Associations of maternal type 1 diabetes with childhood adiposity and metabolic health in the offspring: a prospective cohort study.

AIMS/HYPOTHESIS: Exposure to an intrauterine hyperglycaemic environment has been suggested to increase the offspring's later risk for being overweight or having metabolic abnormalities, but conclusive evidence for pregnancies affected by maternal type 1 diabetes is still lacking. This study aims to analyse the relationship between maternal type 1 diabetes and the offspring's metabolic health and investigate whether birthweight and/or changes in the offspring's metabolome are in the potential pathway. METHODS: We analysed data from 610 and 2169 offspring having a first-degree relative with type 1 diabetes from the TEENDIAB and BABYDIAB/BABYDIET cohorts, respectively. Anthropometric and metabolic outcomes, assessed longitudinally at 0.3-18 years of age, were compared between offspring of mothers with type 1 diabetes and offspring of non-diabetic mothers but with fathers or siblings with type 1 diabetes using mixed regression models. Non-targeted metabolomic measurements were carried out in 500 individuals from TEENDIAB and analysed with maternal type 1 diabetes and offspring overweight status. RESULTS: The offspring of mothers with type 1 diabetes had a higher BMI SD score (SDS) and an increased risk for being overweight than the offspring of non-diabetic mothers (e.g. OR for overweight status in TEENDIAB 2.40 [95% CI 1.41, 4.06]). Further, waist circumference SDS, fasting levels of glucose, insulin and C-peptide, and insulin resistance and abdominal obesity were significantly increased in the offspring of mothers with type 1 diabetes, even when adjusted for potential confounders and birthweight. Metabolite patterns related to androgenic steroids and branched-chain amino acids were found to be associated with offspring's overweight status, but no significant associations were observed between maternal type 1 diabetes and metabolite concentrations in the offspring. CONCLUSIONS/INTERPRETATION: Maternal type 1 diabetes is associated with offspring's overweight status and metabolic health in later life, but this is unlikely to be caused by alterations in the offspring's metabolome.

Evaluating the diet of children at increased risk for type 1 diabetes: first results from the TEENDIAB study.

OBJECTIVE: The development of type 1 diabetes (T1D) is potentially influenced by nutrition. The aim of our study was to assess food and nutrient intakes of children at increased risk of T1D. DESIGN: Dietary intake of the last 4 weeks was assessed using a diet history interview. The daily nutrient and food intakes were compared with the German Dietary Reference Intakes, the Optimized Mixed Diet recommendations and those of a representative sample of children from the EsKiMo study. SETTING: Children included in the analysis participated in the prospective TEENDIAB study. SUBJECTS: First-degree relatives of people with T1D (n 268), aged 8-12 years. RESULTS: The TEENDIAB children consumed 52·0 % of their total energy from carbohydrates, 32·6 % from fat and 14·3 % from protein. Compared with the reference values, their intake was lowest for folate at 61·3 % of the reference, for iodine at 58·1 % and for vitamin D at 8·9 %, and exceeded the reference for vitamin K about 5-fold, for Na about 3·5-fold and for protein about 1·5-fold. Their nutrient intakes were similar to those of a control cohort without increased T1D risk. The consumption of non-desirable food groups (meat products, sweets/snacks) was above the recommendations and the consumption of desirable food groups (fruits, vegetables, carbohydrate-rich foods) was below the recommendations. CONCLUSIONS: The TEENDIAB children had intakes considerably below the recommendations for vitamin D, iodine, folate and plant-based foods, and intakes above for vitamin K, Na, protein, meat products and sweets/snacks. They showed similar dietary patterns to non-risk children.

Prevalence of vitamin D deficiency in pre-type 1 diabetes and its association with disease progression.

AIMS/HYPOTHESIS: Vitamin D deficiency is common in people with type 1 diabetes, but its role in disease progression is unclear. Our aim was to assess the prevalence of vitamin D deficiency in prediabetes (defined as the presence of multiple islet autoantibodies), and investigate whether or not progression to type 1 diabetes is faster in children with vitamin D deficiency and multiple islet autoantibodies. METHODS: Levels of 25-hydroxyvitamin D [25(OH)D] were measured in 108 children with multiple islet autoantibodies within 2 years of islet autoantibody seroconversion, in 406 children who remained islet autoantibody-negative and in 244 patients with newly diagnosed type 1 diabetes. Children with multiple islet autoantibodies were prospectively followed for a median of 5.8 years (interquartile range 3.4-8.6 years) to monitor progression to type 1 diabetes. RESULTS: In the cross-sectional analysis, 25(OH)D levels were lower and the prevalence of vitamin D deficiency (<50 nmol/l) was higher in children with prevalent multiple islet autoantibodies than in islet autoantibody-negative children (59.9 ± 3.0 vs 71.9 ± 1.5 nmol/l; p < 0.001; 39.8% vs 28.3%; p = 0.021). The differences in vitamin D levels between the groups were greatest in summer. The cumulative incidence of type 1 diabetes at 10 years after seroconversion was similar between children with vitamin D deficiency and those with sufficient vitamin D levels (51.8% [95% CI 29.3, 74.3] vs 55.4% [95% CI 35.5, 72.3], p = 0.8). CONCLUSIONS/INTERPRETATION: Vitamin D levels were lower in children with multiple islet autoantibodies and in children with type 1 diabetes than in autoantibody-negative children. However, vitamin D deficiency was not associated with faster progression to type 1 diabetes in children with multiple islet autoantibodies.

Continuous rise of insulin resistance before and after the onset of puberty in children at increased risk for type 1 diabetes - a cross-sectional analysis.

BACKGROUND: Insulin resistance has been postulated to be linked to the frequent onset of type 1 diabetes (T1D) during puberty. Very few studies have investigated the time course of insulin resistance in childhood. To address the question of how insulin resistance develops with age and how this is related to puberty onset, we examined insulin resistance and pubertal development over time in children at increased risk for T1D. METHODS: Homeostasis model assessment of insulin resistance (HOMA-IR) was measured in 1848 fasting samples of 1177 children (aged 5-15 years) in a cross-sectional analysis. All children had a first degree relative with T1D, 120 developed islet autoantibodies. Pubertal development was determined by Tanner staging. RESULTS: Insulin resistance rose continuously from age 5 to 13 years in girls and from age 5 to 14 years in boys with an average increase of 0.09 (95 % confidence interval [CI]: 0.08-0.10) per year for girls and 0.07 (95 % CI: 0.06-0.08) for boys. The rise preceded the onset of puberty (Tanner stage 2), which was reported between 10 and 12 years of age in 80.4 % of the children (mean age: 11.2 ± 0.06 years). No difference was seen between children with or without islet autoantibodies. CONCLUSIONS: There was a constant age-dependent rise of insulin resistance during childhood without observed associations to the onset of puberty or the presence of islet autoimmunity in children at increased risk for T1D. Our data show that insulin resistance emerges well before the initiation of physical changes of puberty.

The holo beta-lactoglobulin lozenge reduces symptoms in cat allergy-Evaluation in an allergen exposure chamber and by titrated nasal allergen challenge.

BACKGROUND: The allergists´ tool box in cat allergy management is limited. Clinical studies have shown that holo beta-lactoglobulin (holoBLG) can restore micronutritional deficits in atopic immune cells and alleviate allergic symptoms in a completely allergen-nonspecific manner. With this study, we aimed to provide proof of principle in cat allergy. METHODS: A novel challenge protocol for cat allergy in a standardized ECARF allergen exposure chamber (AEC) was developed. In an open pilot study (NCT05455749), patients with clinically relevant cat allergy were provoked with cat allergen for 120 min in the AEC before and after a 3-month intervention phase (holoBLG lozenge 2x daily). Nasal, conjunctival, bronchial, and pruritus symptoms were scored every 10 min- constituting the total symptom score (TSS). Peak nasal inspiratory flow (PNIF) was measured every 30 min. In addition, a titrated nasal provocation test (NPT) was performed before and after the intervention. Primary endpoint was change in TSS at the end of final exposure compared to baseline. Secondary endpoints included changes in PNIF, NPT, and occurrence of late reactions up to 24 h after exposure. RESULTS: 35 patients (mean age: 40 years) completed the study. Compared to baseline, holoBLG supplementation resulted in significant improvement in median TSS of 50% (p < 0.001), as well as in median nasal flow by 20 L/min (p = 0.0035). 20% of patients reported late reactions after baseline exposure, but 0% after the final exposure. CONCLUSIONS: Cat allergic patients profited from targeted micronutrition with the holoBLG lozenge. As previously seen in other allergies, holoBLG supplementation also induced immune resilience in cat allergies, resulting in significant symptom amelioration.

Antibody persistence ten years after first and second doses of 23-valent pneumococcal polysaccharide vaccine, and immunogenicity and safety of second and third doses in older adults.

In a study of older adults, first and second doses of 23-valent pneumococcal polysaccharide vaccine (PN23) induced IgG increases for all 8 vaccine serotypes tested. Participants (N=143, mean age 76 years) were re-enrolled to study antibody levels after ten years, and safety and immunogenicity of another PN23 dose. Ten years after first or second doses, mean IgG concentrations exceeded vaccine-naïve levels for 7 of 8 serotypes tested. Second and third doses administered at this time were generally well tolerated and were immunogenic, inducing similar postvaccination levels. Immunogenicity is preserved after multiple PN23 doses without evidence of a lower than expected immune response (i.e., without hyporesponsiveness).

Capillary blood islet autoantibody screening for identifying pre-type 1 diabetes in the general population: design and initial results of the Fr1da study.

INTRODUCTION: Type 1 diabetes can be diagnosed at an early presymptomatic stage by the detection of islet autoantibodies. The Fr1da study aims to assess whether early staging of type 1 diabetes (1) is feasible at a population-based level, (2) prevents severe metabolic decompensation observed at the clinical manifestation of type 1 diabetes and (3) reduces psychological distress through preventive teaching and care. METHODS AND ANALYSIS: Children aged 2-5 years in Bavaria, Germany, will be tested for the presence of multiple islet autoantibodies. Between February 2015 and December 2016, 100 000 children will be screened by primary care paediatricians. Islet autoantibodies are measured in capillary blood samples using a multiplex three-screen ELISA. Samples with ELISA results >97.5th centile are retested using reference radiobinding assays. A venous blood sample is also obtained to confirm the autoantibody status of children with at least two autoantibodies. Children with confirmed multiple islet autoantibodies are diagnosed with pre-type 1 diabetes. These children and their parents are invited to participate in an education and counselling programme at a local diabetes centre. Depression and anxiety, and burden of early diagnosis are also assessed. RESULTS: Of the 1027 Bavarian paediatricians, 39.3% are participating in the study. Overall, 26 760 children have been screened between February 2015 and November 2015. Capillary blood collection was sufficient in volume for islet autoantibody detection in 99.46% of the children. The remaining 0.54% had insufficient blood volume collected. Of the 26 760 capillary samples tested, 0.39% were positive for at least two islet autoantibodies. DISCUSSION: Staging for early type 1 diabetes within a public health setting appears to be feasible. The study may set new standards for the early diagnosis of type 1 diabetes and education. ETHICS DISSEMINATION: The study was approved by the ethics committee of Technische Universität München (Nr. 70/14).

Lack of association of type 2 diabetes susceptibility genotypes and body weight on the development of islet autoimmunity and type 1 diabetes.

AIM: To investigate whether type 2 diabetes susceptibility genes and body weight influence the development of islet autoantibodies and the rate of progression to type 1 diabetes. METHODS: Genotyping for single nucleotide polymorphisms (SNP) of the type 2 diabetes susceptibility genes CDKAL1, CDKN2A/2B, FTO, HHEX-IDE, HMGA2, IGF2BP2, KCNJ11, KCNQ1, MTNR1B, PPARG, SLC30A8 and TCF7L2 was obtained in 1350 children from parents with type 1 diabetes participating in the BABYDIAB study. Children were prospectively followed from birth for islet autoantibodies and type 1 diabetes. Data on weight and height were obtained at 9 months, 2, 5, 8, 11, and 14 years of age. RESULTS: None of type 2 diabetes risk alleles at the CDKAL1, CDKN2A/2B, FTO, HHEX-IDE, HMGA2, IGF2BP2, KCNJ11, KCNQ1, MTNR1B, PPARG and SLC30A8 loci were associated with the development of islet autoantibodies or diabetes. The type 2 diabetes susceptible genotype of TCF7L2 was associated with a lower risk of islet autoantibodies (7% vs. 12% by age of 10 years, P = 0.015, P(corrected) = 0.18). Overweight children at seroconversion did not progress to diabetes faster than non-overweight children (HR: 1.08; 95% CI: 0.48-2.45, P>0.05). CONCLUSIONS: These findings do not support an association of type 2 diabetes risk factors with islet autoimmunity or acceleration of diabetes in children with a family history of type 1 diabetes.

Enzyme-linked immunosorbent assay for measuring antibodies to pneumococcal polysaccharides for the PNEUMOVAX 23 vaccine: assay operating characteristics and correlation to the WHO international assay.

The Merck pneumococcal (Pn) enzyme-linked immunosorbent assays (ELISAs) for measuring antibodies to 12 serotypes (serotypes 1, 3, 4, 6B, 7F, 8, 9V, 12F, 14, 18C, 19F, and 23F) were validated in 1999. Merck Laboratories developed the Pn assays using 10 microg/ml C polysaccharide, 100 microg/ml Pn polysaccharide (PnPs) 25, and 100 microg/ml PnPs 72 for preadsorption of samples, standards, and controls in order to improve the specificity to the Pn serotypes in the vaccine. The Pn assays utilize postimmunization sera obtained from subjects immunized with PNEUMOVAX 23 as standards for measuring immunoglobulin G concentrations in sera obtained from vaccine clinical trials with adults and infants. This material was calibrated to the Pn reference standard serum, 89SF, subjected to the Merck Pn ELISA adsorbants. Comparisons were made between the Merck Pn assay and the international Pn assay, showing moderate agreement between the two assay formats. This work describes the test procedures and operating characteristics of the Merck Pn assays and the results of experiments performed to compare the Merck Pn ELISAs to the international Pn ELISAs.