The temporal development of autoantibodies was studied in 1,353 offspring of parents with type 1 diabetes. Islet cell antibodies (ICAs) and autoantibodies to insulin (IAAs), glutamic acid decarboxylase, and IA-2 were measured at birth, 9 months, 2 years, and 5 years of age. At birth, no offspring had islet autoimmunity other than maternally acquired antibodies, which were shown to influence antibody prevalence up to age 6 months. Antibodies detected thereafter were likely to represent a true de novo production, since prevalences were the same for offspring from mothers and fathers with diabetes, antibodies detected at 9 months were almost always confirmed in the 2-year sample and were associated with an increased likelihood of having or developing other antibodies. By 2 years of age, autoantibodies appeared in 11% of offspring, 3.5% having more than one autoantibody. IAAs were detected most frequently, and few had autoantibodies in the absence of IAAs. In 23 offspring with multiple islet autoantibodies, IAAs preceded other antibodies in 10 cases and were first detected concurrently with other antibodies in 12 and after detection of other antibodies in 1. Development of additional antibodies and changes in levels, including decline of IAAs at older age, was frequent. Nine children, all with IAAs and ICAs, developed diabetes. Overall cumulative risk for disease by 5 years of age was 1.8% (95% CI 0.2-3.4) and was 50% (95% CI 19-81) for offspring with more than one autoantibody in their 2-year sample. Autoimmunity associated with childhood diabetes is an early event and a dynamic process. Presence of IAAs is a consistent feature of this autoimmunity, and IAA detection can identify children at risk.

Seasonal variations are rarely considered a contributing component to human tissue function or health, although many diseases and physiological process display annual periodicities. Here we find more than 4,000 protein-coding mRNAs in white blood cells and adipose tissue to have seasonal expression profiles, with inverted patterns observed between Europe and Oceania. We also find the cellular composition of blood to vary by season, and these changes, which differ between the United Kingdom and The Gambia, could explain the gene expression periodicity. With regards to tissue function, the immune system has a profound pro-inflammatory transcriptomic profile during European winter, with increased levels of soluble IL-6 receptor and C-reactive protein, risk biomarkers for cardiovascular, psychiatric and autoimmune diseases that have peak incidences in winter. Circannual rhythms thus require further exploration as contributors to various aspects of human physiology and disease.

Context Dietary factors modifying type 1 diabetes mellitus (DM) risk have been proposed, but little is known if they trigger the islet autoimmunity that precedes clinical disease.Objective To determine whether breastfeeding duration, food supplementation, or age at introduction of gluten-containing foods influences the risk of developing islet autoantibodies. Design and SettingProspective natural history cohort study conducted from 1989 to 2003 in inpatient/outpatient clinics in Germany.Participants The BABYDIAB study follows newborn children of parents with type 1 DM. Eligibility requirements were met in 1610 children. Blood samples were obtained at birth, age 9 months, 2, 5, and 8 years. Dropout rate was 14.4% by age 5 years. Breastfeeding data were obtained by prospective questionnaires (91% complete), and food supplementation data were obtained by family interview (72% for food supplementation and 80% for age of gluten introduction).Main Outcome Measure Development of islet autoantibodies (insulin, glutamic acid decarboxylase, or IA-2 antibodies) in 2 consecutive blood samples.Results Life-table islet autoantibody frequency was 5.8% (SE, 0.6%) by age 5 years. Reduced total or exclusive breastfeeding duration did not significantly increase the risk of developing islet autoantibodies. Food supplementation with glutencontaining foods before age 3 months, however, was associated with significantly increased islet autoantibody risk (adjusted hazard ratio, 4.0; 95% confidence interval, 1.4-11.5; P=.01 vs children who received only breast milk until age 3 months). Four of 17 children who received gluten foods before age 3 months developed islet autoantibodies (life-table 5-year risk, 24%; SE, 10%). All 4 children had the high-risk DRB1 * 03/04,DQB1 * 0302 genotype. Early exposure to gluten did not significantly increase the risk of developing celiac disease-associated autoantibodies. Children who first received gluten foods after age 6 months did not have increased risks for islet or celiac disease autoantibodies. Conclusion Ensuring compliance to infant feeding guidelines is a possible way to reduce the risk of development of type 1 DM autoantibodies.

Family history of type 1 diabetes and autoantibodies to the islet antigens insulin (IAA), glutamate decarboxylase (GADA), and the protein tyrosine phosphatase-like protein IA-2 (IA-2A) are strong predictors of type 1 diabetes, but the rate of progression to diabetes in multiple islet autoantibody-positive relatives varies widely. We asked whether detailed characterization of islet autoantibodies that included determination of titer, epitope specificity, and IgG subclass would improve diabetes prediction in a large cohort of autoantibodypositive relatives. The study shows a strong association between risk and high titer, broad antibody responses to IA-2 and insulin. The highest risks were associated with high-titer IA-2A and IAA, IgG2, IgG3, and/or IgG4 subclass of IA-2A and IAA, and antibodies to the IA-2-related molecule IA-2␤. Using models based on these antibody characteristics, autoantibody-positive relatives can be classified into groups with risks of diabetes ranging from 7 to 89% within 5 years. Diabetes 53: 384 -392, 2004 A utoantibodies to islet cell antigens such as insulin (IAA), the 65-kDa isoform of glutamate decarboxylase (GADA), and the protein tyrosine phosphatase (PTP)-like antigen IA-2 (IA-2A) are markers of the autoimmune process that precedes type 1 diabetes (1-9). At-risk relatives can be identified on the basis of positivity for these autoantibodies. Diabetes risk is highest in relatives with more than one islet autoantibody (4 -11) or with high-titer islet cell antibodies (10,12), suggesting that the intensity of the humoral response may reflect the stage of ␤-cell destruction. It has however been shown that a proportion of relatives with multiple islet autoantibodies do not develop diabetes for many years (6,13), indicating that additional tests are necessary for accurate prediction of diabetes. IgG subclass and the epitope specificity of autoantibodies may reflect qualitative and quantitative differences in the autoimmune response (14 -16), and their measurement could, therefore, improve our ability to predict diabetes. We have examined islet autoantibody titer, epitope specificity and IgG subclass in prospectively followed islet autoantibodypositive first-degree relatives of patients with type 1 diabetes, and determined how these can be used to stratify the likelihood of progression to clinical diabetes. The findings are consistent with the concept that high-titer multitarget responses signal late or aggressive preclinical diabetes and allow staging of diabetes risk on the basis of antibody measurements. RESEARCH DESIGN AND METHODSSera of all first-degree relatives of patients with type 1 diabetes from the Bart's Oxford (BOX) and the Munich family studies (13,17) were tested for IAA, GADA, and IA-2A. A total of 180 nondiabetic relatives (76 from BOX study and 104 from Munich family study) were selected on the basis of positivity for at least one of these antibodies on two or more occasions and whether a sufficient volume of the first positive sample was available for complete testing...

Aims/hypothesis Seroconversion to islet autoantibodies precedes type 1 diabetes. This study aimed to identify periods of high seroconversion incidence, which could be targeted for mechanistic and therapeutic studies. Methods Incidence of islet autoantibodies was calculated in 1,650 genetically at-risk children followed with measurements of islet autoantibodies and thyroid autoantibodies at age 9 months and 2, 5, 8, 11, 14 and 17 years. Peak incidence periods were confirmed in a second cohort of 150 children followed until age 6 years with three-monthly samples up to age 3 years. Results Islet autoantibody incidence (per 1,000 person-years) was 18.5 until age 9 months, 21 from 9 months to 2 years and <10 for intervals after age 2 years. The second cohort confirmed peak incidence around age 9 months and demonstrated an absence of seroconversion before this age. Seroconversion to insulin autoantibodies occurred earlier than other autoantibodies (p<0.01 against glutamic acid decarboxylase [GAD]-, insulinoma-associated protein 2 [IA-2]-and zinc transporter 8 [ZnT8]-autoantibodies). Early peak seroconversion incidence was most evident in children with highrisk HLA DR3/4-DQ8 or DR4/4-DQ8 genotypes. Conclusion The age period 9 months to 2 years is associated with a high incidence of activation of type 1 diabetesassociated autoimmunity in genetically at-risk children and should be targeted for effective primary prevention strategies.

Women with gestational diabetes mellitus (GDM) have a high risk of developing postpartum type 2 diabetes. Strategies to prevent postpartum type 2 diabetes are important to reduce the epidemic of diabetes and its societal impact. Breastfeeding was reported to improve early postpartum glucose tolerance and reduce the subsequent risk of type 2 diabetes. To investigate whether breastfeeding influences short- and long-term postpartum diabetes outcomes, women with GDM (n = 304) participating in the prospective German GDM study were followed from delivery for up to 19 years postpartum for diabetes development. All participants were recruited between 1989 and 1999. Postpartum diabetes developed in 147 women and was dependent on the treatment received during pregnancy (insulin vs. diet), BMI, and presence/absence of islet autoantibodies. Among islet autoantibody-negative women, breastfeeding was associated with median time to diabetes of 12.3 years compared with 2.3 years in women who did not breastfeed. The lowest postpartum diabetes risk was observed in women who breastfed for >3 months. On the basis of these results, we recommend that breastfeeding should be encouraged among these women because it offers a safe and feasible low-cost intervention to reduce the risk of subsequent diabetes in this high-risk population.

Children at risk for type 1 diabetes can develop early insulin autoantibodies (IAAs). Many, but not all, of these children subsequently develop multiple islet autoantibodies and diabetes. To determine whether disease progression is reflected by autoantibody maturity, IAA affinity was measured by competitive radiobinding assay in first and subsequent IAA-positive samples from children followed from birth in the BABYDIAB cohort. IAA affinity in first positive samples ranged from less than 10 6 l/mol to more than 10 11 l/mol. High affinity was associated with HLA DRB1*04, young age of IAA appearance, and subsequent progression to multiple islet autoantibodies or type 1 diabetes. IAA affinity in multiple antibody-positive children was on average 100-fold higher than in children who remained single IAA positive or became autoantibody negative. All high-affinity IAAs required conservation of human insulin A chain residues 8-13 and were reactive with proinsulin. In contrast, most lower-affinity IAAs were dependent on COOH-terminal B chain residues and did not bind proinsulin. These data are consistent with the concept that type 1 diabetes is associated with sustained early exposure to (pro)insulin in the context of HLA DR4 and show that high-affinity proinsulin-reactive IAAs identify children with the highest diabetes risk.

OBJECTIVEWe tested the associations between genetic background and selected environmental exposures with respect to islet autoantibodies and type 1 diabetes.RESEARCH DESIGN AND METHODSInfants with HLA-DR high-risk genotypes were prospectively followed for diabetes-related autoantibodies. Single nucleotide polymorphisms (SNPs) came from the Illumina ImmunoChip and environmental exposure data were by parental report. Children were followed to age 6 years.RESULTSInsulin autoantibodies occurred earlier than GAD antibody (GADA) and then declined, while GADA incidence rose and remained constant (significant in HLA-DR4 but not in the DR3/3 children). The presence of SNPs rs2476601 (PTPN22) and rs2292239 (ERBB3) demonstrated increased risk of both autoantibodies to insulin (IAA) only and GADA only. SNP rs689 (INS) was protective of IAA only, but not of GADA only. The rs3757247 (BACH2) SNP demonstrated increased risk of GADA only. Male sex, father or sibling as the diabetic proband, introduction of probiotics under 28 days of age, and weight at age 12 months were associated with IAA only, but only father as the diabetic proband and weight at age 12 months were associated with GADA only. Mother as the diabetic proband was not a significant risk factor.CONCLUSIONSThese results show clear differences in the initiation of autoimmunity according to genetic factors and environmental exposures that give rise to IAA or GADA as the first appearing indication of autoimmunity.