Seasonality in the manifestation of type 1 diabetes varies according to age at diagnosis in Finnish children.

AIM: We tested the hypothesis of a more aggressive disease process at diagnosis of type 1 diabetes during fall and winter, the colder seasons with consistently observed higher incidence of type 1 diabetes. METHODS: Seasonality in the manifestation of type 1 diabetes was examined in 4993 Finnish children and adolescents. Metabolic characteristics, beta-cell autoantibodies and HLA class II genetics were analysed at clinical diagnosis. RESULTS: Significant seasonality was observed with higher number of new cases during fall and winter (n = 1353/27.1% and n = 1286/25.8%) compared with spring and summer (n = 1135/22.7% and n = 219/24.4%) (p < 0.001). The youngest children (aged 0.5-4 years) differed from the older ones (aged 5-14 years) as a minority of them were diagnosed in winter (p = 0.019) while the older children followed the same pattern as that seen in the total series. Poorer metabolic decompensation was observed during seasons with lower number of new diagnoses. CONCLUSION: The heterogeneity in the seasonality of diabetes manifestation between younger and older children suggests that different environmental factors may trigger the disease at different ages. Poorer clinical condition associated with seasons with a lower number of new cases may be more likely to be due to a delay in seeking medical help than to a more aggressive autoimmunity.

Family history of type 2 diabetes and characteristics of children with newly diagnosed type 1 diabetes.

AIMS/HYPOTHESIS: Shared aetiopathogenetic factors have been proposed in type 1 diabetes and type 2 diabetes and both diseases have been shown to cluster in families. Characteristics related to type 2 diabetes have been described in patients with type 1 diabetes with a positive family history of type 2 diabetes. We wanted to characterise the family history of type 2 diabetes and its possible effects on the phenotype and genotype of type 1 diabetes in affected children at diagnosis. METHODS: A total of 4993 children under the age of 15 years with newly diagnosed type 1 diabetes from the Finnish Pediatric Diabetes Register were recruited (56.6% boys, median age of 8.2 years) for a cross-sectional, observational, population-based investigation. The family history of diabetes at diagnosis was determined by a structured questionnaire, and markers of metabolic derangement, autoantibodies and HLA class II genetics at diagnosis were analysed. RESULTS: Two per cent of the children had an immediate family member and 36% had grandparents with type 2 diabetes. Fathers and grandfathers were affected by type 2 diabetes more often than mothers and grandmothers. The children with a positive family history for type 2 diabetes were older at the diagnosis of type 1 diabetes (p < 0.001), had higher BMI-for-age (p = 0.01) and more often tested negative for all diabetes-related autoantibodies (p = 0.02). CONCLUSIONS/INTERPRETATION: Features associated with type 2 diabetes, such as higher body weight, older age at diagnosis and autoantibody negativity, are more frequently already present at the diagnosis of type 1 diabetes in children with a positive family history of type 2 diabetes.

Contrasting microbiotas between Finnish and Estonian infants: Exposure to Acinetobacter may contribute to the allergy gap.

BACKGROUND: Allergic diseases are more common in Finland than in Estonia, which-according to the biodiversity hypothesis-could relate to differences in early microbial exposures. METHODS: We aimed at defining possible microbial perturbations preceding early atopic sensitization. Stool, nasal and skin samples of 6-month-old DIABIMMUNE study participants with HLA susceptibility to type 1 diabetes were collected. We compared microbiotas of sensitized (determined by specific IgE results at 18 months of age) and unsensitized Estonian and Finnish children. RESULTS: Sensitization was differentially targeted between populations, as egg-specific and birch pollen-specific IgE was more common in Finland. Microbial diversity and community composition also differed; the genus Acinetobacter was more abundant in Estonian skin and nasal samples. Particularly, the strain-level profile of Acinetobacter lwoffii was more diverse in Estonian samples. Early microbiota was not generally associated with later sensitization. Microbial composition tended to differ between children with or without IgE-related sensitization, but only in Finland. While land-use pattern (ie green areas vs. urban landscapes around the children's homes) was not associated with microbiota as a whole, it associated with the composition of the genus Acinetobacter. Breastfeeding affected gut microbial composition and seemed to protect from sensitization. CONCLUSIONS: In accordance with the biodiversity hypothesis, our results support disparate early exposure to environmental microbes between Finnish and Estonian children and suggest a significant role of the genus Acinetobacter in the allergy gap between the two populations. The significance of the observed differences for later allergic sensitization remains open.

Characteristics of familial type 1 diabetes: effects of the relationship to the affected family member on phenotype and genotype at diagnosis.

AIMS/HYPOTHESIS: In previous studies, the risk of developing familial type 1 diabetes has been reported to be more than two times higher in the offspring of affected fathers than in those of affected mothers. We tested the hypothesis that index children with an affected father may have a more aggressive disease process at diagnosis than those with other affected first-degree relatives. METHODS: A cross-sectional, observational study was performed using the Finnish Pediatric Diabetes Register. Clinical and metabolic characteristics, beta cell autoantibodies and HLA class II genetics were analysed from index children in Finland diagnosed before the age of 15 years between January 2003 and December 2016. Information on the presence of type 1 diabetes in first-degree relatives was collected at diagnosis using a structured questionnaire. RESULTS: Out of 4993 newly diagnosed index children, 519 (10.4%) had familial type 1 diabetes. More than 5% (n = 253, 5.1%) had an affected father, 2.8% (n = 141) had an affected mother, 1.9% (n = 95) had an affected sibling and 0.6% (n = 30) had two or more affected family members. All clinical and metabolic variables were markedly poorer in children with sporadic vs familial diabetes. The index children with an affected father or mother were younger than those with an affected sibling (median age 7.59 vs 6.74 vs 10.73 years, respectively; p < 0.001). After age- and sex-adjusted analyses, index children with an affected father presented more often with ketoacidosis (9.7% vs 3.6%; p = 0.033) and had greater weight loss before diagnosis (3.2% vs 0%; p = 0.006) than those with an affected mother. Children with familial disease tested negative for all autoantibodies more often (3.5% vs 2.1%; p = 0.041) and had insulin autoantibodies more frequently (49.8% vs 42.2%; p = 0.004) than those with sporadic disease. Both major HLA risk haplotypes (DR3-DQ2 and DR4-DQ8) were more often lacking among children with sporadic vs familial disease (15.9% vs 11.2%; p = 0.006). The DR4-DQ8 haplotype was more frequent in the familial vs the sporadic group (75.7% vs 68.5%; p = 0.001) and especially among children with an affected father when compared with children with sporadic disease (77.5% vs 68.5%; p < 0.05). When comparing index children with affected parents diagnosed before or after the birth of the index child, a clear male preponderance was seen among the affected parents diagnosed before the birth of the index child (fathers 66.2% vs mothers 33.8%; p = 0.006), whereas the proportion of fathers and mothers was similar if type 1 diabetes was diagnosed after the birth of the index child. CONCLUSIONS/INTERPRETATION: The more severe metabolic derangement at diagnosis in children with sporadic type 1 diabetes compared with those with familial type 1 diabetes was confirmed. The higher frequency of diabetic ketoacidosis and increased weight loss at diagnosis in index children with an affected father compared with an affected mother support the hypothesis that paternal type 1 diabetes is associated with more severe disease in the offspring than maternal diabetes. The sex difference seen between affected parents diagnosed before and after the birth of the index child supports the hypothesis that maternal insulin treatment protects against type 1 diabetes.

Sex as a determinant of type 1 diabetes at diagnosis.

OBJECTIVE: The present study tested the hypothesis that girls have a more aggressive disease process than boys at the diagnosis of type 1 diabetes (T1D). METHODS: Demographic and clinical characteristics, the humoral autoantibody profile, and the genetic risk assessed by the presence of human leukocyte antigen DR-DQ haplotypes were analyzed in terms of sex in 4993 children and adolescents diagnosed with T1D between January 2003 and December 2016. RESULTS: A clear male preponderance (56.6%) was observed in our cohort and boys were significantly older than girls at clinical diagnosis (mean 8.3 vs 7.7 years, P < .001). Age-adjusted analyses showed a poorer metabolic decompensation in girls than boys at diagnosis. Boys tested more often positive for autoantibodies against insulin autoantibodies (P = .008), islet antigen-2 autoantibodies (P = .033), and zinc transporter 8 autoantibodies (P = .027), whereas girls had a higher frequency of glutamic acid decarboxylase autoantibodies (GADA) (P < .001) and higher GADA (P < .001) and islet cell antibody titers (P = .001). We did not find any significant differences in the genetic risk profile between girls and boys. CONCLUSIONS: Our data show that the metabolic derangement is more severe in girls already at diagnosis of T1D and this finding is independent of age. The immunologic aggressiveness of the disease is more variable as the predominance of different autoantibodies varies between sexes with a higher frequency of GADA in girls, while the 3 other biochemical autoantibodies were more common in boys.

Transglutaminase antibodies and celiac disease in children with type 1 diabetes and in their family members.

OBJECTIVES: We set out to determine the prevalence of tissue transglutaminase antibodies (anti-tTG) and celiac disease (CD) in children with newly diagnosed type 1 diabetes (T1D) and their first-degree relatives (FDR). The hypothesis was that the individuals with both diabetes and CD form a distinct subgroup in terms of human leukocyte antigen (HLA) class II genetics, islet autoantibodies, and clinical characteristics at diabetes diagnosis. SUBJECTS AND METHODS: This population-based observational study included 745 index children with T1D and their 2692 FDR from the Finnish Pediatric Diabetes Register. CD was ascertained by registers, patient records, and screening anti-tTG positive individuals for further testing. RESULTS: Among the index children, 4.8% had anti-tTG at diabetes diagnosis, and at the end of the study 3.2% had CD. Among the relatives, 2.9% had anti-tTG (4.8% mothers, 2.4% fathers, and 2.1% siblings), and 2.5% had CD (4.6% mothers, 2.1% fathers, and 1.4% siblings). Anti-tTG and CD associated with the HLA DR3-DQ2 haplotype. The usual female predominance of CD patients was observed in relatives (70%) but not among index children (46%). The index children with both diseases had a lower number of detectable islet autoantibodies than those with diabetes alone. CONCLUSIONS: The children with double diagnosis differed from those with diabetes alone in HLA genetics, humoral islet autoimmunity directed against fewer antigens, and in the lack of usual female preponderance among CD patients. Compared with 61% of the anti-tTG positive relatives, only 36% of anti-tTG positive index children developed CD implicating transient anti-tTG positivity at diagnosis of T1D.

HLA and non-HLA genes and familial predisposition to autoimmune diseases in families with a child affected by type 1 diabetes.

Genetic predisposition could be assumed to be causing clustering of autoimmunity in individuals and families. We tested whether HLA and non-HLA loci associate with such clustering of autoimmunity. We included 1,745 children with type 1 diabetes from the Finnish Pediatric Diabetes Register. Data on personal or family history of autoimmune diseases were collected with a structured questionnaire and, for a subset, with a detailed search for celiac disease and autoimmune thyroid disease. Children with multiple autoimmune diseases or with multiple affected first- or second-degree relatives were identified. We analysed type 1 diabetes related HLA class II haplotypes and genotyped 41 single nucleotide polymorphisms (SNPs) outside the HLA region. The HLA-DR4-DQ8 haplotype was associated with having type 1 diabetes only whereas the HLA-DR3-DQ2 haplotype was more common in children with multiple autoimmune diseases. Children with multiple autoimmune diseases showed nominal association with RGS1 (rs2816316), and children coming from an autoimmune family with rs11711054 (CCR3-CCR5). In multivariate analyses, the overall effect of non-HLA SNPs on both phenotypes was evident, associations with RGS1 and CCR3-CCR5 region were confirmed and additional associations were implicated: NRP1, FUT2, and CD69 for children with multiple autoimmune diseases. In conclusion, HLA-DR3-DQ2 haplotype and some non-HLA SNPs contribute to the clustering of autoimmune diseases in children with type 1 diabetes and in their families.

Positivity for Zinc Transporter 8 Autoantibodies at Diagnosis Is Subsequently Associated With Reduced ß-Cell Function and Higher Exogenous Insulin Requirement in Children and Adolescents With Type 1 Diabetes.

OBJECTIVE: This study assessed the relationship between autoantibodies against zinc transporter 8 (ZnT8A) and disease characteristics at diagnosis of type 1 diabetes and during the first 2 years. RESEARCH DESIGN AND METHODS: Children, younger than 15 years of age (n = 723) who were newly diagnosed with diabetes, were analyzed for ZnT8A, other diabetes-associated autoantibodies, HLA DR-DQ alleles, and metabolic status, which was monitored by pH, plasma glucose, and occurrence of ketoacidosis at diagnosis and through follow-up of C-peptide concentrations, exogenous insulin dose, and glycosylated hemoglobin for 2 years after the diagnosis. RESULTS: ZnT8A positivity was detected in 530 children (73%). Positivity for ZnT8A was associated with older age (median 8.9 vs. 8.2 years, P = 0.002) and more frequent ketoacidosis (24% vs. 15%, P = 0.013). Children carrying the HLA DR3 allele were less often ZnT8A positive (66% vs. 77%, P = 0.002) than others. ZnT8A-positive children had lower serum C-peptide concentrations (P = 0.008) and higher insulin doses (P = 0.012) over time than their ZnT8A-negative peers. CONCLUSIONS: Positivity for ZnT8A at diagnosis seems to reflect a more aggressive disease process before and after diagnosis.

Extended family history of autoimmune diseases and phenotype and genotype of children with newly diagnosed type 1 diabetes.

OBJECTIVE: Based on the concept of clustering autoimmunity, children with a positive family history of autoimmunity could be expected to have a different pathogenetic form of type 1 diabetes (T1D) and thus a stronger autoimmune reactivity against ß-cells and an increased prevalence of the HLA-DR3-DQ2 haplotype. DESIGN AND METHODS: We tested this hypothesis in a cross-sectional observational study from the Finnish Pediatric Diabetes Register. HLA class II genotypes and ß-cell autoantibodies were analyzed, and data on the extended family history of autoimmunity and clinical markers at diagnosis were collected with a structured questionnaire from 1488 children diagnosed with T1D under the age of 15 years (57% males). RESULTS: Only 23 children (1.5%) had another autoimmune disease (AID) known at diagnosis, and they had a milder metabolic decompensation at diabetes presentation. One-third (31.4%) had at least one relative with an AID other than T1D with affected mothers being overrepresented (8.2%) compared with fathers (2.8%). The children with a positive family history of other AIDs had higher levels of islet cell antibodies (P=0.003), and the HLA-DR3-DQ2 haplotype in the children was associated with celiac disease in the extended family (P<0.001), but not with an increased frequency of autoimmune disorders, in general. CONCLUSIONS: Approximately one-third of children with newly diagnosed T1D have a first- and/or second-degree relative affected by an AID. Our data do not consistently support the hypothesis of differential pathogenetic mechanisms in such children.

Extended family history of type 1 diabetes and phenotype and genotype of newly diagnosed children.

OBJECTIVE: To determine the frequency of newly diagnosed diabetic children with first- and second-degree relatives affected by type 1 diabetes and to characterize the effects of this positive family history on clinical markers, signs of ß-cell autoimmunity, and HLA genotype in the index case. RESEARCH DESIGN AND METHODS: Children (n = 1,488) with type 1 diabetes diagnosed under 15 years of age were included in a cross-sectional study from the Finnish Pediatric Diabetes Register. Data on family history of diabetes and metabolic decompensation at diagnosis were collected using a questionnaire. Antibodies to ß-cell autoantigens (islet cell antibodies, insulin autoantibodies, GAD antibodies, and antibodies to the islet antigen 2 molecule) and HLA genotypes were analyzed. RESULTS: A total of 12.2% of the subjects had a first-degree relative with type 1 diabetes (father 6.2%, mother 3.2%, and sibling 4.8%) and 11.9% had an affected second-degree relative. Children without affected relatives had lower pH (P < 0.001), higher plasma glucose (P < 0.001) and ß-hydroxybutyrate concentrations (P < 0.001), a higher rate of impaired consciousness (P = 0.02), and greater weight loss (P < 0.001). There were no differences in signs of ß-cell autoimmunity. The familial cases carried the HLA DR4-DQ8 haplotype more frequently than sporadic cases (74.0 vs. 67.0%, P = 0.02). CONCLUSIONS: When the extended family history of type 1 diabetes is considered, the proportion of sporadic diabetes cases may be reduced to <80%. A positive family history for type 1 diabetes associates with a less severe metabolic decompensation at diagnosis, even when only second-degree relatives are affected. Autoantibody profiles are similar in familial and sporadic type 1 diabetes, suggesting similar pathogenetic mechanisms.