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AimsType 1 diabetes (T1D) results from an autoimmune attack of the pancreatic β cells that progresses to dysglycemia and symptomatic hyperglycemia. Current biomarkers to track this evolution are limited, with development of islet autoantibodies marking the onset of autoimmunity and metabolic tests used to detect dysglycemia. Therefore, additional biomarkers are needed to better track disease initiation and progression. Multiple clinical studies have used proteomics to identify biomarker candidates. However, most of the studies were limited to the initial candidate identification, which needs to be further validated and have assays developed for clinical use. Here we curate these studies to help prioritize biomarker candidates for validation studies and to obtain a broader view of processes regulated during disease development.MethodsThis systematic review was registered with Open Science Framework (DOI 10.17605/OSF.IO/N8TSA). Using PRISMA guidelines, we conducted a systematic search of proteomics studies of T1D in the PubMed to identify putative protein biomarkers of the disease. Studies that performed mass spectrometry-based untargeted/targeted proteomic analysis of human serum/plasma of control, pre-seroconversion, post-seroconversion, and/or T1D-diagnosed subjects were included. For unbiased screening, 3 reviewers screened all the articles independently using the pre-determined criteria.ResultsA total of 13 studies met our inclusion criteria, resulting in the identification of 251 unique proteins, with 27 (11%) being identified across 3 or more studies. The circulating protein biomarkers were found to be enriched in complement, lipid metabolism, and immune response pathways, all of which are found to be dysregulated in different phases of T1D development. We found a subset of 3 proteins (C3, KNG1 & CFAH), 6 proteins (C3, C4A, APOA4, C4B, A2AP & BTD) and 7 proteins (C3, CLUS, APOA4, C6, A2AP, C1R & CFAI) have consistent regulation between multiple studies in samples from individuals at pre-seroconversion, post-seroconversion and post-diagnosis compared to controls, respectively, making them strong candidates for clinical assay development.ConclusionsBiomarkers analyzed in this systematic review highlight alterations in specific biological processes in T1D, including complement, lipid metabolism, and immune response pathways, and may have potential for further use in the clinic as prognostic or diagnostic assays.

Background Celiac disease has an increasing incidence worldwide and is treated with lifelong adherence to a gluten-free diet. We aimed to describe gluten-free diet adherence rates in children with screening-identified celiac disease, determine adherence-related factors, and compare adherence to food records in a multinational prospective birth cohort study. Methods Children in The Environmental Determinants of Diabetes in the Young study with celiac disease were included. Subjects had at least annual measurement of adherence (parent-report) and completed 3-day food records. Descriptive statistics, t-tests, Kruskal-Wallis tests and multivariable logistic and linear regression were employed. Results Two hundred ninety (73%) and 199 (67%) of subjects were always adherent to a gluten-free diet at 2 and 5 years post celiac disease diagnosis respectively. The percentage of children with variable adherence increased from 1% at 2 years to 15% at 5 years. Children with a first-degree relative with celiac disease were more likely to be adherent to the gluten-free diet. Gluten intake on food records could not differentiate adherent from nonadherent subjects. Adherent children from the United States had more gluten intake based on food records than European children (P < .001 and P = .007 at 2 and 5 years respectively). Conclusion Approximately three-quarters of children with screening-identified celiac disease remain strictly adherent to a gluten-free diet over time. There are no identifiable features associated with adherence aside from having a first-degree relative with celiac disease. Despite good parent-reported adherence, children from the United States have more gluten intake when assessed by food records. Studies on markers of gluten-free diet adherence, sources of gluten exposure (particularly in the United States), and effects of adherence on mucosal healing are needed.

Type 1 diabetes (T1D) is a disease of insulin deficiency that results from autoimmune destruction of pancreatic islet β cells. The exact cause of T1D remains unknown, although asymptomatic islet autoimmunity lasting from weeks to years before diagnosis raises the possibility of intervention before the onset of clinical disease. The number, type, and titer of islet autoantibodies are associated with long-term disease risk but do not cause disease, and robust early predictors of individual progression to T1D onset remain elusive. The Environmental Determinants of Diabetes in the Young (TEDDY) consortium is a prospective cohort study aiming to determine genetic and environmental interactions causing T1D. Here, we analyzed longitudinal blood transcriptomes of 2013 samples from 400 individuals in the TEDDY study before both T1D and islet autoimmunity. We identified and interpreted age-associated gene expression changes in healthy infancy and age-independent changes tracking with progression to both T1D and islet autoimmunity, beginning before other evidence of islet autoimmunity was present. We combined multivariate longitudinal data in a Bayesian joint model to predict individual risk of T1D onset and validated the association of a natural killer cell signature with progression and the model's predictive performance on an additional 356 samples from 56 individuals in the independent Type 1 Diabetes Prediction and Prevention study. Together, our results indicate that T1D is characterized by early and longitudinal changes in gene expression, informing the immunopathology of disease progression and facilitating prediction of its course.

We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P

Glycated hemoglobin (HbA(1c)) is an important measure of glycemia in diabetes. HbA(1c) is influenced by environmental and genetic factors both in people with and in people without diabetes. We performed a genome-wide association study (GWAS) for HbA(1c) in a Finnish type 1 diabetes (T1D) cohort, FinnDiane. Top results were examined for replication in T1D cohorts DCCT/EDIC, WESDR, CACTI, EDC, and RASS, and a meta-analysis was performed. Three SNPs in high linkage disequilibrium on chromosome 13 near relaxin family peptide receptor 2 (RXFP2) were associated with HbA(1c) in FinnDiane at genome-wide significance (P

ObjectiveGenetic risk scores (GRS) have been developed that differentiate individuals with type 1 diabetes from those with other forms of diabetes and are starting to be used for population screening; however, most studies were conducted in European-ancestry populations. This study identifies novel genetic variants associated with type 1 diabetes risk in African-ancestry participants and develops an African-specific GRS.Research design and methodsWe generated single nucleotide polymorphism (SNP) data with the ImmunoChip on 1,021 African-ancestry participants with type 1 diabetes and 2,928 control participants. HLA class I and class II alleles were imputed using SNP2HLA. Logistic regression models were used to identify genome-wide significant (P < 5.0 × 10-8) SNPs associated with type 1 diabetes in the African-ancestry samples and validate SNPs associated with risk in known European-ancestry loci (P < 2.79 × 10-5).ResultsAfrican-specific (HLA-DQA1*03:01-HLA-DQB1*02:01) and known European-ancestry HLA haplotypes (HLA-DRB1*03:01-HLA-DQA1*05:01-HLA-DQB1*02:01, HLA-DRB1*04:01-HLA-DQA1*03:01-HLA-DQB1*03:02) were significantly associated with type 1 diabetes risk. Among European-ancestry defined non-HLA risk loci, six risk loci were significantly associated with type 1 diabetes in subjects of African ancestry. An African-specific GRS provided strong prediction of type 1 diabetes risk (area under the curve 0.871), performing significantly better than a European-based GRS and two polygenic risk scores in independent discovery and validation cohorts.ConclusionsGenetic risk of type 1 diabetes includes ancestry-specific, disease-associated variants. The GRS developed here provides improved prediction of type 1 diabetes in African-ancestry subjects and a means to identify groups of individuals who would benefit from immune monitoring for early detection of islet autoimmunity.

Uricosuria and crystallization are increasingly recognized risk factors for diabetic tubulopathy. This pilot clinical trial aimed to determine the acute effect of urinary alkalinization using oral sodium bicarbonate [NaHCO(3)] on UA crystals in adults with type 1 diabetes (T1D). Adults with T1D ages 18–65 years (n=45, 60% female, HbA1c 7.5±1.2%, 20.2±9.3 years duration) without chronic kidney disease (eGFR ≥60ml/min/1.73m(2) and albumin-to-creatinine ratio

The burden and determinants of complications and comorbidities in contemporary youth-onset diabetes are unknown.

Recent increases in the incidence of both type 1 (T1D) and type 2 diabetes (T2D) in children and adolescents point to the importance of environmental factors in the development of these diseases. Metabolomic analysis explores the integrated response of the organism to environmental changes. Metabolic profiling can identify biomarkers that are predictive of disease incidence and development, potentially providing insight into disease pathogenesis. This review provides an overview of the role of metabolomic analysis in diabetes research and summarizes recent research relating to the development of T1D and T2D in children.

Type 1 diabetes (T1D) or celiac disease (CD) develops in at least 2% of the general population. Early detection of disease-specific autoimmunity and subsequent monitoring would be possible if screening tests were more widely available. Currently, screening for islet autoimmunity is available only in a research setting, and CD-specific autoimmunity screening is limited to those in high-risk groups. This study assessed the feasibility of incorporating T1D and CD autoantibody screening into a pediatric practice.Patient engagement strategies, blood collection preference, blood sample volume, rate of autoantibody detection in the general population, and parental satisfaction were assessed. Over 5 weeks, research staff recruited 200 patients, aged 2-6 yr from two pediatric practices in the Denver area to be screened for islet autoantibodies (IAs) and the transglutaminase antibody.Of the 765 parents approached, 200 (26%) completed the same-day screening. Of the 565 subjects who did not complete the screening, 345 expressed interest, but were unable to make a participation decision. A finger stick, compared with a venous draw, was the preferred method of sample collection. Both methods yielded sufficient blood volume for autoantibody determination. IAs or the transglutaminase antibody were detected in 11 subjects. Parents expressed satisfaction with all aspects of participation.The results of this study suggest that it is feasible to conduct this type of screening in a pediatric clinic. Such screening could lead to increased disease awareness and the possible benefits that can result from early detection.

Deficient soluble fiber intake has been suggested to dysregulate the immune response either directly or through alterations of the microbial composition in the gut.We hypothesized that a high intake of dietary soluble fiber in early childhood decreases the risk of type 1 diabetes (T1D)-associated islet autoimmunity.We analyzed 17,620 food records collected between age 9 and 48 mo from 3358 children from the United States and Germany prospectively followed in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. HRs for the development of any/multiple islet autoantibodies (242 and 151 events, respectively) and T1D (71 events) by soluble fiber intake were calculated in Cox regression models and adjusted for potential confounders.There were no statistically significantly protective associations observed between a high intake of soluble fiber and islet autoimmunity or T1D. For example, the adjusted HRs (95% CIs) for high intake (highest compared with lowest quintile) at age 12 mo were 0.90 (0.55, 1.45) for any islet autoantibody, 1.20 (0.69, 2.11) for multiple islet autoantibodies, and 1.24 (0.57, 2.70) for T1D. In analyzing soluble fiber intake as a time-varying covariate, there were also no short-term associations between soluble fiber intake and islet autoimmunity development, with adjusted HRs of 0.85 (0.51, 1.42) for high intake and development of any islet autoantibody, for example.These results indicate that the intake level of dietary soluble fiber is not associated with islet autoimmunity or T1D in early life.

Objective: The purpose of this study was to explore whether non-human leukocyte antigen (non-HLA) genetic markers can improve type 1 diabetes (T1D) prediction in a prospective cohort with high-risk HLA-DR, DQ genotypes. Methods: The Diabetes Autoimmunity Study in the Young (DAISY) follows prospectively for the development of T1D and islet autoimmunity (IA) children at increased genetic risk. A total of 1709 non-Hispanic White DAISY participants have been genotyped for 27 non-HLA single nucleotide polymorphisms (SNPs) and one microsatellite. Results: In multivariate analyses adjusting for family history and HLA-DR3/4 genotype, PTPN22 (rs2476601) and two UBASH3A (rs11203203 and rs9976767) SNPs were associated with development of IA [hazard ratio (HR) = 1.87, 1.55, and 1.54, respectively, all p Conclusion: Addition of PTPN22 and UBASH3A SNPs to HLA-DR, DQ genotyping can improve T1D risk prediction.