 1050 infants were included, of which 5937 vitamin D levels were available for analyses. VDI was observed in 1464 (24.7%) visits and 507 (46.1%) of these were not resolved at the next visit. The risk of having VDI was independently associated with season (higher in winter), weight (higher with increased weight), age (higher with increased age) and country (higher in England). The risk of not recovering from VDI was independently associated with the season of the previously determined VDI, which was higher if VDI was identified in winter.Conclusions VDI is frequent in infants with increased risk of developing T1D. Treatment guidelines for VDI do not seem effective. Increasing supplementation dosages in this patient population seems warranted, especially during winter, and increasing dosages more aggressively after VDI should be considered.

Aims/hypothesis The aim of this study was to determine whether BMI in early childhood was affected by the COVID-19 pandemic and containment measures, and whether it was associated with the risk for islet autoimmunity. Methods Between February 2018 and May 2023, data on BMI and islet autoimmunity were collected from 1050 children enrolled in the Primary Oral Insulin Trial, aged from 4.0 months to 5.5 years of age. The start of the COVID-19 pandemic was defined as 18 March 2020, and a stringency index was used to assess the stringency of containment measures. Islet autoimmunity was defined as either the development of persistent confirmed multiple islet autoantibodies, or the development of one or more islet autoantibodies and type 1 diabetes. Multivariate linear mixed-effect, linear and logistic regression methods were applied to assess the effect of the COVID-19 pandemic and the stringency index on early-childhood BMI measurements (BMI as a time-varying variable, BMI at 9 months of age and overweight risk at 9 months of age), and Cox proportional hazard models were used to assess the effect of BMI measurements on islet autoimmunity risk. Results The COVID-19 pandemic was associated with increased time-varying BMI ( β = 0.39; 95% CI 0.30, 0.47) and overweight risk at 9 months ( β = 0.44; 95% CI 0.03, 0.84). During the COVID-19 pandemic, a higher stringency index was positively associated with time-varying BMI ( β = 0.02; 95% CI 0.00, 0.04 per 10 units increase), BMI at 9 months ( β = 0.13; 95% CI 0.01, 0.25) and overweight risk at 9 months ( β = 0.23; 95% CI 0.03, 0.43). A higher age-corrected BMI and overweight risk at 9 months were associated with increased risk for developing islet autoimmunity up to 5.5 years of age (HR 1.16; 95% CI 1.01, 1.32 and HR 1.68, 95% CI 1.00, 2.82, respectively). Conclusions/interpretation Early-childhood BMI increased during the COVID-19 pandemic, and was influenced by the level of restrictions during the pandemic. Controlling for the COVID-19 pandemic, elevated BMI during early childhood was associated with increased risk for childhood islet autoimmunity in children with genetic susceptibility to type 1 diabetes. Graphical Abstract

Over 1,000 distinct genetic variants have been associated with diabetes risk by genome-wide association studies (GWAS) but for most their functional impact is unknown and less than 15% of the diabetes GWAS variants have been shown in expression quantitative trait locus (eQTL) studies to alter gene expression in pancreatic islets. To fill this gap, we developed a new co-localization pipeline, called colocRedRibbon, that prefilters eQTL variants by direction of effect on gene expression, shortlists overlapping eQTL and GWAS variants and then runs the co-localization. Applying colocRedRibbon to diabetes and glycemic trait GWAS, we identified 292 co-localizing gene regions - 236 of which are new - including 24 co-localizations for type 1 diabetes and 268 for type 2 diabetes and glycemic traits. We achieved a four-fold increase in co-localizations, with the novel pipeline and updated GWAS each contributing two-fold. Among the co-localizations are a low frequency variant increasing MYO5C expression that reduces type 2 diabetes risk and a type 1 diabetes protective variant that increases FUT2 and decreases RASIP1 expression. These novel co-localizations represent a significant step forward to understand polygenic diabetes genetics and its impact on human islet gene expression. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work has been supported by the European Union's Horizon 2020 research and innovation program T2DSystems under grant agreement no. 667191, the Fonds National de la Recherche Scientifique (FNRS), the Walloon Region SPW-EER Win2Wal project BetaSource, Belgium, the FWO and FRS-FNRS under the Excellence of Science (EOS) programme (Pandarome project 40007487), the Walloon Region strategic axis FRFS-WELBIO, and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 115797 (INNODIA) and 945268 (INNODIA HARVEST). This latter Joint Undertaking received support from the Union's Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations, JDRF, and The Leona M. and Harry B. Helmsley Charitable Trust. A.P. is supported by Fonds David et Alice Van Buuren, Fondation Jaumotte-Demoulin, Fondation Héger-Masson, Fondation Wiener-Anspach and FNRS. F.S. is supported by a Research Fellow FNRS fellowship. D.L.E. is supported by grants from the JDRF International (now T1D Breakthrough) (3-SRA-2022-1201-S-B and 3-SRA-2022-1201-S-B); the National Institutes of Health Human Islet Research Network Consortium on Beta Cell Death & Survival from Pancreatic β-Cell Gene Networks to Therapy (HIRN-CBDS) (grant U01 DK127786); and the National Institutes of Health NIDDK grants RO1DK126444 and RO1DK133881-01. J.M.M. is supported by American Diabetes Association grant #11-22-ICTSPM-16, NHGRI U01HG011723, the National Institute Of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health under Award Number R01DK137993 and U01DK140757, and a Medical University of Bialystok (MUB) grant from the Ministry of Science and Higher Education (Poland). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used (or will use) ONLY openly available human data that were originally located at: - https://tiger.bsc.es/ - https://diagram-consortium.org/downloads.html - https://genetics.opentargets.org/study/GCST90013791 - https://magicinvestigators.org/downloads/ I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

Background: Islet autoantibody screening for type 1 diabetes (T1D) reduces life-threatening diabetic ketoacidosis, hospitalization and identifies individuals eligible for future preventative treatments. 3.5-4 years has been indicated as an optimal time to screen younger children for T1D at a single-time point. We therefore assessed the feasibility and acceptability of screening at this age, to align with the pre-school vaccination visit, in a first of its kind, proof-of-concept study in the UK. Methods: Children attending routine pre-school vaccinations (n= 63; median age 3.5y (IQR 3.4-3.6, range 3.1-5.1y), 26 (41.3%) male) provided capillary blood samples which were posted for IAA, GADA, IA-2A and ZnT8A analysis. Serum volumes >60µL were tested using Radiobinding assay (RBA), and <60µL by Luciferase Immunoprecipitation Systems (LIPS) assay. Acceptability was assessed using open question postcards, and semi structured interviews. Results: There was 97% (61/63 samples) success in sample analysis, with median serum collected 100µL (IQR 80-155) and 83% (52/63)>60µL. One participant screened and confirmed positive by RBA for IAA. Participants (n=15 interviews, n=31 postcards) were uniformly positive about screening aligning to the vaccination programme, citing that they may have been less likely to take part had screening been a separate visit. Themes identified included being prepared in the event of a T1D diagnosis, feeling reassured by a negative test result, and the long-term benefit of screening outweighing short-term upset. Parents reported that the volume of blood was higher, and collection time longer than expected. Conclusions: Capillary islet autoantibody testing is a feasible and acceptable method to screen children for T1D. Aligning sample collection to the pre-school vaccination was not a deterrent to vaccination. The approach of combining screening with a routine health visit may enable uptake and could be cost saving. Disclosure C. Scudder: None. J. Townson: None. R. Besser: Consultant; Provention Bio, Inc. J. Bowen-morris: None. P. H. Evans: None. S. C. Jones: None. N. P. B. Thomas: None. R. Fox: None. J. Todd: Advisory Panel; GlaxoSmithKline plc., Precion, Qlife, Vesalius Therapeutics. S. Greenfield: None. C. Dayan: Advisory Panel; AstraZeneca, Consultant; Provention Bio, Sanofi, Avotres Inc., Other Relationship; Dompé, Merck & Co., Inc. Funding National Institute for Health Research (203948)

OBJECTIVE:INGR1D (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).METHODS:The 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.RESULTS:Between 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).CONCLUSION:The 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.