Aim/hypothesis
Environmental factors are believed to contribute to the risk of developing type 1 diabetes. The aim of this study was to investigate how size for gestational age affects the risk of ...developing childhood type 1 diabetes.
Methods
Using the Swedish paediatric diabetes quality register and the Swedish medical birth register, children with type 1 diabetes diagnosed between 2000 and 2012 (
n
= 9376) were matched with four control children (
n
= 37,504). Small for gestational age (SGA) and large for gestational age (LGA) were defined according to Swedish national standards. Data were initially analysed using Pearson’s
χ
2
and thereafter by single and multiple logistic regression models.
Results
An equal proportion of children were born appropriate for gestational age, but children with type 1 diabetes were more often born LGA and less often born SGA than control children (4.7% vs 3.5% and 2.0% vs 2.6%, respectively,
p
< 0.001). In the multiple logistic regression analysis, being born LGA increased (adjusted OR 1.16 95% CI 1.02, 1.32) and SGA decreased (adjusted OR 0.76 95% CI 0.63, 0.92) the risk for type 1 diabetes, regardless of maternal BMI and diabetes.
Conclusions/interpretation
Size for gestational age of Swedish children affects the risk of type 1 diabetes, with increased risk if the child is born LGA and decreased risk if the child is born SGA. Being born LGA is an independent risk factor for type 1 diabetes irrespective of maternal BMI and diabetes. Thus, reducing the risk for a child being born LGA might to some extent reduce the risk for type 1 diabetes.
Graphical abstract
HLA-DQ molecules account over 50% genetic risk of type 1 diabetes (T1D), but little is known about associated residues. Through next generation targeted sequencing technology and deep learning of DQ ...residue sequences, the aim was to uncover critical residues and their motifs associated with T1D. Our analysis uncovered (αa1, α44, α157, α196) and (β9, β30, β57, β70, β135) on the HLA-DQ molecule. Their motifs captured all known susceptibility and resistant T1D associations. Three motifs, "DCAA-YSARD" (OR = 2.10, p = 1.96*10
), "DQAA-YYARD" (OR = 3.34, 2.69*10
) and "DQDA-YYARD" (OR = 3.71, 1.53*10
) corresponding to DQ2.5 and DQ8.1 (the latter two motifs) associated with susceptibility. Ten motifs were significantly associated with resistance to T1D. Collectively, homozygous DQ risk motifs accounted for 43% of DQ-T1D risk, while homozygous DQ resistant motifs accounted for 25% protection to DQ-T1D risk. Of the identified nine residues five were within or near anchoring pockets of the antigenic peptide (α44, β9, β30, β57 and β70), one was the N-terminal of the alpha chain (αa1), one in the CD4-binding region (β135), one in the putative cognate TCR-induced αβ homodimerization process (α157), and one in the intra-membrane domain of the alpha chain (α196). Finding these critical residues should allow investigations of fundamental properties of host immunity that underlie tolerance to self and organ-specific autoimmunity.
Maturity Onset Diabetes of the Young (MODY) is a young-onset, monogenic form of diabetes without needing insulin treatment. Diagnostic testing is expensive. To aid decisions on who to test, we aimed ...to develop a MODY probability calculator for paediatric cases at the time of diabetes diagnosis, when the existing "MODY calculator" cannot be used. Firth logistic regression models were developed on data from 3541 paediatric patients from the Swedish 'Better Diabetes Diagnosis' (BDD) population study (n = 46 (1.3%) MODY (HNF1A, HNF4A, GCK)). Model performance was compared to using islet autoantibody testing. HbA1c, parent with diabetes, and absence of polyuria were significant independent predictors of MODY. The model showed excellent discrimination (c-statistic = 0.963) and calibrated well (Brier score = 0.01). MODY probability > 1.3% (ie. above background prevalence) had similar performance to being negative for all 3 antibodies (positive predictive value (PPV) = 10% v 11% respectively i.e. ~ 1 in 10 positive test rate). Probability > 1.3% and negative for 3 islet autoantibodies narrowed down to 4% of the cohort, and detected 96% of MODY cases (PPV = 31%). This MODY calculator for paediatric patients at time of diabetes diagnosis will help target genetic testing to those most likely to benefit, to get the right diagnosis.
Several studies show that good metabolic control is important for children and adolescents with type 1 diabetes. In Sweden, there are large differences in mean haemoglobin A1c (HbA1c) in different ...hospitals and difficulties implementing national guidelines in everyday practice. This study shows how the participation in an improvement collaborative could facilitate improvements in the quality of care by paediatric diabetes teams. The Swedish paediatric diabetes quality registry, SWEDIABKIDS was used as a tool and resource for feedback and outcome measures.
Twelve teams at paediatric diabetes centres, caring for 30% (2302/7660) of patients in Sweden, participated in an 18-month quality improvement program. Each team defined treatment targets, areas needing improvement, and action plans. The main outcome was the centre patients' mean HbA1c levels, but other clinical variables and change concepts were also studied. Data from the previous six months were compared with the first six months after starting the program, and the long-term follow up after another eleven months.
All centres reduced mean HbA1c during the second and third periods compared with the first. The mean reduction for all was 3·7 mmol/mol (p<0.001), compared with non-participating centres who improved their mean HbA1c with 1·7 mmol/mol during the same period. Many of the participating centres reduced the frequency of severe hypoglycaemia and/or ketoacidosis, and five centres reached their goal of ensuring that all patients had some sort of physical activity at least once weekly. Change concepts were, for example, improved guidelines, appointment planning, informing the patients, improving teamwork and active use of the registry, and health promotion activities.
By involving paediatric diabetes teams in a quality improvement collaborative together with access to a quality register, the quality of paediatric diabetes care can improve, thereby contributing to a reduced risk of late complications for children and adolescents with diabetes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aims
Between 1985 and 1996, Sweden experienced an “epidemic” of celiac disease with a fourfold increase in incidence in young children. Timing and amount of gluten introduced during infancy have been ...thought to explain this “epidemic”. We aimed to study whether the cumulative incidence of type 1 diabetes differs between children born during the “epidemic” compared to children born after.
Methods
This is a national register study in Sweden comparing the cumulative incidence of type 1 diabetes in two birth cohorts of 240 844 children 0–17 years old born 1992–1993, during the “epidemic”, and 179 530 children born 1997–1998, after the “epidemic”. Children diagnosed with type 1 diabetes were identified using three national registers.
Results
The cumulative incidence of type 1 diabetes by the age of 17 was statistically significantly higher in those born after the “epidemic” 0.77% than in those born during the “epidemic” 0.68% (
p
< 0.001).
Conclusion
The incidence of type 1 diabetes is higher in those born after the epidemic compared to those born during the epidemic, which does not support the hypothesis that gluten introduction increases the incidence of T1D. Changes in gluten introduction did not halt the increased incidence of type 1 diabetes in Sweden.
Recent systematic reviews on the topic of mindfulness- and acceptance-based approaches in sport psychology conclude that there is a need for further trials using a more robust research methodology ...with direct performance as outcome. Acceptance and Commitment Training (ACT) is a contextual behavioral change method that focuses on facilitating psychological processes such as values, committed action, acceptance and mindfulness. In the present study designed as a randomized controlled trial, 34 junior elite ice hockey players were allocated into either an ACT group intervention or a wait list control group. Results showed significant effects on both objective performance outcomes (goals, assists, and taken shots) and blinded coach ratings of players' performance, focus and commitment to their development in favor of the ACT group. Effects lasted at 3-month follow-up for the coach ratings, but not for the objective performance measures. All ACT trained players recommended ACT to other players and considered the training as important for their development as ice hockey players. The results add to the growing body of evidence on ACT interventions for athletes and its effect on performance. Future studies should investigate the maintenance of effects from the psychological training over time, using robust research methodology and investigate theoretical coherent potential mediating variables.
Context:
Screening of autoimmune thyroid disease in children and young adults with Type 1 diabetes is important but vary greatly between clinics.
Objective:
The aim was to determine the predictive ...value of thyroid autoantibodies, thyroid function, islet autoantibodies, and HLA- DQ at diagnosis of Type 1 diabetes for autoimmune thyroid disease during subsequent follow-up.
Setting:
43 Paediatric Endocrinology units Sweden.
Design, patients and main outcome measures:
At diagnosis of Type 1 diabetes, samples from 2433 children were analysed for autoantibodies against thyroid peroxidase (TPOAb), thyroglobulin (TGAb), glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated protein-2 (IA-2A), and the three variants of the zinc transporter 8 (ZnT8W/R/QA) as well as HLA-DQA1-B1 genotypes and thyroid function. After 5.1–9.5 years disease duration, children treated with thyroxine were identified in the Swedish National Board of Health and Welfare Prescribed Drug Register.
Results:
Thyroxine had been prescribed to 6% (147/2433; 66% girls). In patients below 5 years, female gender (HR=4.60, p=0.008) and GADA (HR=5.80, p=0.02) were significant predictors. In patients 5–10 years, TPOAb (HR=20.56, p<0.0001), TGAb (HR=3.40, p=0.006) and TSH outside the reference limit (HR=3.64, p<0.001) were predictors while in the 10–15 year olds, TPOAb (HR=17.00, p<0.001) and TSH outside the reference limit (HR=4.11, p<0.001) predicted future thyroxine prescription.
Conclusion:
In addition to TPOAb and TSH, positive GADA tested at the diagnosis of type 1 diabetes is important for the prediction of autoimmune thyroid disease in children below 5 years of age.
HLA-DR4, a common antigen of HLA-DRB1, has multiple subtypes that are strongly associated with risk of type 1 diabetes (T1D); however, some are risk neutral or resistant. The pathobiological ...mechanism of HLA-DR4 subtypes remains to be elucidated.
We used a population-based case-control study of T1D (962 patients and 636 controls) to decipher genetic associations of HLA-DR4 subtypes and specific residues with susceptibility to T1D. Using a birth cohort of 7865 children with periodically measured islet autoantibodies (GADA, IAA or IA-2A), we proposed to validate discovered genetic associations with a totally different study design and time-to-seroconversions prior to clinical onset of T1D. A novel analytic strategy hierarchically organized the HLA-DRB1 alleles by sequence similarity and identified critical amino acid residues by minimizing local genomic architecture and higher-order interactions.
Three amino acid residues of HLA-DRB1 (β71, β74, β86) were found to be predictive of T1D risk in the population-based study. The “KAG” motif, corresponding to HLA-DRB1×04:01, was most strongly associated with T1D risk (Odds Ratio=3.64, p = 3.19 × 10−64). Three less frequent motifs (“EAV”, OR = 2.55, p = 0.025; “RAG”, OR = 1.93, p = 0.043; and “RAV”, OR = 1.56, p = 0.003) were associated with T1D risk, while two motifs (“REG” and “REV”) were equally protective (OR = 0.11, p = 4.23 × 10−4). In an independent birth cohort of HLA-DR3 and HLA-DR4 subjects, those having the “KAG” motif had increased risk for time-to-seroconversion (Hazard Ratio = 1.74, p = 6.51 × 10−14) after adjusting potential confounders.
DNA sequence variation in HLA-DRB1 at positions β71, β74, and β86 are non-conservative (β74 A→E, β71 E vs K vs R and β86 G vs V). They result in substantial differences in peptide antigen anchor pocket preferences at p1, p4 and potentially neighboring regions such as pocket p7. Differential peptide antigen binding is likely to be affected. These sequence substitutions may account for most of the HLA-DR4 contribution to T1D risk as illustrated in two HLA-peptide model complexes of the T1D autoantigens preproinsulin and GAD65.
National Institute of Diabetes and Digestive and Kidney Diseases and the Swedish Child Diabetes Foundation and the Swedish Research Council.
Double-blind placebo-controlled intervention using glutamic acid decarboxylase (GAD)-alum, vitamin D and Ibuprofen in recent onset Type I diabetes (T1D). Methods: 64 patients (T1D since <4 months, ...age 10–17.99, fasting sC-peptide ≥0.12 nmol/l, GADA-positive) were randomized into Day(D) 1–90 400 mg/day Ibuprofen, D1–450 vitamin D 2000 IU/day, D15, 45 sc. 20 μg GAD-alum; as A but placebo instead of Ibuprofen; as B but 40 μg GAD-alum D15, 45; placebo.
Treatment was safe and tolerable. No C-peptide preservation was observed. We observed a linear correlation of baseline C-peptide, HbA1c and insulin/per kilogram/24 h with change in C-peptide AUC at 15 months (r = -0.776, p < 0.0001).
Ibuprofen, vitamin D + GAD-alum did not preserve C-peptide. Treatment efficacy was influenced by baseline clinical and immunological factors and vitamin D concentration. Clinical Trial Registration: NCT01785108 (
).
In many countries, Type I diabetes with insufficient own insulin secretion is a common life-threatening disease in children and adults. There is no prevention and no cure. In spite of very intense treatment, the disease leads to serious complications. There is no efficaceous method to save own insulin secretion without serious risks and adverse events, but autoantigen treatment with glutamic acid decarboxylase has shown some efficacy. We have tried a combination therapy with vitamin D and anti-inflammatory treatment (ibuprofen). Vitamin D in combination with glutamic acid decarboxylase-alum seems to have beneficial effects, but not Ibuprofen. The effect is influenced by basal clinical and immunological status.
Aims/hypothesis
Genetic and environmental factors are believed to cause type 1 diabetes. The aim of this study was to investigate the influence of maternal BMI and gestational weight gain on the ...subsequent risk of childhood type 1 diabetes.
Methods
Children in the Swedish National Quality Register for Diabetes in Children were matched with control children from the Swedish Medical Birth Register. Children were included whose mothers had data available on BMI in early pregnancy and gestational weight gain, giving a total of 16,179 individuals: 3231 children with type 1 diabetes and 12,948 control children.
Results
Mothers of children with type 1 diabetes were more likely to be obese (9%
n
= 292/3231 vs 7.7%
n
= 991/12,948;
p
= 0.02) and/or have diabetes themselves (2.8%
n
= 90/3231 vs 0.8%
n
= 108/12,948;
p
< 0.001) compared with mothers of control children. Gestational weight gain did not differ significantly between the two groups of mothers. In mothers without diabetes, maternal obesity was a significant risk factor for type 1 diabetes in the offspring (
p
= 0.04). A child had an increased risk of developing type 1 diabetes if the mother had been obese in early pregnancy (crude OR 1.20; 95% CI 1.05, 1.38; adjusted OR 1.18; 95% CI 1.02, 1.36). Among children with type 1 diabetes (
n
= 3231) there was a difference (
p
< 0.001) in age at onset in relation to the mother’s BMI. Among children in the oldest age group (15–19 years), there were more mothers who had been underweight during pregnancy, while in the youngest age group (0–4 years) the pattern was reversed.
Conclusions/interpretation
Maternal obesity, in the absence of maternal diabetes, is a risk factor for type 1 diabetes in the offspring, and influences the age of onset of type 1 diabetes. This emphasises the importance of a normal maternal BMI to potentially decrease the incidence of type 1 diabetes.
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