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1.  A Type I Interferon Transcriptional Signature Precedes Autoimmunity in Children Genetically at Risk for Type 1 Diabetes 
Diabetes  2014;63(7):2538-2550.
Diagnosis of the autoimmune disease type 1 diabetes (T1D) is preceded by the appearance of circulating autoantibodies to pancreatic islets. However, almost nothing is known about events leading to this islet autoimmunity. Previous epidemiological and genetic data have associated viral infections and antiviral type I interferon (IFN) immune response genes with T1D. Here, we first used DNA microarray analysis to identify IFN-β–inducible genes in vitro and then used this set of genes to define an IFN-inducible transcriptional signature in peripheral blood mononuclear cells from a group of active systemic lupus erythematosus patients (n = 25). Using this predefined set of 225 IFN signature genes, we investigated the expression of the signature in cohorts of healthy controls (n = 87), patients with T1D (n = 64), and a large longitudinal birth cohort of children genetically predisposed to T1D (n = 109; 454 microarrayed samples). Expression of the IFN signature was increased in genetically predisposed children before the development of autoantibodies (P = 0.0012) but not in patients with established T1D. Upregulation of IFN-inducible genes was transient, temporally associated with a recent history of upper respiratory tract infections (P = 0.0064), and marked by increased expression of SIGLEC-1 (CD169), a lectin-like receptor expressed on CD14+ monocytes. DNA variation in IFN-inducible genes altered T1D risk (P = 0.007), as exemplified by IFIH1, one of the genes in our IFN signature for which increased expression is a known risk factor for disease. These findings identify transient increased expression of type I IFN genes in preclinical diabetes as a risk factor for autoimmunity in children with a genetic predisposition to T1D.
PMCID: PMC4066333  PMID: 24561305
2.  A type I interferon transcriptional signature precedes autoimmunity in children genetically at-risk of type 1 diabetes 
Diabetes  2014;63(7):2538-2550.
Diagnosis of the autoimmune disease type 1 diabetes (T1D) is preceded by the appearance of circulating autoantibodies to pancreatic islets. However, almost nothing is known about events leading to this islet autoimmunity. Previous epidemiological and genetic data have associated viral infections and anti-viral type I interferon (IFN) immune response genes with T1D. Here, we first used DNA microarray analysis to identify IFN-β inducible genes in vitro and then used this set of genes to define an IFN-inducible transcriptional signature in peripheral blood mononuclear cells from a group of active systemic lupus erythematosus patients (N=25). Using this predefined set of 225 IFN signature genes, we investigated expression of the signature in cohorts of healthy controls (N=87), T1D patients (N=64) and a large longitudinal birth cohort of children genetically predisposed to T1D (N=109; 454 microarrayed samples). Expression of the IFN signature was increased in genetically-predisposed children prior to the development of autoantibodies (P=0.0012), but not in established T1D patients. Upregulation of IFN-inducible genes was transient, temporally associated with a recent history of upper respiratory tract infections (P=0.0064) and marked by increased expression of SIGLEC-1 (CD169), a lectin-like receptor expressed on CD14+ monocytes. DNA variation in IFN-inducible genes altered T1D risk (P=0.007), as exemplified by IFIH1, one of the genes in our IFN signature and for which increased expression is a known disease risk factor. These findings identify transient increased expression of type I IFN genes in pre-clinical diabetes as a risk factor for autoimmunity in children with a genetic predisposition to T1D.
PMCID: PMC4066333  PMID: 24561305
3.  Beneficial effects of breastfeeding in women with gestational diabetes mellitus☆ 
Molecular Metabolism  2014;3(3):284-292.
Gestational diabetes mellitus (GDM) increases the future risk of developing type 2 diabetes mellitus (T2DM). There is now a growing evidence that breastfeeding has short- and long-term health benefits for mothers with GDM. Mothers with GDM who breastfeed have improved lipid and glucose metabolic profiles for the first 3 months after birth. However, women with GDM are less likely to breastfeed and, if they do, breastfeeding is usually continued for a shorter duration compared with women without GDM. One long-term prospective study followed women with GDM from delivery for up to 19 years postpartum, and found that breastfeeding for ≥3 months reduced the risk of T2DM and delayed the development of T2DM by a further 10 years compared with breastfeeding for <3 months. However, the physiological mechanisms underlying the protective effects of breastfeeding are still unknown, even though it is important to gain a full understanding of the pathways involved in these effects. Therefore, the purpose of this review is to provide a comprehensive analysis of the recent developments in the field of GDM and breastfeeding. We reviewed data from animal experiments and human studies. We also provide insight into the molecular pathways and describe promising topics for future research.
PMCID: PMC3986583  PMID: 24749058
Breastfeeding; Gestational diabetes mellitus; Glucose homeostasis; Type 2 diabetes mellitus
4.  Long-Term Protective Effect of Lactation on the Development of Type 2 Diabetes in Women With Recent Gestational Diabetes Mellitus 
Diabetes  2012;61(12):3167-3171.
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.
PMCID: PMC3501852  PMID: 23069624
5.  Cesarean Section and Interferon-Induced Helicase Gene Polymorphisms Combine to Increase Childhood Type 1 Diabetes Risk 
Diabetes  2011;60(12):3300-3306.
The incidence of type 1 diabetes is increasing. Delivery by cesarean section is also more prevalent, and it is suggested that cesarean section is associated with type 1 diabetes risk. We examine associations between cesarean delivery, islet autoimmunity and type 1 diabetes, and genes involved in type 1 diabetes susceptibility.
Cesarean section was examined as a risk factor in 1,650 children born to a parent with type 1 diabetes and followed from birth for the development of islet autoantibodies and type 1 diabetes.
Children delivered by cesarean section (n = 495) had more than twofold higher risk for type 1 diabetes than children born by vaginal delivery (hazard ratio [HR] 2.5; 95% CI 1.4–4.3; P = 0.001). Cesarean section did not increase the risk for islet autoantibodies (P = 0.6) but was associated with a faster progression to diabetes after the appearance of autoimmunity (P = 0.015). Cesarean section–associated risk was independent of potential confounder variables (adjusted HR 2.7;1.5–5.0; P = 0.001) and observed in children with and without high-risk HLA genotypes. Interestingly, cesarean section appeared to interact with immune response genes, including CD25 and in particular the interferon-induced helicase 1 gene, where increased risk for type 1 diabetes was only seen in children who were delivered by cesarean section and had type 1 diabetes–susceptible IFIH1 genotypes (12-year risk, 9.1 vs. <3% for all other combinations; P < 0.0001).
These findings suggest that type 1 diabetes risk modification by cesarean section may be linked to viral responses in the preclinical autoantibody-positive disease phase.
PMCID: PMC3219940  PMID: 22110093
6.  Prediction and Pathogenesis in Type 1 Diabetes 
Immunity  2010;32(4):468-478.
A combination of genetic and immunological features is useful for prediction of autoimmune diabetes. Patterns of immune response correspond to the progression from a pre-clinical phase of disease to end-stage islet damage, with biomarkers indicating transition from susceptibility to active autoimmunity, and to a final loss of immune regulation. Here we review the markers that provide evidence for immunological checkpoint failure and that also provide tools for assessment of individualized disease risk. When viewed in the context of genetic variation that influences immune response thresholds, progression from susceptibility to overt disease displays predictable modalities of clinical presentation resulting from a sequential series of failed homeostatic checkpoints for selection and activation of immunity.
PMCID: PMC2861716  PMID: 20412757
7.  A method for reporting and classifying acute infectious diseases in a prospective study of young children: TEDDY 
BMC Pediatrics  2015;15:24.
Early childhood environmental exposures, possibly infections, may be responsible for triggering islet autoimmunity and progression to type 1 diabetes (T1D). The Environmental Determinants of Diabetes in the Young (TEDDY) follows children with increased HLA-related genetic risk for future T1D. TEDDY asks parents to prospectively record the child’s infections using a diary book. The present paper shows how these large amounts of partially structured data were reduced into quantitative data-sets and further categorized into system-specific infectious disease episodes. The numbers and frequencies of acute infections and infectious episodes are shown.
Study subjects (n = 3463) included children who had attended study visits every three months from age 3 months to 4 years, without missing two or more consecutive visits during the follow-up. Parents recorded illnesses prospectively in a TEDDY Book at home. The data were entered into the study database during study visits using ICD-10 codes by a research nurse. TEDDY investigators grouped ICD-10 codes and fever reports into infectious disease entities and further arranged them into four main categories of infectious episodes: respiratory, gastrointestinal, other, and unknown febrile episodes. Incidence rate of infections was modeled as function of gender, HLA-DQ genetic risk group and study center using the Poisson regression.
A total of 113,884 ICD-10 code reports for infectious diseases recorded in the database were reduced to 71,578 infectious episodes, including 74.0% respiratory, 13.1% gastrointestinal, 5.7% other infectious episodes and 7.2% febrile episodes. Respiratory and gastrointestinal infectious episodes were more frequent during winter. Infectious episode rates peaked at 6 months and began declining after 18 months of age. The overall infectious episode rate was 5.2 episodes per person-year and varied significantly by country of residence, sex and HLA genotype.
The data reduction and categorization process developed by TEDDY enables analysis of single infectious agents as well as larger arrays of infectious agents or clinical disease entities. The preliminary descriptive analyses of the incidence of infections among TEDDY participants younger than 4 years fits well with general knowledge of infectious disease epidemiology. This protocol can be used as a template in forthcoming time-dependent TEDDY analyses and in other epidemiological studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-015-0333-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4377063  PMID: 25884839
Childhood infections; Prospective study; Type 1 diabetes
8.  Clinical Immunologic Interventions for the Treatment of Type 1 Diabetes 
Type 1 diabetes is an autoimmune disease, hence the rationale for immunotherapy to halt disease progression. Based on knowledge gained from other autoimmune diseases and from transplantation, the first immunointervention trials used immunosuppressive drugs, e.g., cyclosporin, in patients with recently diagnosed type 1 diabetes. Although remarkable, the effect vanished following drug withdrawal. Efforts were then devoted to devise strategies to induce/restore self-tolerance and avoid chronic immunosuppression. Various approaches were identified from work in spontaneous models of autoimmune diabetes, including the use of β-cell autoantigens and monoclonal antibodies directed at relevant immune molecules such as costimulatory ligands, T-cell receptor molecules such as CD3, and B cells. Phase II and phase III trials were launched, results of which are now available. Although the endeavor is challenging, the experience gained indicates that immunotherapy appears as the real hope of inducing long-term remission of the disease provided the treatment is started early and that protocols are adapted based on lessons from the past.
Immunosuppression versus tolerance is a primary criterion underlying the evaluation of immune therapy in type 1 diabetes.
PMCID: PMC3405831  PMID: 22908194
9.  Age- and Islet Autoimmunity–Associated Differences in Amino Acid and Lipid Metabolites in Children at Risk for Type 1 Diabetes 
Diabetes  2011;60(11):2740-2747.
Islet autoimmunity precedes type 1 diabetes and often initiates in childhood. Phenotypic variation in islet autoimmunity relative to the age of its development suggests heterogeneous mechanisms of autoimmune activation. To support this notion, we examined whether serum metabolite profiles differ between children with respect to islet autoantibody status and the age of islet autoantibody development.
The study analyzed 29 metabolites of amino acid metabolism and 511 lipids assigned to 12 lipid clusters in children, with a type 1 diabetic parent, who first developed autoantibodies at age 2 years or younger (n = 13), at age 8 years or older (n = 22), or remained autoantibody-negative, and were matched for age, date of birth, and HLA genotypes (n = 35). Ultraperformance liquid chromatography and mass spectroscopy were used to measure metabolites and lipids quantitatively in the first autoantibody-positive and matched autoantibody-negative serum samples and in a second sample after 1 year of follow-up.
Differences in the metabolite profiles were observed relative to age and islet autoantibody status. Independent of age-related differences, autoantibody-positive children had higher levels of odd-chain triglycerides and polyunsaturated fatty acid–containing phospholipids than autoantibody-negative children and independent of age at first autoantibody appearance (P < 0.0001). Consistent with our hypothesis, children who developed autoantibodies by age 2 years had twofold lower concentration of methionine compared with those who developed autoantibodies in late childhood or remained autoantibody-negative (P < 0.0001).
Distinct metabolic profiles are associated with age and islet autoimmunity. Pathways that use methionine are potentially relevant for developing islet autoantibodies in early infancy.
PMCID: PMC3198092  PMID: 22025777
10.  Accelerated progression from islet autoimmunity to diabetes is causing the escalating incidence of type 1 diabetes in young children 
Journal of autoimmunity  2011;37(1):3-7.
The incidence of type 1 diabetes is rising worldwide, particularly in young children. Since type 1 diabetes is preceded by autoimmunity to islet antigens, there must be a consequent increase in the incidence of islet autoimmunity in young children or a more rapid rate of progression to diabetes once islet autoimmunity initiates. This study was to determine whether the incidence of islet autoimmunity or the rate of progression from autoimmunity to diabetes onset has changed over a 20-year period in children genetically predisposed to type 1 diabetes. Between 1989 and 2010, children who were first-degree relatives of patients with type 1 diabetes and who were born in Germany were prospectively followed from birth without intervention. A total of 324 children (BABYDIAB study) born between 1989 and 2000 and 216 children (TEDDY study) born between 2004 and 2010 with matched HLA genotypes were recruited before age 3 months and included for analysis. Children were followed for the development of autoantibodies to insulin, GAD, and IA-2, and for progression to diabetes. The cumulative frequency of diabetes by age 4 years was 2.5% (95% CI 0.8–4.2%) in BABYDIAB children and 6.2% (95% CI 2.3–10.1%) in TEDDY children (p=0.03). The cumulative frequency of islet autoantibodies by age 4 years was similar in the children from both studies (11.3% vs 13.9%). Progression to diabetes from the development of islet autoantibodies was markedly increased in autoantibody-positive children from the more recently recruited TEDDY cohort (50% progression within 85.2 months for BABYDIAB children vs 9.6 months for TEDDY children; p=0.009), also if children were further selected on the basis of high-risk HLA genotypes or the development of autoantibodies to multiple islet antigens (p=0.01). The findings suggest that recent increasing incidence of type 1 diabetes in young children could be due to weakening of mechanisms that normally regulate autoimmune destruction of islet beta cells.
PMCID: PMC3110538  PMID: 21376535
type 1 diabetes; islet autoimmunity; incidence; progression
11.  Primary Dietary Intervention Study to Reduce the Risk of Islet Autoimmunity in Children at Increased Risk for Type 1 Diabetes 
Diabetes Care  2011;34(6):1301-1305.
To determine whether delaying the introduction of gluten in infants with a genetic risk of islet autoimmunity is feasible, safe, and may reduce the risk of type 1 diabetes–associated islet autoimmunity.
A total of 150 infants with a first-degree family history of type 1 diabetes and a risk HLA genotype were randomly assigned to a first gluten exposure at age 6 months (control group) or 12 months (late-exposure group) and were followed 3 monthly until the age of 3 years and yearly thereafter for safety (for growth and autoantibodies to transglutaminase C [TGCAs]), islet autoantibodies to insulin, GAD, insulinoma-associated protein 2, and type 1 diabetes.
Adherence to the dietary-intervention protocol was reported from 70% of families. During the first 3 years, weight and height were similar in children in the control and late-exposure groups, as was the probability of developing TGCAs (14 vs. 4%; P = 0.1). Eleven children in the control group and 13 children in the late-exposure group developed islet autoantibodies (3-year risk: 12 vs. 13%; P = 0.6). Seven children developed diabetes, including four in the late-exposure group. No significant differences were observed when children were analyzed as per protocol on the basis of the reported first gluten exposure of the children.
Delaying gluten exposure until the age of 12 months is safe but does not substantially reduce the risk for islet autoimmunity in genetically at-risk children.
PMCID: PMC3114350  PMID: 21515839
12.  No Effect of the 1α,25-Dihydroxyvitamin D3 on β-Cell Residual Function and Insulin Requirement in Adults With New-Onset Type 1 Diabetes 
Diabetes Care  2010;33(7):1443-1448.
To determine whether daily intake of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] is safe and improves β-cell function in patients with recently diagnosed type 1 diabetes.
Safety was assessed in an open study of 25 patients aged 18–39 years with recent-onset type 1 diabetes who received 0.25 μg 1,25(OH)2D3 daily for 9 months. An additional 40 patients were randomly assigned to 0.25 μg 1,25(OH)2D3 or placebo daily for 9 months and followed for a total of 18 months for safety, β-cell function, insulin requirement, and glycemic control.
Safety assessment showed values in the normal range in nearly all patients, regardless of whether they received 1,25(OH)2D3 or placebo. No differences in AUC C-peptide, peak C-peptide, and fasting C-peptide after a mixed-meal tolerance test between the treatment and placebo groups were observed at 9 and 18 months after study entry, with ∼40% loss for each parameter over the 18-month period. A1C and daily insulin requirement were similar between treatment and placebo groups throughout the study follow-up period.
Treatment with 1,25(OH)2D3 at a daily dose of 0.25 μg was safe but did not reduce loss of β-cell function.
PMCID: PMC2890336  PMID: 20357369
13.  No Effect of the Altered Peptide Ligand NBI-6024 on β-Cell Residual Function and Insulin Needs in New-Onset Type 1 Diabetes 
Diabetes Care  2009;32(11):2036-2040.
This randomized, four-arm, placebo-controlled, dose-ranging phase 2 trial was conducted to determine whether repeated subcutaneous injections of the altered peptide ligand, NBI-6024, designed to inhibit autoreactive T-cells, improves β-cell function in patients with recently diagnosed type 1 diabetes.
A total of 188 patients, aged 10–35 years, with recently diagnosed type 1 diabetes were randomly assigned for a treatment consisting of the subcutaneous administration of placebo or 1, 0.5, or 0.1 mg NBI-6024 at baseline, weeks 2 and 4, and then monthly until month 24. Fasting, peak, and area under the curve (AUC) C-peptide concentrations during a 2-h mixed-meal tolerance test were measured at 3-month intervals during treatment. Immune function parameters (islet antibodies and CD4 and CD8 T-cells) were also studied.
The mean peak C-peptide concentration at 24 months after study entry showed no significant difference between the groups treated with 0.1 mg (0.59 pmol/ml), 0.5 mg (0.57 pmol/ml), and 1.0 mg NBI-6024 (0.48 pmol/ml) and the placebo group (0.54 pmol/ml). Fasting, stimulated peak, and AUC C-peptide concentrations declined linearly in all groups by ∼60% over the 24-month treatment period. The average daily insulin needs at month 24 were also comparable between the four groups. No treatment-related changes in islet antibodies and T cell numbers were observed.
Treatment with altered peptide ligand NBI-6024 at repeated doses of 0.1, 0.5, or 1.0 mg did not improve or maintain β-cell function.
PMCID: PMC2768201  PMID: 19690081
14.  Predictors of Overweight During Childhood in Offspring of Parents With Type 1 Diabetes 
Diabetes Care  2009;32(5):921-925.
To study which perinatal factors affect the risk of childhood overweight in offspring with a first-degree relative (FDR) with type 1 diabetes and to determine whether maternal diabetes is an independent contributor to overweight risk.
Data on a child's weight and height were collected at age 2, 5, and 8 years from 1,214 children participating in the prospective BABYDIAB study. All children had an FDR with type 1 diabetes, including 783 whose mothers had type 1 diabetes. Overweight was defined as BMI percentile ≥90. Data on birth size, breast-feeding, maternal age, and smoking during pregnancy were collected by questionnaires. Risk estimates were calculated by logistic regression analyses.
Breastfeeding duration and birth size both contributed significantly to overweight risk at all age intervals. Full breast-feeding >4 months or any breast-feeding >6 months reduced risk of overweight (aged 8 years: odds ratio 0.3 [95% CI 0.2–0.7], P = 0.004; and 0.3 [0.1–0.6], P = 0.001). Large-for-gestational-age status increased risk of overweight (aged 8 years: 2.4 [1.4–4.3], P = 0.002). Importantly, no evidence was found for an independent contribution of maternal type 1 diabetes to childhood overweight.
Our findings indicate that maternal type 1 diabetes is not an independent risk factor for overweight during childhood in offspring of type 1 diabetic mothers but that factors associated with maternal type 1 diabetes, such as short breast-feeding duration and high birth size, predispose children to overweight during childhood.
PMCID: PMC2671121  PMID: 19228867
15.  Biomarker discovery study design for type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study 
The Environmental Determinants of Diabetes in the Young (TEDDY) planned biomarker discovery studies on longitudinal samples for persistent confirmed islet cell autoantibodies and type 1 diabetes (T1D) using dietary biomarkers, metabolomics, microbiome/viral metagenomics and gene expression.
This paper describes the details of planning the TEDDY biomarker discovery studies using a nested case-control design that was chosen as an alternative to the full cohort analysis. In the frame of a nested case-control design, it guides the choice of matching factors, selection of controls, preparation of external quality control samples, and reduction of batch effects along with proper sample allocation.
Results and Conclusion:
Our design is to reduce potential bias and retain study power while reduce the costs by limiting the numbers of samples requiring laboratory analyses. It also covers two primary end points (the occurrence of diabetes-related autoantibodies and the diagnosis of T1D). The resulting list of case-control matched samples for each laboratory was augmented with external quality control (QC) samples.
PMCID: PMC4058423  PMID: 24339168
batch effects; biomarker discovery; nested case-control design; TEDDY; type 1 diabetes
16.  Prevalence of Obesity was Related to HLA-DQ in 2–4 Year Old Children at Genetic Risk for Type 1 Diabetes 
Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or an accelerator to clinical onset after seroconversion. As overweight and obesity continue to rise among children, the aim of this study was to determine whether human leukocyte antigen DQ (HLA-DQ) genotypes may be related to body size among children genetically at risk for type 1 diabetes.
Repeated measures of weight and height were collected from 5 969 children 2–4 years of age enrolled in The Environmental Determinants of Diabetes in the Young prospective study. Overweight and obesity was determined by the International Obesity Task Force cutoff values that correspond to body mass index of 25 and 30 kg/m2 at age 18.
The average BMI was comparable across specific HLA genotypes at every age point. The proportion of overweight was not different by HLA, but percent obesity varied by age with a decreasing trend among DQ2/8 carriers (p for trend = 0.0315). A multivariable regression model suggested DQ2/2 was associated with higher obesity risk at age four (OR, 2.41; 95% CI, 1.21–4.80) after adjusting for the development of islet autoantibody and/or type 1 diabetes.
The HLA-DQ2/2 genotype may predispose to obesity among 2–4 year old children with genetic risk for type 1 diabetes.
PMCID: PMC4185013  PMID: 24694666
Body Mass Index; HLA Genotype; Type 1 Diabetes; Pediatric; Autoantibodies
17.  Widespread seasonal gene expression reveals annual differences in human immunity and physiology 
Nature Communications  2015;6:7000.
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.
Infectious and chronic diseases display seasonal patterns, yet seasonal changes in physiology are rarely thought to affect human health. Here the authors show seasonal variation in all major blood cells and in gene and protein expression in diverse tissues, suggesting a mechanism for seasonal disease proneness and physiology.
PMCID: PMC4432600  PMID: 25965853
18.  Methods, Quality Control and Specimen Management in an International Multi-Center Investigation of Type 1 Diabetes: TEDDY 
The Environmental Determinants of Diabetes in the Young (TEDDY) is a multi-center, international prospective study (n = 8,677) designed to identify environmental triggers of type 1 diabetes (T1D) in genetically at-risk children from age 3 months until 15 years. The study is conducted through six primary clinical centers located in four countries. As of May 2012, over three million biological samples and 250 million total data points have been collected which will be analyzed to assess autoimmunity status, presence of inflammatory biomarkers, genetic factors, exposure to infectious agents, dietary biomarkers, and other potentially important environmental exposures in relation to autoimmunity and progression to T1D. The vast array and quantity of longitudinal samples collected in the TEDDY study present a series of challenges in terms of quality control procedures and data validity. To address this, pilot studies have been conducted to standardize and enhance both biospecimen collection and sample obtainment in terms of autoantibody collection, stool sample preservation, RNA, biomarker stability, metabolic biomarkers, and T-cell viability. This paper details the procedures utilized to standardize both data harmonization and management when handling a large quantity of longitudinal samples obtained from multiple locations. In addition, we provide a description of the available specimens that serve as an invaluable repository for the elucidation of determinants in T1D focusing on autoantibody concordance and harmonization, transglutaminase autoantibody (tGA), inflammatory biomarkers (T-cells), genetic proficiency testing, RNA lab internal quality control testing, infectious agents (monitoring cross contamination, virus preservation, and nasal swab collection validity), and HbA1c testing.
PMCID: PMC3992860  PMID: 23674484
quality control; data integrity; stool sample preservation; RNA; biomarker stability; metabolic biomarkers; T-cell viability
19.  Concentration and Activity of the Soluble Form of the Interleukin-7 Receptor α in Type 1 Diabetes Identifies an Interplay Between Hyperglycemia and Immune Function 
Diabetes  2013;62(7):2500-2508.
Soluble interleukin-7 (IL-7) receptor α (sCD127) is implicated in the pathogenesis of autoimmune diseases. We show that serum sCD127 concentrations are increased at the onset of type 1 diabetes (T1D; n = 390) as compared with concentrations in age-matched islet autoantibody–negative first-degree relatives of patients (n = 392; P = 0.00001). sCD127 concentration in patients was influenced by islet autoantibody status (P = 0.003) and genotype of the rs6897932 single nucleotide polymorphism within the IL-7RA gene (P = 0.006). Release of sCD127 in vitro was strongly upregulated by activation of T lymphocytes and affected by exposure to cytokines. sCD127 bound IL-7 and was antagonistic to IL-7 signaling and IL-7–mediated T-cell proliferation, suggesting a regulatory feedback mechanism on T-cell expansion. Remarkably, high glucose led to a glycated form of sCD127 that was ineffective as an IL-7 antagonist. The finding of glycated sCD127 in the circulation of patients at onset of T1D suggested that physiological regulation of IL-7–mediated T-cell survival and expansion by sCD127 may be compromised in T1D. The findings indicate that genetic, immunologic, and metabolic factors contribute to a dysregulation of the IL-7/IL-7 receptor pathway in T1D and identify a novel hyperglycemia-mediated interference of immune regulatory networks.
PMCID: PMC3712069  PMID: 23454692
20.  Activation of Islet Autoreactive Naïve T Cells in Infants Is Influenced by Homeostatic Mechanisms and Antigen-Presenting Capacity 
Diabetes  2013;62(6):2059-2066.
Islet autoimmunity precedes type 1 diabetes onset. We previously found that islet autoimmunity rarely starts before 6 months of age but reaches its highest incidence already at ∼1 year of age. We now examine whether homeostatic expansion and immune competence changes seen in a maturating immune system may account for this marked variation in islet autoimmunity risk in the first year of life. We found naïve proinsulin- and GAD65-responsive T cells in cord blood (CB) of healthy newborns, with highest responses observed in children with type 1 diabetes-susceptible HLA-DRB1/DQB1 genotypes. Homeostatic expansion characteristics with increased IL-7 concentrations and enhanced T-cell responsiveness to IL-7 were observed throughout the first year of life. However, the ability of antigen-presenting cells to activate naïve T cells was compromised at birth, and CB monocytes had low surface expression of CD40 and HLA class II. In contrast, antigen presentation and expression of these molecules had reached competent adult levels by the high incidence age of 8 months. We propose that temporal changes in islet autoimmunity seroconversion in infants are a consequence of the changing balance between homeostatic drive and antigen presentation competence. These findings are relevant for early prevention of type 1 diabetes.
PMCID: PMC3661654  PMID: 23349478
21.  Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials 
Lancet  2013;381(9881):10.1016/S0140-6736(13)60023-9.
Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes.
We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6–45 years and those in the anakinra trial were aged 18–35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34.
Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI −0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (−0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group.
Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders.
National Institutes of Health and Juvenile Diabetes Research Foundation.
PMCID: PMC3827771  PMID: 23562090
22.  The Environmental Determinants of Diabetes in the Young (TEDDY): Genetic Criteria and International Diabetes Risk Screening of 421,000 infants 
Pediatric Diabetes  2011;12(8):733-743.
The TEDDY study seeks to identify environmental factors influencing the development of type 1 diabetes (T1D) using intensive follow-up of children at elevated genetic risk. The study requires a cost-effective yet accurate screening strategy to identify the high-risk cohort.
The TEDDY cohort was identified through newborn screening using HLA class II genes based on criteria established with pre-TEDDY data. HLA typing was completed at six international centers using different genotyping methods that can achieve >98% accuracy.
TEDDY developed separate inclusion criteria for the general population (GP) and first degree relatives (FDR) of T1D patients. The FDR eligibility includes nine haplogenotypes (DR3/4, DR4/4, DR4/8, DR3/3, DR4/4b, DR4/1, DR4/13, DR4/9 and DR3/9) for broad HLA diversity, while the GP eligibility includes only the first four haplogenotypes with DRB1*0403 as an exclusion allele. TEDDY has screened 414,714 GP infants, of which 19,906 (4.8%) were eligible, while 1,415 of the 6,333 screened FDR infants (22.2%) were eligible. High resolution confirmation testing of the eligible subjects indicated that the low-cost and low-resolution genotyping techniques employed at the screening centers yielded an accuracy of 99%. There were considerable variations in eligibility rates among the centers for GP (3.5% – 7.4%) and FDR (19% – 32%) subjects. The eligibility rates among US ethnic groups were 0.9%, 1.3%, 5.0% and 6.9% for Asians, Black, Caucasians and Hispanics, respectively.
Different low-cost and low-resolution genotyping methods are useful for the efficient and accurate identification of a high-risk cohort for follow-up based on the TEDDY HLA inclusion criteria ( NCT00279318).
PMCID: PMC3315186  PMID: 21564455
genetic screening; prediction; autoimmunity; type 1 diabetes; population-based
23.  Prevalence and Predictors of Overweight and Insulin Resistance in Offspring of Mothers With Gestational Diabetes Mellitus 
Diabetes Care  2010;33(8):1845-1849.
Gestational diabetes mellitus (GDM) is associated with high birth weight in the offspring. This may lead to overweight and insulin resistance during childhood. The aim of the study was to assess the impact of GDM on overweight risk and insulin resistance in offspring.
BMI measurements were collected at age 2, 8, and 11 years from 232 offspring of mothers with GDM (OGDM) and compared with those from 757 offspring of mothers with type 1 diabetes (OT1D) and 431 offspring of nondiabetic mothers (ONDM) born between 1989 and 2000. Insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]) was determined at age 8 and 11 years in 751 children (74 OGDM). Overweight was defined as BMI percentile ≥90; insulin resistance was defined by HOMA-IR.
Overweight prevalence was increased in OGDM compared with OT1D and to ONDM throughout childhood (age 11 years 31.1, 15.8, and 15.5%; P = 0.005). Maternal obesity was an important predictor of overweight risk in children (age 11 years odds ratio 7.0 [95% CI 1.8–27.7]; P = 0.006); birth size and maternal smoking during pregnancy were inconsistently associated with and treatment of GDM during pregnancy did not affect overweight risk. HOMA-IR was increased in OGDM compared with offspring of ONDM mothers (P = 0.01, adjusted for sex and age) and was associated with the child's BMI (P = 0.004).
Overweight and insulin resistance in children is increased in OGDM compared with OT1D or ONDM. The finding that overweight risk is associated mainly with maternal obesity suggests that familial predisposition contributes to childhood growth in these offspring.
PMCID: PMC2909075  PMID: 20435793
24.  Influence of Early Nutritional Components on the Development of Murine Autoimmune Diabetes 
Annals of Nutrition & Metabolism  2009;54(3):208-217.
Infant diet is suggested to modify autoimmune diabetes risk. The aim of this study was to determine whether infant food components affect diabetes development in the nonobese autoimmune diabetes (NOD) mouse.
A basal low-diabetogenic diet was identified by feeding litter-matched female NOD mice standardized diets with and without casein and wheat proteins after weaning. In subsequent trials, basal diet with supplements of wheat (5, 10 and 30%), gluten, wheat globulin/albumin, corn (5%), potato (5%), apple (5%) or carrot (5%) was fed to litter-matched female NOD mice after weaning. Mice were followed for diabetes development and insulin autoantibodies.
A casein- and wheat-free diet was associated with the lowest rate of diabetes development (37% by age 25 weeks). Increased diabetes rates were observed when the basal diet was supplemented with 5% wheat (71% by age 25 weeks; p = 0.023) and 5% corn (57% by age 25 weeks; p = 0.05). Increasing wheat concentrations returned diabetes development to that in basal diet-fed mice. Other food supplements had no or minimal effects on diabetes development.
Early supplementation of a basal low-diabetogenic diet with low concentrations of the cereals wheat or corn is associated with a moderate increase in the rate of diabetes. Removal of cereals, however, does not abrogate diabetes development in NOD mice.
PMCID: PMC2814014  PMID: 19478481
Type 1 diabetes; Autoimmunity; NOD mice; Diet; Prevention; Gluten; Casein
25.  Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes 
Journal of Clinical Investigation  2004;114(4):589-597.
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 106 l/mol to more than 1011 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.
PMCID: PMC503771  PMID: 15314696

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