Distinct cellular immune responses in children en route to type 1 diabetes with different first-appearing autoantibodies.

Previous studies have revealed heterogeneity in the progression to clinical type 1 diabetes in children who develop islet-specific antibodies either to insulin (IAA) or glutamic acid decarboxylase (GADA) as the first autoantibodies. Here, we test the hypothesis that children who later develop clinical disease have different early immune responses, depending on the type of the first autoantibody to appear (GADA-first or IAA-first). We use mass cytometry for deep immune profiling of peripheral blood mononuclear cell samples longitudinally collected from children who later progressed to clinical disease (IAA-first, GADA-first, ≥2 autoantibodies first groups) and matched for age, sex, and HLA controls who did not, as part of the Type 1 Diabetes Prediction and Prevention study. We identify differences in immune cell composition of children who later develop disease depending on the type of autoantibodies that appear first. Notably, we observe an increase in CD161 expression in natural killer cells of children with ≥2 autoantibodies and validate this in an independent cohort. The results highlight the importance of endotype-specific analyses and are likely to contribute to our understanding of pathogenic mechanisms underlying type 1 diabetes development.

Association between anti-capsular IgG levels at birth and risk of invasive group B streptococcus disease in Finnish newborns: a retrospective case-control study.

BACKGROUND: Group B streptococcus is a major cause of neonatal disease. Natural history studies have linked maternally transferred anti-group B streptococcus capsular polysaccharide antibodies with protection against infant group B streptococcus disease. Previous studies of capsular polysaccharide antibody concentration in European populations have used maternal (not infant) sera and a non-standardised assay. This study aimed to evaluate anti-capsular polysaccharide IgG concentrations associated with protection against invasive group B streptococcus disease in Finnish infants. METHODS: In this retrospective case-control study, we used cord sera from the Finnish DIPP study repository, which was obtained between Jan 1, 1995, and Dec 31, 2017. We included infants aged 6 months or younger with group B streptococcus infection (cases) and healthy infants (controls). We enrolled infants with invasive neonatal group B streptococcus (55 cases) and matched controls (229 controls) aged 6 months or younger after identification from Finnish health registers. We measured anti-capsular polysaccharide IgG (serotypes Ia-V) concentration using a standardised immunoassay and we estimated its relationship to disease risk using a Bayesian model. We used the derived risk-concentration curve to predict potential efficacy of six-valent group B streptococcus capsular polysaccharide vaccine (GBS6) based on previously reported immunogenicity data. FINDINGS: Most (32 [58%] of 55 cases) group B streptococcus cases were due to serotype III and anti-serotype III streptococcus capsular IgG concentrations were higher in serotype III-matched controls than in cases (p<0·001). 0·120-0·266 µg/mL serotype III-specific IgG was estimated to confer 75-90% risk reduction against serotype III disease. A universal risk-concentration curve, aggregating results across all six serotypes, yielded similar results. Application of this curve to GBS6 immunogenicity data predicted maternal immunisation to be more than 80% efficacious for prevention of infant group B streptococcus disease. INTERPRETATION: Higher neonatal anti-capsular polysaccharide serum IgG concentration at birth correlated with reduced risk of infant group B streptococcus disease in Finland. Based on these results, a maternal group B streptococcus capsular conjugate vaccine currently in development is predicted to be efficacious. FUNDING: Pfizer.

Gestational age at birth and type 1 diabetes in childhood and young adulthood: a nationwide register study in Finland, Norway and Sweden.

AIMS/HYPOTHESIS: Children and adults born preterm have an increased risk of type 1 diabetes. However, there is limited information on risk patterns across the full range of gestational ages, especially after extremely preterm birth (23-27 weeks of gestation). We investigated the risk of type 1 diabetes in childhood and young adulthood across the full range of length of gestation at birth. METHODS: Data were obtained from national registers in Finland, Norway and Sweden. In each country, information on study participants and gestational age was collected from the Medical Birth Registers, information on type 1 diabetes diagnoses was collected from the National Patient Registers, and information on education, emigration and death was collected from the respective national register sources. Individual-level data were linked using unique personal identity codes. The study population included all individuals born alive between 1987 and 2016 to mothers whose country of birth was the respective Nordic country. Individuals were followed until diagnosis of type 1 diabetes, death, emigration or end of follow-up (31 December 2016 in Finland, 31 December 2017 in Norway and Sweden). Gestational age was categorised as extremely preterm (23-27 completed weeks), very preterm (28-31 weeks), moderately preterm (32-33 weeks), late preterm (34-36 weeks), early term (37-38 weeks), full term (39-41 weeks; reference) and post term (42-45 weeks). HRs and 95% CIs from country-specific covariate-adjusted Cox regression models were combined in a meta-analysis using a common-effect inverse-variance model. RESULTS: Among 5,501,276 individuals, 0.2% were born extremely preterm, 0.5% very preterm, 0.7% moderately preterm, 4.2% late preterm, 17.7% early term, 69.9% full term, and 6.7% post term. A type 1 diabetes diagnosis was recorded in 12,326 (0.8%), 6364 (0.5%) and 16,856 (0.7%) individuals at a median age of 8.2, 13.0 and 10.5 years in Finland, Norway and Sweden, respectively. Individuals born late preterm or early term had an increased risk of type 1 diabetes compared with their full-term-born peers (pooled, multiple confounder-adjusted HR 1.12, 95% CI 1.07, 1.18; and 1.15, 95% CI 1.11, 1.18, respectively). However, those born extremely preterm or very preterm had a decreased risk of type 1 diabetes (adjusted HR 0.63, 95% CI 0.45, 0.88; and 0.78, 95% CI 0.67, 0.92, respectively). These associations were similar across all three countries. CONCLUSIONS/INTERPRETATION: Individuals born late preterm and early term have an increased risk of type 1 diabetes while individuals born extremely preterm or very preterm have a decreased risk of type 1 diabetes compared with those born full term.

Fruit, berry, and vegetable consumption and the risk of islet autoimmunity and type 1 diabetes in children-the Type 1 Diabetes Prediction and Prevention birth cohort study.

BACKGROUND: Prospective studies investigating the association among fruit, berry, and vegetable consumption and the risk of islet autoimmunity (IA) and type 1 diabetes (T1D) are few. OBJECTIVES: In this cohort study, we explored whether the consumption of fruits, berries, and vegetables is associated with the IA and T1D development in genetically susceptible children. METHODS: Food consumption data in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) cohort study were available from 5674 children born between September 1996 and September 2004 in the Oulu and Tampere University Hospitals. Diet was assessed with 3-d food records at the age of 3 and 6 mo and annually from 1 to 6 y. The association between food consumption and the risk of IA and T1D was analyzed using joint models adjusted for energy intake, sex, human leukocyte antigen (HLA) genotype, and a family history of diabetes. RESULTS: During the 6-y follow-up, 247 children (4.4%) developed IA and 94 (1.7%) T1D. Furthermore, 64 of 505 children with at least 1 repeatedly positive autoantibody (12.7%) progressed from islet autoantibody positivity to T1D. The consumption of cruciferous vegetables was associated with decreased risk of IA [hazard ratio (HR): 0.83; 95% credible intervals (CI): 0.72, 0.95, per 1 g/MJ increase in consumption] and the consumption of berries with decreased risk of T1D (0.60; 0.47, 0.89). The consumption of banana was associated with increased risk of IA (1.08; 1.04, 1.12) and T1D (1.11; 1.01, 1.21). Only the association between banana and IA remain significant after multiple testing correction. CONCLUSIONS: In children genetically at risk for T1D, the consumption of cruciferous vegetables was associated with decreased risk of IA and consumption of berries with decreased risk of T1D. In addition, the consumption of banana was associated with increased risk of IA and T1D.

CXADR polymorphism rs6517774 modifies islet autoimmunity characteristics and exhibits sex disparity.

Enteroviral infections have been linked to the development of islet autoimmunity (IA) and type 1 diabetes (T1D), and the coxsackie and adenovirus receptor (CXADR) is one of the ligands used by adenoviruses and enteroviruses for cell internalization. Two CXADR single nucleotide polymorphisms (SNPs), rs6517774 and rs2824404, were previously associated with an increased susceptibility to IA in the international TEDDY study (The Environmental Determinants of Diabetes in the Young). This study aimed to replicate the results by genotyping 2886 children enrolled in the Finnish Diabetes Prediction and Prevention study (DIPP). In our preliminary analysis of the SNPs' allelic distributions, we could not find any association with IA susceptibility. However, a stratified analysis revealed a sex disparity, since the allelic distribution of rs6517774 was different when comparing autoantibody positive females with males; a difference not seen in healthy subjects. By using HLA risk groups and sex as covariates, a Cox regression survival analysis found that the rs6517774 (A/G) SNP was associated with a lower age at seroconversion in females (Female*rs6517774-AA; HR = 1.53, p = 0.002), while introducing a protective effect in males. Accordingly, we propose that rs6517774 alters IA characteristics by modifying the age at seroconversion in a sex-dependent manner. In light of this observation, rs6517774 now joins a limited set on SNPs found to introduce sex-dependent risk effects on the age at IA initiation.

Metformin Versus Insulin for Gestational Diabetes: Cognitive and Neuropsychological Profiles of Children Aged 9 years.

OBJECTIVE: We compared cognitive profile and neuropsychological performance in 9-year-old offspring of mothers who were treated with metformin or insulin for gestational diabetes mellitus (GDM). METHODS: A total of 172 children whose mothers were randomly assigned to receive either metformin or insulin for GDM were studied at the age of 9 years. Of these children, 127 were from Turku, Finland (63 metformin and 64 insulin), and 45 from Oulu, Finland (19 metformin and 26 insulin). Clinical and demographic background characteristics were obtained at enrolment, birth, and 9-year follow-up. Cognitive profiles were examined at age 9 years with the Wechsler Intelligence Scale for Children. Neuropsychological functions were examined with 2 subtests of the Developmental Neuropsychological Assessment test battery assessing comprehension of instructions and narrative memory, Trail Making Test assessing attention and with Behavioral Rating Inventory of Executive Functioning, including parent-rated and teacher-rated evaluations. Academic functioning was studied with reading fluency subtest of the Screening test for reading, writing, and calculus for first to sixth grades and information about educational support received at school reported by parents. RESULTS: The cognitive profiles, including indexes of verbal comprehension, perceptual reasoning, working memory, and processing speed, did not differ significantly between metformin-treated and insulin-treated groups. Significant differences were not found between the treatment groups in assessed neuropsychological functions, reading fluency, or received level of support at school. CONCLUSION: Cognitive and neuropsychological outcomes were similar in 9-year-old children whose mothers had either metformin or insulin treatment of GDM.

Circulating metabolic signatures of rapid and slow progression to type 1 diabetes in islet autoantibody-positive children.

Aims/hypothesis: Appearance of multiple islet cell autoantibodies in early life is indicative of future progression to overt type 1 diabetes, however, at varying rates. Here, we aimed to study whether distinct metabolic patterns could be identified in rapid progressors (RP, disease manifestation within 18 months after the initial seroconversion to autoantibody positivity) vs. slow progressors (SP, disease manifestation at 60 months or later from the appearance of the first autoantibody). Methods: Longitudinal samples were collected from RP (n=25) and SP (n=41) groups at the ages of 3, 6, 12, 18, 24, or ≥ 36 months. We performed a comprehensive metabolomics study, analyzing both polar metabolites and lipids. The sample series included a total of 239 samples for lipidomics and 213 for polar metabolites. Results: We observed that metabolites mediated by gut microbiome, such as those involved in tryptophan metabolism, were the main discriminators between RP and SP. The study identified specific circulating molecules and pathways, including amino acid (threonine), sugar derivatives (hexose), and quinic acid that may define rapid vs. slow progression to type 1 diabetes. However, the circulating lipidome did not appear to play a major role in differentiating between RP and SP. Conclusion/interpretation: Our study suggests that a distinct metabolic profile is linked with the type 1 diabetes progression. The identification of specific metabolites and pathways that differentiate RP from SP may have implications for early intervention strategies to delay the development of type 1 diabetes.

Serum APOC1 levels are decreased in young autoantibody positive children who rapidly progress to type 1 diabetes.

Better understanding of the early events in the development of type 1 diabetes is needed to improve prediction and monitoring of the disease progression during the substantially heterogeneous presymptomatic period of the beta cell damaging process. To address this concern, we used mass spectrometry-based proteomics to analyse longitudinal pre-onset plasma sample series from children positive for multiple islet autoantibodies who had rapidly progressed to type 1 diabetes before 4 years of age (n = 10) and compared these with similar measurements from matched children who were either positive for a single autoantibody (n = 10) or autoantibody negative (n = 10). Following statistical analysis of the longitudinal data, targeted serum proteomics was used to verify 11 proteins putatively associated with the disease development in a similar yet independent and larger cohort of children who progressed to the disease within 5 years of age (n = 31) and matched autoantibody negative children (n = 31). These data reiterated extensive age-related trends for protein levels in young children. Further, these analyses demonstrated that the serum levels of two peptides unique for apolipoprotein C1 (APOC1) were decreased after the appearance of the first islet autoantibody and remained relatively less abundant in children who progressed to type 1 diabetes, in comparison to autoantibody negative children.

DNA methylation differences within INS, PTPN22 and IL2RA promoters in lymphocyte subsets in children with type 1 diabetes and controls.

We elucidated the effect of four known T1D-susceptibility associated single nucleotide polymorphism (SNP) markers in three genes (rs12722495 and rs2104286 in IL2RA, rs689 in INS and rs2476601 in PTPN22) on CpG site methylation of their proximal promoters in different lymphocyte subsets using pyrosequencing. The study cohort comprised 25 children with newly diagnosed T1D and 25 matched healthy controls. The rs689 SNP was associated with methylation at four CpG sites in INS promoter: -234, -206, -102 and -69. At all four CpG sites, the susceptibility genotype AA was associated with a higher methylation level compared to the other genotypes. We also found an association between rs12722495 and methylation at CpG sites -373 and -356 in IL2RA promoter in B cells, where the risk genotype AA was associated with lower methylation level compared to the AG genotype. The other SNPs analyzed did not demonstrate significant associations with CpG site methylation in the examined genes. Additionally, we compared the methylation between children with T1D and controls, and found statistically significant methylation differences at CpG -135 in INS in CD8+ T cells (p = 0.034), where T1D patients had a slightly higher methylation compared to controls (87.3 ± 7.2 vs. 78.8 ± 8.9). At the other CpG sites analyzed, the methylation was similar. Our results not only confirm the association between INS methylation and rs689 discovered in earlier studies but also report this association in sorted immune cells. We also report an association between rs12722495 and IL2RA promoter methylation in B cells. These results suggest that at least part of the genetic effect of rs689 and rs12722495 on T1D pathogenesis may be conveyed by DNA methylation.

Evaluation of plasma IL-21 as a potential biomarker for type 1 diabetes progression.

IL-21 is a multifunctional cytokine linked with the pathophysiology of several autoimmune diseases, including type 1 diabetes. In this study, our aim was to examine plasma IL-21 levels in individuals at different stages of type 1 diabetes progression. We measured plasma IL-21 levels, as well as levels of other key pro-inflammatory cytokines (IL-17A, TNF-α and IL-6), from 37 adults with established type 1 diabetes and 46 healthy age-matched adult controls, as well as from 53 children with newly diagnosed type 1 diabetes, 48 at-risk children positive for type 1 diabetes-associated autoantibodies and 123 healthy age-matched pediatric controls using the ultrasensitive Quanterix SiMoA technology. Adults with established type 1 diabetes had higher plasma IL-21 levels compared to healthy controls. However, the plasma IL-21 levels showed no statistically significant correlation with clinical variables, such as BMI, C-peptide, HbA1c, or hsCRP levels, evaluated in parallel. In children, plasma IL-21 levels were almost ten times higher than in adults. However, no significant differences in plasma IL-21 levels were detected between healthy children, autoantibody-positive at-risk children, and children with newly diagnosed type 1 diabetes. In conclusion, plasma IL-21 levels in adults with established type 1 diabetes were increased, which may be associated with autoimmunity. The physiologically high plasma IL-21 levels in children may, however, reduce the potential of IL-21 as a biomarker for autoimmunity in pediatric subjects.

Metformin versus insulin for gestational diabetes: Adiposity variables and adipocytokines in offspring at age of 9 years.

AIMS: To compare body composition, visceral adiposity, adipocytokines, and low-grade inflammation markers in prepubertal offspring of mothers who were treated with metformin or insulin for gestational diabetes mellitus (GDM). METHODS: 172 offspring of 311 mothers randomized to receive metformin (n = 82) or insulin (n = 90) for GDMwere studied at 9 years of age (follow-up rate 55%). Measurements included anthropometrics, adipocytokines, markers of the low-grade inflammation, abdominal magnetic resonance imaging (MRI), magnetic liver spectrometry (MRS), and whole body dual-energy X-ray absorptiometry (DXA). RESULTS: Serum markers of low-grade inflammation, visceral adipose tissue volume, total fat percentage, and liver fat percentage were similar between the study groups. Serum adiponectin concentration was higher in children in the metformin group compared to insulin group (median 10.37 vs 9.50 µg/ml, p = 0.016). This difference between groups was observed in boys only (median 12.13 vs 7.50 µg/ml, p < 0.001). Leptin/adiponectin-ratio was lower in boys in the metformin group than in the insulin group (median 0.30 vs 0.75; p = 0.016). CONCLUSIONS: Maternal metformin treatment for GDM had no effects on adiposity, body composition, liver fat, or inflammation markers in prepubertal offspring compared to maternal insulin treatment but was associated with higher adiponectin concentration and lower leptin/adiponectin-ratio in boys.

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.

Refining the Definition of Stage 1 Type 1 Diabetes: An Ontology-Driven Analysis of the Heterogeneity of Multiple Islet Autoimmunity.

OBJECTIVE: To estimate the risk of progression to stage 3 type 1 diabetes based on varying definitions of multiple islet autoantibody positivity (mIA). RESEARCH DESIGN AND METHODS: Type 1 Diabetes Intelligence (T1DI) is a combined prospective data set of children from Finland, Germany, Sweden, and the U.S. who have an increased genetic risk for type 1 diabetes. Analysis included 16,709 infants-toddlers enrolled by age 2.5 years and comparison between groups using Kaplan-Meier survival analysis. RESULTS: Of 865 (5%) children with mIA, 537 (62%) progressed to type 1 diabetes. The 15-year cumulative incidence of diabetes varied from the most stringent definition (mIA/Persistent/2: two or more islet autoantibodies positive at the same visit with two or more antibodies persistent at next visit; 88% [95% CI 85-92%]) to the least stringent (mIA/Any: positivity for two islet autoantibodies without co-occurring positivity or persistence; 18% [5-40%]). Progression in mIA/Persistent/2 was significantly higher than all other groups (P < 0.0001). Intermediate stringency definitions showed intermediate risk and were significantly different than mIA/Any (P < 0.05); however, differences waned over the 2-year follow-up among those who did not subsequently reach higher stringency. Among mIA/Persistent/2 individuals with three autoantibodies, loss of one autoantibody by the 2-year follow-up was associated with accelerated progression. Age was significantly associated with time from seroconversion to mIA/Persistent/2 status and mIA to stage 3 type 1 diabetes. CONCLUSIONS: The 15-year risk of progression to type 1 diabetes risk varies markedly from 18 to 88% based on the stringency of mIA definition. While initial categorization identifies highest-risk individuals, short-term follow-up over 2 years may help stratify evolving risk, especially for those with less stringent definitions of mIA.

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.

Islet autoantibody screening in at-risk adolescents to predict type 1 diabetes until young adulthood: a prospective cohort study.

BACKGROUND: 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. METHODS: Data were harmonised from prospective studies from Finland (the Diabetes Prediction and Prevention study), Germany (the BABYDIAB study), and the USA (Diabetes Autoimmunity Study in the Young and the Diabetes Evaluation in Washington study). Autoantibodies against insulin, glutamic acid decarboxylase, and insulinoma-associated protein 2 were measured at each follow-up visit. Children who were lost to follow-up or diagnosed with type 1 diabetes before 10 years of age were excluded. Inverse probability censoring weighting was used to include data from remaining participants. Sensitivity and the positive predictive value of these autoantibodies, tested at one or two ages, to predict type 1 diabetes by the age of 18 years were the main outcomes. FINDINGS: Of 20 303 children with an increased type 1 diabetes risk, 8682 were included for the analysis with inverse probability censoring weighting. 1890 were followed up to 18 years of age or developed type 1 diabetes between the ages of 10 years and 18 years, and their median follow-up was 18·3 years (IQR 14·5-20·3). 442 (23·4%) of 1890 adolescents were positive for at least one islet autoantibody, and 262 (13·9%) developed type 1 diabetes. Time from seroconversion to diabetes diagnosis increased by 0·64 years (95% CI 0·34-0·95) for each 1-year increment of diagnosis age (Pearson's correlation coefficient 0·88, 95% CI 0·50-0·97, p=0·0020). The median interval between the last prediagnostic sample and diagnosis was 0·3 years (IQR 0·1-1·3) in the 227 participants who were autoantibody positive and 6·8 years (1·6-9·9) for the 35 who were autoantibody negative. Single screening at the age of 10 years was 90% (95% CI 86-95) sensitive, with a positive predictive value of 66% (60-72) for clinical diabetes. Screening at two ages (10 years and 14 years) increased sensitivity to 93% (95% CI 89-97) but lowered the positive predictive value to 55% (49-60). INTERPRETATION: Screening of adolescents at risk for type 1 diabetes only once at 10 years of age for islet autoantibodies was highly effective to detect type 1 diabetes by the age of 18 years, which in turn could enable prevention of diabetic ketoacidosis and participation in secondary prevention trials. FUNDING: JDRF International.

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.

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.

Quantifying the utility of islet autoantibody levels in the prediction of type 1 diabetes in children.

AIMS/HYPOTHESIS: The aim of this study was to explore the utility of islet autoantibody (IAb) levels for the prediction of type 1 diabetes in autoantibody-positive children. METHODS: Prospective cohort studies in Finland, Germany, Sweden and the USA followed 24,662 children at increased genetic or familial risk of developing islet autoimmunity and diabetes. For the 1403 who developed IAbs (523 of whom developed diabetes), levels of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA) and insulinoma-associated antigen-2 (IA-2A) were harmonised for analysis. Diabetes prediction models using multivariate logistic regression with inverse probability censored weighting (IPCW) were trained using 10-fold cross-validation. Discriminative power for disease was estimated using the IPCW concordance index (C index) with 95% CI estimated via bootstrap. RESULTS: A baseline model with covariates for data source, sex, diabetes family history, HLA risk group and age at seroconversion with a 10-year follow-up period yielded a C index of 0.61 (95% CI 0.58, 0.63). The performance improved after adding the IAb positivity status for IAA, GADA and IA-2A at seroconversion: C index 0.72 (95% CI 0.71, 0.74). Using the IAb levels instead of positivity indicators resulted in even better performance: C index 0.76 (95% CI 0.74, 0.77). The predictive power was maintained when using the IAb levels alone: C index 0.76 (95% CI 0.75, 0.76). The prediction was better for shorter follow-up periods, with a C index of 0.82 (95% CI 0.81, 0.83) at 2 years, and remained reasonable for longer follow-up periods, with a C index of 0.76 (95% CI 0.75, 0.76) at 11 years. Inclusion of the results of a third IAb test added to the predictive power, and a suitable interval between seroconversion and the third test was approximately 1.5 years, with a C index of 0.78 (95% CI 0.77, 0.78) at 10 years follow-up. CONCLUSIONS/INTERPRETATION: Consideration of quantitative patterns of IAb levels improved the predictive power for type 1 diabetes in IAb-positive children beyond qualitative IAb positivity status.