Elimination of dietary gluten and development of type 1 diabetes in high risk subjects

Removal of dietary gluten is associated with a lower frequency of type 1 diabetes (T1D) in patients with celiac disease. Therefore, we performed a pilot study in which seven islet-antibody-positive first degree relatives of patients with T1D were placed on a gluten-free diet for 12 months, followed by gluten re-exposure for 12 months, to investigate whether this could reduce levels of circulating autoantibodies. We found that islet autoantibody levels at the end of the gluten-free period were not different to those before the commencement of the diet nor to antibody levels at the end of the gluten re-exposure period. In the present study, we have followed the 7 children formerly placed on a gluten-free diet for the manifestation of T1D for up to 5 years (mean follow-up time after fulfilling inclusion criteria: 4.8 years, SE 0.82 years) and compared them to 30 siblings and offspring of patients with T1D with similar characteristics to the intervention group (mean follow-up time: 5 years, SE 0.62 years). The cumulative 5-year risk of T1D in the intervention group did not differ from that in the prediabetic control group (42.9%, 95 CI (6.3-79.5%) vs. 49.7%, 95 CI (30.9-68.5%), p=0.87, log-rank test). These findings suggest that removing gluten from the diet over a period of one year is effective neither in the short nor in the long term in high-risk prediabetic individuals with a fully activated immune response to different islet antigens close to manifestation of T1D. These and recent data showing that exposure to dietary gluten in offspring of mothers and fathers with T1D very early in life is associated with an increased risk of developing islet antibodies also suggest that removal of dietary gluten should be tested as early as possible in children with an increased risk of islet autoimmunity, i.e. before an immune response to islet antigens is established.     

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.     

The prenatal environment and type 1 diabetes

There is ample evidence that environmental factors are involved in the aetiology of type 1 diabetes, but the nature and timing of the interactions are poorly understood. The intrauterine environment is known to play a role in the later development of type 2 diabetes, and this review considers a possible role in type 1 diabetes. Autoimmune type 1 diabetes is rare in those diagnosed before 6 months of age, but endogenous autoantibodies predictive of future type 1 diabetes may be detectable by 6–12 months of age, suggesting that environmental factors may operate before this age in some cases. Indirect evidence of a protective effect for the intrauterine environment comes from the observation that mothers with type 1 diabetes are less likely than affected fathers to transmit diabetes to their offspring, although the precise role (if any) is unclear. The risk of childhood-onset type 1 diabetes increases with maternal age at delivery, and with high birthweight, but these associations are weak and heterogeneous, and these factors are unlikely to be directly causally related to type 1 diabetes. No firm conclusion can be drawn from studies of maternal enteroviral infection or from various nutritional exposures. The birth process itself may play a role, as suggested by the slightly increased risk in children born by Caesarean section; lack of contact with maternal bacteria is one suggested mechanism. In sum, there is circumstantial evidence, but no proof of principle, that maternal or intrauterine conditions may modulate genetic risk of type 1 diabetes. The disease process culminating in type 1 diabetes typically begins in early life, but it is not clear whether the trail begins before or after birth.     

Human enterovirus infections in children at increased risk for type 1 diabetes: the Babydiet study

Aims/hypothesis

The aim of this study was to examine human enteroviruses (HEVs) and other intestinal viruses derived from children who participated in the Babydiet intervention study and to analyse the findings according to the appearance of islet autoantibodies, dietary intervention, maternal type 1 diabetes and clinical symptoms.

Methods

In the Babydiet study the influence of first gluten exposure (6 or 12?months) on the development of islet autoimmunity was investigated in 150 children with increased genetic and familial risk for type 1 diabetes. Blood and stool samples were collected at 3 monthly intervals until the age of 3?years and yearly thereafter. Infections and clinical symptoms were recorded daily for the first year. In the present study, 339 stool samples collected from 104 children during the first year of life were analysed for HEVs and a certain proportion of the samples were analysed for other intestinal viruses.

Results

HEV was detected in 32 (9.4%) samples from 24 (23.1%) children. Altogether 13 serotypes were identified, with HEV-A species being the most common. Children with gastrointestinal symptoms had norovirus (3/11) and sapovirus (1/11) infections in addition to HEV (1/11). Of the 104 children, 22 developed islet autoantibodies. HEV infections were detected in 18% (4/22) and 24% (20/82) of islet-autoantibody-positive and -negative children, respectively (p?=?0.5). The prevalence of HEV was similar in the gluten-exposed groups and in children from mothers with type 1 diabetes or from affected fathers and/or siblings (p?=?1.0 and 0.6, respectively).

Conclusions/interpretation

No correlation was found between the presence of HEV in the first year of life and the development of islet autoantibodies. There was no association between HEV infections and dietary intervention, maternal diabetes or clinical symptoms.     

Sexual dimorphism in transmission of expression of islet autoantibodies to offspring

Summary To help elucidate the mode of inheritance of insulin-dependent diabetes mellitus (IDDM), we measured GAD (glutamic acid decarboxylase) autoantibodies (GAD65Ab), insulin autoantibodies (IAA), and cytoplasmic islet cell autoantibodies (ICA) in 292 sequentially screened non-diabetic offspring of patients with IDDM. The prevalence of these islet autoantibodies was higher in offspring of diabetic fathers than in offspring of diabetic mothers. The prevalences of GAD65Ab, IAA, and ICA in the offspring of diabetic fathers were 11.5%, 10.8%, and 8.1% vs 2.1%, 1.4%, and 2.8%, respectively in the offspring of diabetic mothers (p<0.002, p<0.001, and p=0.06 NS). Amongst autoantibody-positive relatives the IAA and ICA levels were significantly higher in offspring of diabetic fathers than of diabetic mothers (p<0.002 and p<0.01, respectively). The frequencies of these autoantibodies were equal in male and female offspring. We conclude that IDDM mothers transmitted islet autoimmunity less frequently to their offspring than IDDM fathers. Given the markedly lower frequency of autoantibodies in offspring of mothers, larger sample sizes will be required to determine whether islet autoantibodies are influenced by age of IDDM onset of mothers, maternal age of pregnancy, and presence of diabetes in these mothers prior to conception.Abbreviations IDDM Insulin-dependent diabetes mellitus - GAD glutamic acid decarboxylase - GAD65Ab glutamic acid decarboxylase autoantibodies - IAA insulin autoantibodies - ICA cytoplasmic islet cell autoantibodies - JDF Juvenile Diabetes Foundation     

Randomized trial of vitamin supplements in relation to transmission of HIV-1 through breastfeeding and early child mortality

BACKGROUND: HIV-1 transmission through breastfeeding is a global problem and has been associated with poor maternal micronutrient status. METHODS: A total of 1078 HIV-infected pregnant women from Tanzania were randomly assigned to vitamin A or multivitamins excluding A from approximately 20 weeks' gestation and throughout lactation. RESULTS: Multivitamins excluding A had no effect on the total risk of HIV-1 transmission (RR 1.04, 95% CI 0.82-1.32, P= 0.76). Vitamin A increased the risk of transmission (RR 1.38, 95% CI 1.09-1.76, P = 0.009). Multivitamins were associated with non-statistically significant reductions in transmission through breastfeeding, and mortality by 24 months among those alive and not infected at 6 weeks. Multivitamins significantly reduced breastfeeding transmission in infants of mothers with low baseline lymphocyte counts (RR 0.37; 95% CI 0.16-0.85, P = 0.02) compared with infants of mothers with higher counts (RR 0.99, 95% CI 0.68-1.45, P = 0.97; -for-interaction 0.03). Multivitamins also protected against transmission among mothers with a high erythrocyte sedimentation rate (P-for-interaction 0.06), low hemoglobin (P-for-interaction 0.06), and low birthweight babies (P-for-interaction 0.04). Multivitamins reduced death and prolonged HIV-free survival significantly among children born to women with low maternal immunological or nutritional status. Vitamin A alone increased breastfeeding transmission but had no effect on mortality by 24 months. CONCLUSION: Vitamin A increased the risk of HIV-1 transmission. Multivitamin (B, C, and E) supplementation of breastfeeding mothers reduced child mortality and HIV-1 transmission through breastfeeding among immunologically and nutritionally compromised women. The provision of these supplements to HIV-infected lactating women should be considered.     

Maternal smoking during pregnancy and the risk of childhood type 1 diabetes in Western Australia

Aims/hypothesis

The aim of this study was to investigate the association between maternal smoking during pregnancy and type 1 diabetes in the offspring, using complete population data sources available in Western Australia.

Methods

A prospective cohort study was undertaken with cases defined as children born in Western Australia between 1998 and 2008 who were diagnosed with type 1 diabetes at <15 years of age up to 31 December 2010. Eligible cases were identified from the prospective, population-based Western Australian Children’s Diabetes Database. Record linkage was performed to identify perinatal records of cases from the Western Australian Midwives’ Notification System, which contains data on >99% of all births in Western Australia. Cox regression was used to analyse the data and adjust for recognised risk factors such as birthweight, gestational age, maternal age and socioeconomic status.

Results

The unadjusted HR for babies born to mothers who smoked during pregnancy being diagnosed with childhood type 1 diabetes was 0.70 (95% CI: 0.50, 0.97). After adjustment, the confidence interval widened but the point estimate remained relatively unchanged at 0.76 (95% CI: 0.54, 1.08).

Conclusions/interpretation

Analyses of data from this population-based study indicate that maternal smoking during pregnancy may be associated with a reduced risk of childhood type 1 diabetes. Further investigation in larger populations with more detailed smoking data could lead to novel hypotheses regarding mechanisms that influence the immunopathogenesis of type 1 diabetes in early life.     

Diabetes-associated HLA genotypes affect birthweight in the general population

Aims/hypothesis The aim of our study was to test the hypothesis that HLA genotypes conferring risk of diabetes, cord blood autoantibodies, or both are associated with increased birthweight.Methods HLA genotypes were determined in dried blood spots of cord blood from a total of 16,709 children born to healthy mothers in the Diabetes Prediction in Skåne (DiPiS) study, a population-based observational clinical investigation of newborn children. Children born to mothers with diabetes or gestational diabetes were excluded. Autoantibodies to glutamic acid decarboxylase (GAD65Ab) and insulinoma-associated protein 2 were determined in standard radioligand binding assays. Birthweight was adjusted for gestational age and divided into quartiles. The upper quartile was defined as high relative birthweight (HrBW) and the lower quartile as low relative birthweight (LrBW).Results Genotypes conferring risk of type 1 diabetes were strongly associated with relative birthweight (rBW) (p=0.01). The high-risk HLA-DQ2/8, DQ8/0604 and DQ8/X genotypes were associated with HrBW (odds ratio [OR] [95% CI]=1.20 [1.08–1.33], p=0.0006). The HLA-DQB1*0603 allele, which is negatively associated with type 1 diabetes, was also associated with HrBW (p=0.025), confirming a previous report on DQB1*0603-linked HLA-DR13. GAD65Ab were negatively associated with HrBW (OR [95% CI]=0.72 [0.56–0.93], p=0.01). Regression analysis showed that the HLA-associated increase in rBW was independent of confounding factors.Conclusions/interpretation HLA genotypes may be associated with intrauterine growth independent of type 1 diabetes risk. The epidemiological observation that high birthweight is a risk factor for type 1 diabetes could possibly result from a moderating effect on intrauterine growth of HLA genotypes conferring a high risk of diabetes.     

Psychological impact of childhood islet autoantibody testing in families participating in the BABYDIAB study.

AIMS: To determine anxiety in parents of children undergoing testing for islet autoantibodies. SUBJECTS AND METHODS: Children of parents with Type 1 diabetes (T1DM) were tested at birth, age 9 months, 2 years and 5 years for islet autoantibodies. Families were informed about islet autoantibody status in the child after each visit. The psychological impact of islet autoantibody testing was assessed in parents before and after the 5 years visit. Anxiety was measured using a subscale of the State-Trait-Anxiety Inventory (STAI) and structured single-item questions. Four hundred and sixty-three parents were evaluated before blood drawing and 317 parents at notification of islet autoantibody status. RESULTS: Before blood withdrawal, anxiety was increased in mothers and in particular in mothers of islet autoantibody-positive offspring compared with a normative control group. At notification of islet antibody status, anxiety significantly decreased in parents of islet autoantibody-negative offspring, and increased in parents of islet autoantibody-positive offspring. Blood withdrawal was considered a burden for parents and offspring (15% and 48%, respectively). Most parents from islet autoantibody-negative and -positive offspring wished to know the diabetes risk of their child (95% and 100%, respectively) and were glad to be informed about their child's islet antibody status (97% and 87%). CONCLUSIONS: Overall, islet autoantibody testing in early childhood reduces anxiety in T1DM families. The increased anxiety associated with islet autoantibody-positive status suggests, however, that testing should be performed in centres which can provide accurate risk information and counselling if required.     

Relationship between increased relative birthweight and infections during pregnancy in children with a high-risk diabetes HLA genotype

Aims/hypothesis

Children with high-risk type 1 diabetes HLA genotype have increased risk of high relative birthweight (HrBW), while cord blood islet autoantibodies decrease the risk. As gestational infections may affect offspring type 1 diabetes risk, the aims were to test whether: (1) children of mothers reporting gestational infections have increased HrBW; (2) gestational infections explain islet autoantibody reduction of HrBW; and (3) gestational infections affect the association between HLA and HrBW.

Subjects and methods

HLA genotypes and autoantibodies to glutamic acid decarboxylase, insulinoma-associated protein 2 and insulin were determined in cord blood of children born to non-diabetic mothers in the Diabetes Prediction in Skåne (DiPiS) study. Mothers reported gestational infections when the child was 2 months old.

Results

Fever or gastroenteritis during pregnancy was reported by 2,848/19,756 mothers (14%); 339 in more than one trimester. Children whose mothers reported infections had increased risk of HrBW (p?=?0.0003), particularly in the absence of cord blood islet autoantibodies (interaction between HrBW, islet autoantibodies and infections, p?=?0.0005). The effect on HrBW by high-risk HLA-DQ2/8 was aggravated by infections in more than one trimester (odds ratio [OR]?=?5.24; p?=?0.003) (interaction; p?=?0.022). When infections were reported, cord blood islet autoantibodies decreased HrBW (OR?=?0.34; p?=?0.0002).

Conclusions/interpretation

This study revealed that: (1) gestational fever, gastroenteritis, or both, increased the risk of HrBW; (2) cord blood islet autoantibodies decreased the risk of HrBW only in combination with infections; and (3) infections aggravated the association between HLA-DQ2/8 and HrBW. These data suggest an interaction between HLA, gestational infections, islet autoantibodies and fetal growth.

     

Prevalence, characteristics and diabetes risk associated with transient maternally acquired islet antibodies and persistent islet antibodies in offspring of parents with type 1 diabetes

Accurate assessment of type 1 diabetes risk in young children requires discrimination between antibodies that are produced by the child and antibodies acquired through the placenta from an islet antibody-positive mother. We studied 682 offspring from mothers with type 1 diabetes and 329 offspring from fathers with type 1 diabetes and nondiabetic mothers for insulin (auto)antibodies, glutamic acid decarboxylase antibodies, and tyrosine phosphatase IA-2 antibodies before age 1 yr and again at age 2 yr to ascertain transience or persistence. Antibodies were detected at age 9 months in 5 (1.5%) offspring from fathers with type 1 diabetes; all were insulin (auto)antibodies only, all persisted and developed multiple antibodies, and 1 developed type 1 diabetes. In contrast, 31 (4.5%) offspring from mothers with type 1 diabetes had antibodies at 9 months; 12 (1.8%) persisted at age 2 yr, and 19 (2.8%) did not persist, suggestive of transient residual maternal antibodies. Multiple antibodies at 9 months were usually persistent (3 of 4 offspring), as were single insulin (auto)antibodies in offspring from mothers with type 1 diabetes (8 of 13 offspring), whereas persistent glutamic acid decarboxylase antibodies (1 of 12) and tyrosine phosphatase IA-2 antibodies (0 of 2) were rare. Offspring with persistent antibodies at age 9 months had a high type 1 diabetes risk (100% by age 5 yr for those with multiple antibodies and 27% for single antibodies at 9 months), whereas offspring with transient antibodies had 0% type 1 diabetes risk (P < 0.01). Transience was associated with very high antibody levels at birth. For insulin (auto)antibodies, the measurement of subclass was also informative. Residual maternal antibody was indicated by similar insulin (auto)antibodies subclasses at 9 months and at birth, whereas different subclasses were indicative of nonmaternal antibody. Moreover, the presence of IgG1-insulin (auto)antibodies was associated with antibody persistence and type 1 diabetes risk. These strategies are helpful in discriminating high and low risk antibodies before age 1 yr and should be important for prognosis and reducing unnecessary parent anxiety.     

Autoimmunity to islet proteins in children diagnosed with new-onset diabetes

Autoantibody and T cells reacting with islet proteins have been demonstrated in patients with type 1 diabetes. In recent years an increasing number of children have been clinically classified with type 2 (not ketosis prone, evidence of insulin resistance, presence of acanthosis nigricans, and obesity) or indeterminant diabetes (admixture of clinical features of types 1 and 2). In this study, we compared the islet cell autoantibody and T-cell responses to islet proteins in type 2 (n = 19) and indeterminant (n = 16) children (<18 yr of age) to classic type 1 (n = 37) diabetic patients. We observed that 37 of 37 type 1 diabetic children demonstrated autoantibody and/or T-cell reactivity to islet proteins. Fourteen of the 19 type 2 patients were positive for islet cell autoantibodies, and six of 14 were positive for T-cell responses to islet proteins. For the indeterminant patients, 11 of 16 of the patients were positive for autoantibodies, and six of 16 patients were positive for T-cell responses to islet proteins. These results demonstrate that autoimmunity to islet proteins is present in a high percentage of children classified as indeterminant or type 2 diabetes. Moreover, the presence of obesity or acanthosis nigracans does not reliably distinguish children with or without islet cell autoimmunity.     

Endocrine autoimmunity in families with type 1 diabetes: frequent appearance of thyroid autoimmunity during late childhood and adolescence

Aims/hypothesis  Thyroid autoimmunity clusters with other endocrine and non-endocrine forms of autoimmunity. The aim of this study was to determine the chronological appearance of thyroid autoantibodies in relation to other forms of autoimmunity in at-risk children. Methods  The BABYDIAB study follows children of parents with type 1 diabetes. Children born in Germany between 1989 and 2000 were recruited at birth and followed up at 9 months and at 2, 5, 8, 11, 14 and 17 years. Antibodies to thyroid peroxidase were measured in samples taken at the last study visit in 1,489 children and in all previous samples in children who tested positive. Islet antibodies and antibodies to 21-hydroxylase and transglutaminase were also measured in all children. Median follow-up was 8 years. Results  The cumulative risk for developing antibodies to thyroid peroxidase was 20.3% (95% CI 12.3–28.3) by age 14 years. The risk was increased in girls (adjusted HR 2.0; 95% CI 1.2–3.4; p = 0.008), in children who had multiple first-degree family history of type 1 diabetes (adjusted HR 3.3; 95% CI 1.4–8.0; p = 0.006) and in children who also had antibodies to GAD (adjusted HR 3.0; 95% CI 1.5–5.9; p = 0.001). Thyroid peroxidase antibody appearance was most common from age 8 years and was often the last autoantibody to develop in children with other autoantibodies. Conclusions/interpretation  Among children of patients with type 1 diabetes, the appearance of thyroid autoantibodies is frequent, is not synchronous to the appearance of other autoantibodies and is most common in late childhood and adolescence.     

Immunoglobulin G insulin autoantibodies in BABYDIAB offspring appear postnatally: sensitive early detection using a protein A/G-based radiobinding assay

Insulin autoantibodies (IAA) are early sensitive markers of pre-diabetes in the young. The aim of this study was to assess whether, using IgG-specific measurement with a protein A/G assay, IAA are already present at birth, and whether this assay is suitable for early autoantibody screening. Cord blood and follow-up samples from offspring of parents with type 1 diabetes included in the BABYDIAB study were analyzed. Although insulin antibodies in cord blood from children of mothers with type 1 diabetes were readily detected and correlated well with levels in the maternal circulation, no insulin binding was detected in 247 cord blood samples from children of father probands. IgG IAA were detected at 2 yr in all 21 children who had multiple islet autoantibodies or who later developed type 1 diabetes, but were confirmed in only 6 of 58 with IAA by the conventional IAA assay in the absence of other islet autoantibodies. False positive IAAs in the conventional assay were often attributable to hemolysis. Hemolysis did not affect protein A/G IAA measurement, and results in whole capillary blood samples were comparable to those in corresponding serum samples (r2 = 0.99). These data show that IgG IAA appear early and after birth, and that the protein A/G IAA assay is sufficiently sensitive for early screening. The specificity of this assay requires further evaluation.     

Development of autoimmunity to transglutaminase C in children of patients with type 1 diabetes: relationship to islet autoantibodies and infant feeding

Aims/hypothesis  Coeliac disease and transglutaminase antibodies are common in patients with type 1 diabetes and their relatives. We investigated the development of transglutaminase antibodies and analysed potential risk factors for coeliac disease autoimmunity in first-degree relatives of patients with type 1 diabetes. Methods  The study was conducted by prospective observational follow-up from birth of 1,511 children at increased risk of type 1 diabetes or coeliac disease born in Germany between 1989 and 2000. Mean follow-up was to age 7.6 years. Children were tested for transglutaminase and islet autoantibodies. Children were classified as transglutaminase antibody-positive if antibodies were detected by both ELISA and radiobinding assays. Results  The risk of developing transglutaminase antibodies was 4.9% by age 8 years (n=63; 95% CI, 3.7–6.1%). Transglutaminase antibodies developed at an older age than islet autoantibodies (median age, 4.9 vs 2.3 years; p<0.005), and only three children developed both transglutaminase antibodies and islet autoantibodies. Multivariate analysis indicated an increased risk of transglutaminase antibodies in children with the HLA-DRB1*03 allele (hazard ratio for heterozygous DR3, 5.5; 95% CI, 2.9–10.2; hazard ratio for homozygous DR3, 16.2; 95% CI, 6.7–39; p<0.0001) and in children with impaired uterine growth (birth weight ≤ 1st percentile, hazard ratio, 3.1; 95% CI, 1.1–7.8, p=0.03). Neither breast-feeding or its duration nor the age of first exposure to gluten was associated with the risk of developing transglutaminase antibodies. Conclusions/interpretation  Coeliac disease autoimmunity is initiated later than islet autoimmunity in children who are at risk. An influence of infant nutrition on the development of coeliac disease autoimmunity could not be confirmed in this prospective study.     

Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study

Aims/hypothesis

Respiratory infections and onset of islet autoimmunity are reported to correlate positively in two small prospective studies. The Environmental Determinants of Diabetes in the Young (TEDDY) study is the largest prospective international cohort study on the environmental determinants of type 1 diabetes that regularly monitors both clinical infections and islet autoantibodies. The aim was to confirm the influence of reported respiratory infections and to further characterise the temporal relationship with autoantibody seroconversion.

Methods

During the years 2004–2009, 8676 newborn babies with HLA genotypes conferring an increased risk of type 1 diabetes were enrolled at 3 months of age to participate in a 15 year follow-up. In the present study, the association between parent-reported respiratory infections and islet autoantibodies at 3 month intervals up to 4 years of age was evaluated in 7869 children. Time-dependent proportional hazard models were used to assess how the timing of respiratory infections related to persistent confirmed islet autoimmunity, defined as autoantibody positivity against insulin, GAD and/or insulinoma antigen-2, concordant at two reference laboratories on two or more consecutive visits.

Results

In total, 87,327 parent-reported respiratory infectious episodes were recorded while the children were under study surveillance for islet autoimmunity, and 454 children seroconverted. The number of respiratory infections occurring in a 9 month period was associated with the subsequent risk of autoimmunity (p < 0.001). For each 1/year rate increase in infections, the hazard of islet autoimmunity increased by 5.6% (95% CI 2.5%, 8.8%). The risk association was linked primarily to infections occurring in the winter (HR 1.42 [95% CI 1.16, 1.74]; p < 0.001). The types of respiratory infection independently associated with autoimmunity were common cold, influenza-like illness, sinusitis, and laryngitis/tracheitis, with HRs (95% CI) of 1.38 (1.11, 1.71), 2.37 (1.35, 4.15), 2.63 (1.22, 5.67) and 1.76 (1.04, 2.98), respectively.

Conclusions/interpretation

Recent respiratory infections in young children correlate with an increased risk of islet autoimmunity in the TEDDY study. Further studies to identify the potential causative viruses with pathogen-specific assays should focus especially on the 9 month time window leading to autoantibody seroconversion.

     

The influence of maternal body mass index,maternal diabetes mellitus,and maternal smoking during pregnancy on the risk of childhood‐onset type 1 diabetes mellitus in the offspring: Systematic review and meta‐analysis of observational studies

There is emerging evidence that events occurring before and shortly after birth may be important in determining the risk of childhood‐onset type 1 diabetes mellitus (T1DM). We aimed to summarize and synthesize the associations between maternal body mass index (BMI), maternal diabetes mellitus (DM), and maternal smoking during pregnancy and the risk of childhood‐onset T1DM in the offspring by performing a systematic review and meta‐analysis of observational studies. A random effects model was used to generate the summary risk estimates. The PubMed and Web of Science databases were searched to identify relevant observational studies. Twenty one observational studies were included in the present meta‐analysis. Compared with offspring of mothers with normal weight, offspring of women with overweight or obesity were at an increased risk of developing childhood‐onset T1DM (overweight: relative risk [RR] 1.09, 95% confidence interval [CI], 1.03‐1.15; obesity: RR 1.25, 95% CI, 1.16‐1.34; per 5 kg m^?2 increase in BMI: RR 1.10, 95% CI, 1.06‐1.13). No association was found for maternal underweight (RR 0.92, 95% CI, 0.75‐1.13). Maternal DM was associated with an increased risk of childhood‐onset T1DM (RR 3.26, 95% CI, 2.84‐3.74). Regarding the type of maternal DM, the greatest risk of T1DM in the offspring appeared to be conferred by maternal T1DM (RR 4.46, 95% CI, 2.89‐6.89), followed by maternal gestational diabetes mellitus (RR 1.66, 95% CI, 1.16‐2.36), and lastly by maternal type 2 diabetes mellitus (RR 1.11, 95% CI, 0.69‐1.80). Additional analysis of studies comparing maternal versus paternal T1DM within the same population revealed that offspring of fathers with T1DM had a 1.5 times higher risk of developing childhood‐onset T1DM than offspring of mothers with T1DM (RR 9.58, 95% CI, 6.33‐14.48 vs. RR 6.24, 95% CI, 5.52‐7.07). Furthermore, a reduced risk of childhood‐onset T1DM was observed in infants born to mothers who smoked during pregnancy compared with infants born to mothers who did not smoke during pregnancy (RR 0.79, 95% CI, 0.71‐0.87). In summary, our findings add further evidence that early‐life events or environmental factors may play a role in modulating infants' risk of developing T1DM later in life.     

Maternal age and family history are risk factors for ankylosing spondylitis

OBJECTIVE: To investigate prevalence and gender distribution in parents of children with ankylosing spondylitis (AS). METHODS: Family history of AS (parents, uncles, and aunts), maternal age at delivery, and consecutive pregnancy number were assessed in the relatives of 40 Mexican Mestizo patients with definite AS (New York Criteria). RESULTS: We evaluated the family history of AS in 34 families of 40 AS patients; 12 with none, 4 with a paternal history (4 healthy fathers with a brother with AS) (odds ratio, OR, 1.37, p = 0.75), 15 with a maternal history of AS, (15 healthy mothers with a brother with AS) (OR 1.4, p = 0.55), and 3 with both lines (OR 0.84, p = 0.92). In these families AS was more frequent in males (29%) than in females (10%), OR 3.40 (95% confidence interval, CI: 1.43-8.29, p = 0.003). Juvenile onset was more common in the offspring of mothers with family history (72%) (OR 13.0, 95% CI: 1.68-147.48, p = 0.009). The number of first-born children with AS (18%) was similar to the later-born children (23%) (OR 1.37, 95% CI: 0.38-5.31, p = 0.78). The frequency of AS increased when the maternal age at delivery was < or = 30 years (OR 0.20, 95% CI: 0.04-0.75, p = 0.01). CONCLUSION: In Mexican Mestizo patients, there is no correlation between the risk for AS and the gender of the affected parent. However we found an association between juvenile onset and maternal family history with an increased incidence in patients with younger mothers.     

Glutamic acid decarboxylase (GAD) autoantibodies are additional predictive markers of Type 1 (insulin-dependent) diabetes mellitus in high risk individuals

Summary The prevalence of glutamic acid decarboxylase autoantibodies was determined with an immunotrapping enzyme activity assay in newly-diagnosed Type 1 (insulin-dependent) diabetic patients as well as in first-degree relatives using rat brain homogenate as a source of glutamate decarboxylase. Twenty-six out of 86 islet-cell cytoplasmic autoantibody positive and one out of 24 islet cell autoantibody negative patients of recent onset, had autoantibodies to glutamate decarboxylase above the upper 99% confidence limit obtained from 89 control sera. Among 27 islet cell autoantibody positive relatives including 19 siblings and 8 parents, antibodies to glutamate decarboxylase were found in 8 of 9 (89%) relatives and 7 of 8 (87.5%) siblings with islet cell autoantibody titres above 20 JDF units, in 1 of 19 (5.2%) relatives with islet cell autoantibody titres between 2 and 5 JDF units, in 2 of 263 (0.7%) siblings and 1 of 139 parents without islet cell autoantibodies. In first-degree relatives, high titre islet cell autoantibodies and autoantibodies to glutamate decarboxylase were tightly associated (X²=182, p=0.0001). None of the relatives with low genetic risk (n=64), i.e. HLA-different to the diabetic proband, was found to be antibody positive. Antibodies to glutamate decarboxylase were present only in those relatives sharing at least one haplotype with the diabetic proband, including two islet cell autoantibody negative but HLA-identical siblings. Autoantibodies to glutamate decarboxylase were present in 7 of 9 (77%) relatives who developed the disease, including one islet cell autoantibody negative sibling. Altogether, the simultaneous presence of autoantibodies to glutamate decarboxylase and high titre islet cell autoantibody increases the positive predictive value for the disease from 66% to 75%. This study indicates therefore that autoantibodies to glutamate decarboxylase detected by an immunotrapping enzyme activity assay are additional predictive markers for future development of Type 1 diabetes and should be now prospectively studied in high risk individuals as well as other autoantibodies to Beta-cell autoantigens.