Mobile genetic elements from the maternal microbiome shape infant gut microbial assembly and metabolism.

The perinatal period represents a critical window for cognitive and immune system development, promoted by maternal and infant gut microbiomes and their metabolites. Here, we tracked the co-development of microbiomes and metabolomes from late pregnancy to 1 year of age using longitudinal multi-omics data from a cohort of 70 mother-infant dyads. We discovered large-scale mother-to-infant interspecies transfer of mobile genetic elements, frequently involving genes associated with diet-related adaptations. Infant gut metabolomes were less diverse than maternal but featured hundreds of unique metabolites and microbe-metabolite associations not detected in mothers. Metabolomes and serum cytokine signatures of infants who received regular-but not extensively hydrolyzed-formula were distinct from those of exclusively breastfed infants. Taken together, our integrative analysis expands the concept of vertical transmission of the gut microbiome and provides original insights into the development of maternal and infant microbiomes and metabolomes during late pregnancy and early life.

Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans.

According to the hygiene hypothesis, the increasing incidence of autoimmune diseases in western countries may be explained by changes in early microbial exposure, leading to altered immune maturation. We followed gut microbiome development from birth until age three in 222 infants in Northern Europe, where early-onset autoimmune diseases are common in Finland and Estonia but are less prevalent in Russia. We found that Bacteroides species are lowly abundant in Russians but dominate in Finnish and Estonian infants. Therefore, their lipopolysaccharide (LPS) exposures arose primarily from Bacteroides rather than from Escherichia coli, which is a potent innate immune activator. We show that Bacteroides LPS is structurally distinct from E. coli LPS and inhibits innate immune signaling and endotoxin tolerance; furthermore, unlike LPS from E. coli, B. dorei LPS does not decrease incidence of autoimmune diabetes in non-obese diabetic mice. Early colonization by immunologically silencing microbiota may thus preclude aspects of immune education.

Gut microbiome shifts in people with type 1 diabetes are associated with glycaemic control: an INNODIA study.

AIMS/HYPOTHESIS: The gut microbiome is implicated in the disease process leading to clinical type 1 diabetes, but less is known about potential changes in the gut microbiome after the diagnosis of type 1 diabetes and implications in glucose homeostasis. We aimed to analyse potential associations between the gut microbiome composition and clinical and laboratory data during a 2 year follow-up of people with newly diagnosed type 1 diabetes, recruited to the Innovative approaches to understanding and arresting type 1 diabetes (INNODIA) study. In addition, we analysed the microbiome composition in initially unaffected family members, who progressed to clinical type 1 diabetes during or after their follow-up for 4 years. METHODS: We characterised the gut microbiome composition of 98 individuals with newly diagnosed type 1 diabetes (ND cohort) and 194 autoantibody-positive unaffected family members (UFM cohort), representing a subgroup of the INNODIA Natural History Study, using metagenomic sequencing. Participants from the ND cohort attended study visits within 6 weeks from the diagnosis and 3, 6, 12 and 24 months later for stool sample collection and laboratory tests (HbA1c, C-peptide, diabetes-associated autoantibodies). Participants from the UFM cohort were assessed at baseline and 6, 12, 18, 24 and 36 months later. RESULTS: We observed a longitudinal increase in 21 bacterial species in the ND cohort but not in the UFM cohort. The relative abundance of Faecalibacterium prausnitzii was inversely associated with the HbA1c levels at diagnosis (p=0.0019). The rate of the subsequent disease progression in the ND cohort, as assessed by change in HbA1c, C-peptide levels and insulin dose, was associated with the abundance of several bacterial species. Individuals with rapid decrease in C-peptide levels in the ND cohort had the lowest gut microbiome diversity. Nineteen individuals who were diagnosed with type 1 diabetes in the UFM cohort had increased abundance of Sutterella sp. KLE1602 compared with the undiagnosed UFM individuals (p=1.2 × 10-4). CONCLUSIONS/INTERPRETATION: Our data revealed associations between the gut microbiome composition and the disease progression in individuals with recent-onset type 1 diabetes. Future mechanistic studies as well as animal studies and human trials are needed to further validate the significance and causality of these associations.

Safety, tolerability and immunogenicity of PRV-101, a multivalent vaccine targeting coxsackie B viruses (CVBs) associated with type 1 diabetes: a double-blind randomised placebo-controlled Phase I trial.

AIMS/HYPOTHESIS: Infection with coxsackie B viruses (CVBs) can cause diseases ranging from mild common cold-type symptoms to severe life-threatening conditions. CVB infections are considered to be prime candidates for environmental triggers of type 1 diabetes. This, together with the significant disease burden of acute CVB infections and their association with chronic diseases other than diabetes, has prompted the development of human CVB vaccines. The current study evaluated the safety and immunogenicity of the first human vaccine designed against CVBs associated with type 1 diabetes in a double-blind randomised placebo-controlled Phase I trial. METHODS: The main eligibility criteria for participants were good general health, age between 18 and 45 years, provision of written informed consent and willingness to comply with all trial procedures. Treatment allocation (PRV-101 or placebo) was based on a computer-generated randomisation schedule and people assessing the outcomes were masked to group assignment. In total, 32 participants (17 men, 15 women) aged 18-44 years were randomised to receive a low (n=12) or high (n=12) dose of a multivalent, formalin-inactivated vaccine including CVB serotypes 1-5 (PRV-101), or placebo (n=8), given by intramuscular injections at weeks 0, 4 and 8 at a single study site in Finland. The participants were followed for another 24 weeks. Safety and tolerability were the primary endpoints. Anti-CVB IgG and virus-neutralising titres were analysed using an ELISA and neutralising plaque reduction assays, respectively. RESULTS: Among the 32 participants (low dose, n=12; high dose, n=12; placebo, n=8) no serious adverse events or adverse events leading to study treatment discontinuation were observed. Treatment-emergent adverse events considered to be related to the study drug occurred in 37.5% of the participants in the placebo group and 62.5% in the PRV-101 group (injection site pain, headache, injection site discomfort and injection site pruritus being most common). PRV-101 induced dose-dependent neutralising antibody responses against all five CVB serotypes included in the vaccine in both the high- and low-dose groups. Protective titres ≥8 against all five serotypes were seen in >90% of participants over the entire follow-up period. CONCLUSIONS/INTERPRETATION: The results indicate that the tested multivalent CVB vaccine is well tolerated and immunogenic, supporting its further clinical development. TRIAL REGISTRATION: ClinicalTrials.gov NCT04690426. FUNDING: This trial was funded by Provention Bio, a Sanofi company.

The INNODIA Type 1 Diabetes Natural History Study: a European cohort of newly diagnosed children, adolescents and adults.

AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: The study population included 649 individuals (57.3% male; age 12.1±8.3 years), 96.9% of whom were positive for one or more diabetes-related antibodies. Baseline (IQR) fasting C-peptide was 242.0 (139.0-382.0) pmol/l (AUC 749.3 [466.2-1106.1] pmol/l × min), with levels increasing with age (p<0.001). Over time, C-peptide remained lower in participants aged <10 years but it declined in all age groups. In parallel, glucose levels progressively increased. Lower baseline fasting C-peptide, BMI SD score and presence of diabetic ketoacidosis at diagnosis were associated with lower stimulated C-peptide over time. HbA1c decreased during the first 3 months (p<0.001), whereas insulin requirement increased from 3 months post diagnosis (p<0.001). CONCLUSIONS/INTERPRETATION: In this large cohort with newly diagnosed type 1 diabetes, we identified age-related differences in clinical and biochemical variables. Of note, C-peptide was lower in younger children but there were no main age differences in its rate of decline.

Assisting the implementation of screening for type 1 diabetes by using artificial intelligence on publicly available data.

The type 1 diabetes community is coalescing around the benefits and advantages of early screening for disease risk. To be accepted by healthcare providers, regulatory authorities and payers, screening programmes need to show that the testing variables allow accurate risk prediction and that individualised risk-informed monitoring plans are established, as well as operational feasibility, cost-effectiveness and acceptance at population level. Artificial intelligence (AI) has the potential to contribute to solving these issues, starting with the identification and stratification of at-risk individuals. ASSET (AI for Sustainable Prevention of Autoimmunity in the Society; www.asset.healthcare ) is a public/private consortium that was established to contribute to research around screening for type 1 diabetes and particularly to how AI can drive the implementation of a precision medicine approach to disease prevention. ASSET will additionally focus on issues pertaining to operational implementation of screening. The authors of this article, researchers and clinicians active in the field of type 1 diabetes, met in an open forum to independently debate key issues around screening for type 1 diabetes and to advise ASSET. The potential use of AI in the analysis of longitudinal data from observational cohort studies to inform the design of improved, more individualised screening programmes was also discussed. A key issue was whether AI would allow the research community and industry to capitalise on large publicly available data repositories to design screening programmes that allow the early detection of individuals at high risk and enable clinical evaluation of preventive therapies. Overall, AI has the potential to revolutionise type 1 diabetes screening, in particular to help identify individuals who are at increased risk of disease and aid in the design of appropriate follow-up plans. We hope that this initiative will stimulate further research on this very timely topic.

Multi-omics analysis reveals drivers of loss of ß-cell function after newly diagnosed autoimmune type 1 diabetes: An INNODIA multicenter study.

AIMS: Heterogeneity in the rate of ß-cell loss in newly diagnosed type 1 diabetes patients is poorly understood and creates a barrier to designing and interpreting disease-modifying clinical trials. Integrative analyses of baseline multi-omics data obtained after the diagnosis of type 1 diabetes may provide mechanistic insight into the diverse rates of disease progression after type 1 diabetes diagnosis. METHODS: We collected samples in a pan-European consortium that enabled the concerted analysis of five different omics modalities in data from 97 newly diagnosed patients. In this study, we used Multi-Omics Factor Analysis to identify molecular signatures correlating with post-diagnosis decline in ß-cell mass measured as fasting C-peptide. RESULTS: Two molecular signatures were significantly correlated with fasting C-peptide levels. One signature showed a correlation to neutrophil degranulation, cytokine signalling, lymphoid and non-lymphoid cell interactions and G-protein coupled receptor signalling events that were inversely associated with a rapid decline in ß-cell function. The second signature was related to translation and viral infection was inversely associated with change in ß-cell function. In addition, the immunomics data revealed a Natural Killer cell signature associated with rapid ß-cell decline. CONCLUSIONS: Features that differ between individuals with slow and rapid decline in ß-cell mass could be valuable in staging and prediction of the rate of disease progression and thus enable smarter (shorter and smaller) trial designs for disease modifying therapies as well as offering biomarkers of therapeutic effect.

Gut Inflammation Markers, Diet, and Risk of Islet Autoimmunity in Finnish Children - A Nested Case-Control Study.

BACKGROUND: Gut dysbiosis and increased intestinal permeability have been reported to precede type 1 diabetes-related autoimmunity. The role of gut inflammation in autoimmunity is not understood. OBJECTIVES: This study aimed to assess whether gut inflammation markers are associated with risk of islet autoimmunity and whether diet is associated with gut inflammation markers. METHODS: A nested case-control sample of 75 case children with islet autoimmunity and 88 control children was acquired from the Finnish Type 1 Diabetes Prediction and Prevention cohort. Diet was assessed with 3-d food records, and calprotectin and human ß-defensin-2 (HBD-2) were analyzed from stool samples at 6 and 12 mo of age. Conditional logistic regression analysis was used in a matched case-control setting to assess risk of autoimmunity. Analysis of variance, independent samples t test, and a general linear model were used in secondary analyses to test associations of background characteristics and dietary factors with inflammation markers. RESULTS: In unadjusted analyses, calprotectin was not associated with risk of islet autoimmunity, whereas HBD-2 in the middle (odds ratio [OR]: 3.23; 95% confidence interval [CI]: 1.03, 10.08) or highest tertile (OR: 3.02; 95% CI: 1.05, 8.69) in comparison to the lowest at 12 mo of age showed borderline association (P-trend = 0.063) with higher risk of islet autoimmunity. Excluding children with cow milk allergy in sensitivity analyses strengthened the association of HBD-2 with islet autoimmunity, whereas adjusting for dietary factors and maternal education weakened it. At age 12 mo, higher fat intake was associated with higher HBD-2 (ß: 0.219; 95% CI: 0.110, 0.328) and higher intake of dietary fiber (ß: -0.294; 95% CI: -0.510, -0.078), magnesium (ß: -0.036; 95% CI: -0.059, -0.014), and potassium (ß: -0.003; 95% CI: -0.005, -0.001) with lower HBD-2. CONCLUSIONS: Higher HBD-2 in infancy may be associated with higher risk of islet autoimmunity. Dietary factors play a role in gut inflammatory status.

High Concentrations of Immunoglobulin G Against Cow Milk Proteins and Frequency of Cow Milk Consumption Are Associated With the Development of Islet Autoimmunity and Type 1 Diabetes-The Trial to Reduce Insulin-dependent Diabetes Mellitus (IDDM) in the Genetically at Risk (TRIGR) Study.

BACKGROUND: The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) (NCT00179777) found no difference type 1 diabetes risk between hydrolyzed and regular infant formula. However, cow milk consumption during childhood is consistently linked to type 1 diabetes risk in prospective cohort studies. OBJECTIVES: Our primary aim was to study whether humoral immune responses to cow milk and cow milk consumption are associated with type 1 diabetes in TRIGR children. METHODS: TRIGR comprised 2159 children with genetic susceptibility to type 1 diabetes born between 2002 and 2007 in 15 countries. Children were randomly assigned into groups receiving extensively hydrolyzed casein or a regular cow milk formula and followed up until age 10 y. Type 1 diabetes-related autoantibodies and antibodies to cow milk proteins were analyzed. Infant formula intake was measured by structured dietary interviews and milk consumption with a food frequency questionnaire. Associations of milk antibodies and milk consumption with risk to develop type 1 diabetes were analyzed using Cox survival model. RESULTS: Cow milk antibody concentrations both in cord blood [hazards ratio (HR) for islet autoimmunity: 1.30; 95% CI: 1.05, 1.61; HR for type 1 diabetes: 1.32; 95% CI: 1.02, 1.71] and longitudinally from birth to 3 years (HR for islet autoimmunity: 1.39; 95% CI: 1.07, 1.81; HR for type 1 diabetes: 1.43; 95% CI: 1.04, 1.96) were associated with increased risk of developing type 1 diabetes. The amount of regular infant formula was associated with reduced islet autoimmunity risk in the regular infant formula group (HR: 0.92; 95% CI: 0.85, 0.99). Furthermore, frequent liquid milk consumption after infancy was associated with increased risk of islet autoimmunity or type 1 diabetes. CONCLUSIONS: Elevated cow milk antibody concentrations and high consumption of liquid milk after infancy are related to type 1 diabetes development in children with an increased genetic susceptibility to type 1 diabetes. Enhanced antibody concentrations to cow milk may provide a biomarker of immune system prone to develop islet autoimmunity. This trial was registered at clinicaltrials.gov as NCT00179777.

Identification of monogenic variants in more than ten per cent of children without type 1 diabetes-related autoantibodies at diagnosis in the Finnish Pediatric Diabetes Register.

AIMS/HYPOTHESIS: Monogenic forms of diabetes (MODY, neonatal diabetes mellitus and syndromic forms) are rare, and affected individuals may be misclassified and treated suboptimally. The prevalence of type 1 diabetes is high in Finnish children but systematic screening for monogenic diabetes has not been conducted. We assessed the prevalence and clinical manifestations of monogenic diabetes in children initially registered with type 1 diabetes in the Finnish Pediatric Diabetes Register (FPDR) but who had no type 1 diabetes-related autoantibodies (AABs) or had only low-titre islet cell autoantibodies (ICAs) at diagnosis. METHODS: The FPDR, covering approximately 90% of newly diagnosed diabetic individuals aged ≤15 years in Finland starting from 2002, includes data on diabetes-associated HLA genotypes and AAB data (ICA, and autoantibodies against insulin, GAD, islet antigen 2 and zinc transporter 8) at diagnosis. A next generation sequencing gene panel including 42 genes was used to identify monogenic diabetes. We interpreted the variants in HNF1A by using the gene-specific standardised criteria and reported pathogenic and likely pathogenic findings only. For other genes, we also reported variants of unknown significance if an individual's phenotype suggested monogenic diabetes. RESULTS: Out of 6482 participants, we sequenced DNA for 152 (2.3%) testing negative for all AABs and 49 (0.8%) positive only for low-titre ICAs (ICAlow). A monogenic form of diabetes was revealed in 19 (12.5%) of the AAB-negative patients (14 [9.2%] had pathogenic or likely pathogenic variants) and two (4.1%) of the ICAlow group. None had ketoacidosis at diagnosis or carried HLA genotypes conferring high risk for type 1 diabetes. The affected genes were GCK, HNF1A, HNF4A, HNF1B, INS, KCNJ11, RFX6, LMNA and WFS1. A switch from insulin to oral medication was successful in four of five patients with variants in HNF1A, HNF4A or KCNJ11. CONCLUSIONS/INTERPRETATION: More than 10% of AAB-negative children with newly diagnosed diabetes had a genetic finding associated with monogenic diabetes. Because the genetic diagnosis can lead to major changes in treatment, we recommend referring all AAB-negative paediatric patients with diabetes for genetic testing. Low-titre ICAs in the absence of other AABs does not always indicate a diagnosis of type 1 diabetes.

Targeted serum proteomics of longitudinal samples from newly diagnosed youth with type 1 diabetes distinguishes markers of disease and C-peptide trajectory.

AIMS/HYPOTHESIS: There is a growing need for markers that could help indicate the decline in beta cell function and recognise the need and efficacy of intervention in type 1 diabetes. Measurements of suitably selected serum markers could potentially provide a non-invasive and easily applicable solution to this challenge. Accordingly, we evaluated a broad panel of proteins previously associated with type 1 diabetes in serum from newly diagnosed individuals during the first year from diagnosis. To uncover associations with beta cell function, comparisons were made between these targeted proteomics measurements and changes in fasting C-peptide levels. To further distinguish proteins linked with the disease status, comparisons were made with measurements of the protein targets in age- and sex-matched autoantibody-negative unaffected family members (UFMs). METHODS: Selected reaction monitoring (SRM) mass spectrometry analyses of serum, targeting 85 type 1 diabetes-associated proteins, were made. Sera from individuals diagnosed under 18 years (n=86) were drawn within 6 weeks of diagnosis and at 3, 6 and 12 months afterwards (288 samples in total). The SRM data were compared with fasting C-peptide/glucose data, which was interpreted as a measure of beta cell function. The protein data were further compared with cross-sectional SRM measurements from UFMs (n=194). RESULTS: Eleven proteins had statistically significant associations with fasting C-peptide/glucose. Of these, apolipoprotein L1 and glutathione peroxidase 3 (GPX3) displayed the strongest positive and inverse associations, respectively. Changes in GPX3 levels during the first year after diagnosis indicated future fasting C-peptide/glucose levels. In addition, differences in the levels of 13 proteins were observed between the individuals with type 1 diabetes and the matched UFMs. These included GPX3, transthyretin, prothrombin, apolipoprotein C1 and members of the IGF family. CONCLUSIONS/INTERPRETATION: The association of several targeted proteins with fasting C-peptide/glucose levels in the first year after diagnosis suggests their connection with the underlying changes accompanying alterations in beta cell function in type 1 diabetes. Moreover, the direction of change in GPX3 during the first year was indicative of subsequent fasting C-peptide/glucose levels, and supports further investigation of this and other serum protein measurements in future studies of beta cell function in type 1 diabetes.

HLA-DQ-conferred risk for type 1 diabetes does not alter neutralizing antibody response to a widely used enterovirus vaccine, the poliovirus vaccine.

This study investigated whether children with HLA-DQ-conferred risk for type 1 diabetes (T1D) have an altered immune response to the widely-used enterovirus vaccine, namely poliovirus vaccine, and whether initiation of autoimmunity to pancreatic islets modulates this response. Neutralizing antibodies induced by the inactivated poliovirus vaccine against poliovirus type 1 (Salk) were analysed as a marker of protective immunity at the age of 18 months in a prospective birth cohort. No differences were observed in antibody titers between children with and without genetic risk for T1D (odds ratio [OR] = 0.90 [0.83, 1.06], p = 0.30). In the presence of the genetic risk, no difference was observed between children with and without islet autoimmunity (OR = 1.00 [0.78, 1.28], p = 1.00). This did not change when only children with the autoimmunity before 18 months of age were included in the analyses (OR = 1.00 [0.85, 1.18], p = 1.00). No effect was observed when groups were stratified based on autoantigen specificity of the first-appearing autoantibody (IAA or GADA). The children in each comparison group were matched for sex, calendar year and month of birth, and municipality. Accordingly, we found no indication that children who are at risk to develop islet autoimmunity would have a compromised humoral immune response which could have increased their susceptibility for enterovirus infections. In addition, the proper immune response supports the idea of testing novel enterovirus vaccines for the prevention of T1D among these individuals.

Longitudinal consumption of fruits and vegetables and risk of asthma by 5 years of age.

BACKGROUND: Fruit and vegetable consumption has been linked to a decreased risk of asthma, but prospective evidence on longitudinal consumption in childhood is scarce. We aimed to investigate the association between fruit and vegetable consumption in childhood and the risk of asthma by the age of 5 years, and to explore the role of processing of fruits and vegetables in the Finnish Type 1 Diabetes Prediction and Prevention Allergy Study. METHODS: Child's food consumption was assessed by 3-day food records completed at the age of 3 and 6 months, and 1, 2, 3, 4, and 5 years, and asthma and allergies by a validated modified version of the ISAAC questionnaire at the age of 5 years. Consumption of processed and unprocessed fruits and vegetables was calculated. Joint models with a current value association structure for longitudinal and time-to-event data were used for statistical analyses. RESULTS: Of the 3053 children, 184 (6%) developed asthma by the age of 5 years. The risk of asthma was not associated with the consumption of all fruits and vegetables together (HR 1.00, 95%CI 0.99-1.01 per consumption of 1 g/MJ, adjusted for energy and other covariates), or with most subgroups. Weak inverse associations were seen between all leafy vegetables and asthma (HR = 0.87, 0.77-0.99), and unprocessed vegetables and nonatopic asthma (HR = 0.90, 95% CI 0.81-0.98). CONCLUSION: Total consumption of fruits and vegetables in childhood was not associated with the development of asthma by the age of 5 years. Weak inverse associations found for vegetables need to be confirmed or rejected in future studies.

Intake and sources of dietary fibre and dietary fibre fractions in Finnish children.

The current definition of dietary fibre was adopted by the Codex Alimentarius Commission in 2009, but implementation requires updating food composition databases with values based on appropriate analysis methods. Previous data on population intakes of dietary fibre fractions are sparse. We studied the intake and sources of total dietary fibre (TDF) and dietary fibre fractions insoluble dietary fibre (IDF), dietary fibre soluble in water but insoluble in 76 % aqueous ethanol (SDFP) and dietary fibre soluble in water and soluble in 76 % aqueous ethanol (SDFS) in Finnish children based on new CODEX-compliant values of the Finnish National Food Composition Database Fineli. Our sample included 5193 children at increased genetic risk of type 1 diabetes from the Type 1 Diabetes Prediction and Prevention birth cohort, born between 1996 and 2004. We assessed the intake and sources based on 3-day food records collected at the ages of 6 months, 1, 3 and 6 years. Both absolute and energy-adjusted intakes of TDF were associated with age, sex and breast-feeding status of the child. Children of older parents, parents with a higher level of education, non-smoking mothers and children with no older siblings had higher energy-adjusted TDF intake. IDF was the major dietary fibre fraction in non-breastfed children, followed by SDFP and SDFS. Cereal products, fruits and berries, potatoes and vegetables were major food sources of dietary fibre. Breast milk was a major source of dietary fibre in 6-month-olds due to its human milk oligosaccharide content and resulted in high SDFS intakes in breastfed children.

What is the role of puberty in the development of islet autoimmunity and progression to type 1 diabetes?

In many populations, the peak period of incidence of type 1 diabetes (T1D) has been observed to be around 10-14 years of age, coinciding with puberty, but direct evidence of the role of puberty in the development of T1D is limited. We therefore aimed to investigate whether puberty and the timing of its onset are associated with the development of islet autoimmunity (IA) and subsequent progression to T1D. A Finnish population-based cohort of children with HLA-DQB1-conferred susceptibility to T1D was followed from 7 years of age until 15 years of age or until a diagnosis of T1D (n = 6920). T1D-associated autoantibodies and growth were measured at 3- to 12-month intervals, and pubertal onset timing was assessed based on growth. The analyses used a three-state survival model. IA was defined as being either positive for islet cell antibodies plus at least one biochemical autoantibody (ICA + 1) or as being repeatedly positive for at least one biochemical autoantibody (BC1). Depending on the IA definition, either 303 (4.4%, ICA + 1) or 435 (6.3%, BC1) children tested positive for IA by the age of 7 years, and 211 (3.2%, ICA + 1)) or 198 (5.3%, BC1) developed IA during follow-up. A total of 172 (2.5%) individuals developed T1D during follow-up, of whom 169 were positive for IA prior to the clinical diagnosis. Puberty was associated with an increase in the risk of progression to T1D, but only from ICA + 1-defined IA (hazard ratio 1.57; 95% confidence interval 1.14, 2.16), and the timing of pubertal onset did not affect the association. No association between puberty and the risk of IA was detected. In conclusion, puberty may affect the risk of progression but is not a risk factor for IA.

Dietary fatty acid intake in childhood and the risk of islet autoimmunity and type 1 diabetes: the DIPP birth cohort study.

PURPOSE: The aim was to study the associations between dietary intake of fatty acids in childhood and the risk of islet autoimmunity and type 1 diabetes (T1D). METHODS: The prospective Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study included children with genetic susceptibility to T1D born between 1996 and 2004. Participants were followed up every 3 to 12 months up to 6 years for diet, islet autoantibodies, and T1D. Dietary intake of several fatty acids at the age of 3 months to 6 years was assessed 1-8 times per participant with a 3-day food record. Joint models adjusted for energy intake, sex, HLA genotype and familial diabetes were used to investigate the associations of longitudinal intake of fatty acids and the development of islet autoimmunity and T1D. RESULTS: During the 6-year follow-up, 247 (4.4%) children of 5626 developed islet autoimmunity and 94 (1.7%) children of 5674 developed T1D. Higher intake of monounsaturated fatty acids (HR 0.63; 95% CI 0.47, 0.82), arachidonic acid (0.69; 0.50, 0.94), total n-3 fatty acids (0.64; 0.48, 0.84), and long-chain n-3 fatty acids (0.14; 0.04, 0.43), was associated with a decreased risk of islet autoimmunity with and without energy adjustment. Higher intake of total fat (0.73; 0.53, 0.98), and saturated fatty acids (0.55; 0.33, 0.90) was associated with a decreased risk of T1D only when energy adjusted. CONCLUSION: Intake of several fatty acids was associated with a decreased risk of islet autoimmunity or T1D among high-risk children. Our findings support the idea that dietary factors, including n-3 fatty acids, may play a role in the disease process of T1D.

Infant Feeding, Gut Permeability, and Gut Inflammation Markers.

OBJECTIVES: Increased gut permeability and gut inflammation have been linked to the development of type 1 diabetes. Little is known on whether and how intake of different foods is linked to these mechanisms in infancy. We investigated whether the amount of breast milk and intake of other foods are associated with gut inflammation marker concentrations and permeability. METHODS: Seventy-three infants were followed from birth to 12 months of age. Their diet was assessed with structured questionnaires and 3-day weighed food records at the age of 3, 6, 9, and 12 months. Gut permeability was assessed with the lactulose/mannitol test and fecal calprotectin and human ß-defensin-2 (HBD-2) concentrations were analyzed from stool samples at the age of 3, 6, 9, and 12 months. The associations between foods and gut inflammation marker concentrations and permeability were analyzed using generalized estimating equations. RESULTS: Gut permeability and gut inflammation marker concentrations decreased during the first year of life. Intake of hydrolyzed infant formula ( P = 0.003) and intake of fruits and juices ( P = 0.001) were associated with lower intestinal permeability. Intake of fruits and juices ( P < 0.001), vegetables ( P < 0.001), and oats ( P = 0.003) were associated with lower concentrations of HBD-2. Higher intake of breast milk was associated with higher fecal calprotectin concentrations ( P < 0.001), while intake of fruits and juices ( P < 0.001), vegetables ( P < 0.001), and potatoes ( P = 0.007) were associated with lower calprotectin concentrations. CONCLUSIONS: Higher intake of breast milk may contribute to higher calprotectin concentration, whereas several complementary foods may decrease gut permeability and concentrations of calprotectin and HBD-2 in infant gut.

Infant liver biochemistry is different than current laboratory accepted norms.

The purpose is to study liver biochemistry in a well-defined cohort of term infants. The methods include healthy term infants (n = 619) provided blood samples at 3 and 6 months of age when participating to the DIABIMMUNE study. The infants were followed up at clinical study visits 3, 6, 12, 18, 24, and 36 months the participation rate being 88.6% at the end of follow-up, while none disclosed any signs of a liver disease. The serum levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total bilirubin (BIL), and conjugated bilirubin (BIL-conj) were determined using Siemens Atellica CH 930 analyzers. The results are at 3 months of age, the upper 90% CI for ALT, AST, ALP, GGT, BIL, and BIL-conj were higher than the current upper reference limits in our accredited hospital laboratory. At 6 months, the upper 90% CIs for ALT had declined but was still higher than the cut-offs for a raised value. The upper 90% CI for AST remained as high as at 3 months, whereas ALP, BIL-conj, and GGT had decreased close to the current cut-offs. The type of feeding was associated with the levels of liver biochemistry. Exclusively or partially breastfed infants showed higher ALT, AST, BIL, and BIL-conj values at 3 months than formula-fed. Breastfed infants had higher AST, Bil, and Bil-conj values also at 6 months.  Conclusion: We encourage setting appropriate reference ranges for liver biochemistry for the first year of life and to note the type of feeding. What is Known: • Healthy infants may show higher values of liver biochemistry during their first year of life than in later life. • It has been speculated that type of feeding may play a role in liver biochemistry levels among infants. What is New: • In a cohort of healthy infants, several analytes of liver biochemistry were higher than the currently used upper reference limits at 3 and 6 months of age, and exclusively or partially breastfed infants showed higher values than formula-fed. • The findings address the importance of setting appropriate reference ranges for liver biochemistry for the first year of life.

Increased HLA class II risk is associated with a more aggressive presentation of clinical type 1 diabetes.

AIM: To determine the association of HLA class II risk with the demographic and clinical characteristics of type 1 diabetes at diagnosis. METHODS: We conducted a register-based retrospective cohort study of 4993 Finnish children (2169 girls) - diagnosed with type 1 diabetes under the age of 15 years in 2003-2016. The participants were divided into six risk groups based on their HLA DR/DQ genotype. Demographic characteristics, family history of type 1 diabetes and metabolic markers at the time of diagnosis were compared between the groups. RESULTS: In total, 4056/4993 children (81.2%) carried an HLA genotype associated with an increased risk of type 1 diabetes (risk groups 3-5), whereas 937/4993 children (18.8%) carried a HLA genotype conferring no or decreased disease risk. Children with higher HLA risk were younger at diagnosis (p < 0.001) and had a shorter duration of classical symptoms before diagnosis (p = 0.016). Subjects in the high-risk group were more likely to have a family member affected by type 1 diabetes when compared to those in the neutral risk group (11.5% vs. 8.8%, p = 0.05). CONCLUSION: Children with stronger HLA disease susceptibility are younger at their disease manifestation and have a shorter period of symptoms before diagnosis, suggesting that the HLA class II genes are associated with a more aggressive disease presentation.