Search

Oxylipins, pro-inflammatory and pro-resolving lipid mediators, are associated with the risk of type 1 diabetes (T1D) and may be influenced by diet. This study aimed to develop a nutrient pattern related to oxylipin profiles and test their associations with the risk of T1D among youth. The nutrient patterns were developed with a reduced rank regression in a nested case-control study (n = 335) within the Diabetes Autoimmunity Study in the Young (DAISY), a longitudinal cohort of children at risk of T1D. The oxylipin profiles (adjusted for genetic predictors) were the response variables. The nutrient patterns were tested in the case-control study (n = 69 T1D cases, 69 controls), then validated in the DAISY cohort using a joint Cox proportional hazards model (n = 1933, including 81 T1D cases). The first nutrient pattern (NP1) was characterized by low beta cryptoxanthin, flavanone, vitamin C, total sugars and iron, and high lycopene, anthocyanidins, linoleic acid and sodium. After adjusting for T1D family history, the HLA genotype, sex and race/ethnicity, NP1 was associated with a lower risk of T1D in the nested case-control study (OR: 0.44, p = 0.0126). NP1 was not associated with the risk of T1D (HR: 0.54, p-value = 0.1829) in the full DAISY cohort. Future studies are needed to confirm the nested case-control findings and investigate the modifiable factors for oxylipins.

Environmental factors including viruses, diet, and the metabolome have been linked with the appearance of islet autoimmunity (IA) that precedes development of type 1 diabetes (T1D). We measured global DNA methylation (DNAm) and untargeted metabolomics prior to IA and at the time of seroconversion to IA in 92 IA cases and 91 controls from the Diabetes Autoimmunity Study in the Young (DAISY). Causal mediation models were used to identify seven DNAm probe-metabolite pairs in which the metabolite measured at IA mediated the protective effect of the DNAm probe measured prior to IA against IA risk. These pairs included five DNAm probes mediated by histidine (a metabolite known to affect T1D risk), one probe (cg01604946) mediated by phostidyl choline p-32:0 or o-32:1, and one probe (cg00390143) mediated by sphingomyelin d34:2. The top 100 DNAm probes were over-represented in six reactome pathways at the FDR

Aims/hypothesisOxylipins are lipid mediators derived from polyunsaturated fatty acids. Some oxylipins are proinflammatory (e.g. those derived from arachidonic acid [ARA]), others are pro-resolving of inflammation (e.g. those derived from α-linolenic acid [ALA], docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) and others may be both (e.g. those derived from linoleic acid [LA]). The goal of this study was to examine whether oxylipins are associated with incident type 1 diabetes.MethodsWe conducted a nested case-control analysis in the Diabetes Autoimmunity Study in the Young (DAISY), a prospective cohort study of children at risk of type 1 diabetes. Plasma levels of 14 ARA-derived oxylipins, ten LA-derived oxylipins, six ALA-derived oxylipins, four DHA-derived oxylipins and two EPA-related oxylipins were measured by ultra-HPLC-MS/MS at multiple timepoints related to autoantibody seroconversion in 72 type 1 diabetes cases and 71 control participants, which were frequency matched on age at autoantibody seroconversion (of the case), ethnicity and sample availability. Linear mixed models were used to obtain an age-adjusted mean of each oxylipin prior to type 1 diabetes. Age-adjusted mean oxylipins were tested for association with type 1 diabetes using logistic regression, adjusting for the high risk HLA genotype HLA-DR3/4,DQB1*0302. We also performed principal component analysis of the oxylipins and tested principal components (PCs) for association with type 1 diabetes. Finally, to investigate potential critical timepoints, we examined the association of oxylipins measured before and after autoantibody seroconversion (of the cases) using PCs of the oxylipins at those visits.ResultsThe ARA-related oxylipin 5-HETE was associated with increased type 1 diabetes risk. Five LA-related oxylipins, two ALA-related oxylipins and one DHA-related oxylipin were associated with decreased type 1 diabetes risk. A profile of elevated LA- and ALA-related oxylipins (PC1) was associated with decreased type 1 diabetes risk (OR 0.61; 95% CI 0.40, 0.94). A profile of elevated ARA-related oxylipins (PC2) was associated with increased diabetes risk (OR 1.53; 95% CI 1.03, 2.29). A critical timepoint analysis showed type 1 diabetes was associated with a high ARA-related oxylipin profile at post-autoantibody-seroconversion but not pre-seroconversion.Conclusions/interpretationThe protective association of higher LA- and ALA-related oxylipins demonstrates the importance of both inflammation promotion and resolution in type 1 diabetes. Proinflammatory ARA-related oxylipins may play an important role once the autoimmune process has begun.

Context In Colorado children, the prevalence of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes has been increasing over time. Objective To evaluate the prevalence of and factors involved in DKA at type 1 diabetes diagnosis among participants followed in monitoring research studies before diagnosis compared to patients from the community. Methods We studied patients < 18 years diagnosed with type 1 diabetes between 2005 and 2021 at the Barbara Davis Center for Diabetes and compared the prevalence of and factors associated with DKA at diagnosis among participants in preclinical monitoring studies vs those diagnosed in the community. Results Of 5049 subjects, 164 were active study participants, 42 inactive study participants, and 4843 were community patients. Active study participants, compared to community patients, had lower HbA1c (7.3% vs 11.9%; P <.001) and less frequently experienced DKA (4.9% vs 48.5%; P <.001), including severe DKA (1.2% vs 16.2%; P <.001). Inactive study participants had intermediate levels for both prevalence and severity of DKA. DKA prevalence increased in community patients, from 44.0% to 55%, with less evidence for a temporal trend in study participants. DKA prevalence was highest in children < 2 years (13% in active study participants vs 83% in community patients). In community patients, younger age (P =.0038), public insurance (P <.0001), rural residence (P <.0076), higher HbA1c (P <.0001), and ethnicity minority status (P <.0001) were associated with DKA at diagnosis. Conclusion While DKA prevalence increases in community patients over time, it stayed < 5% in active research participants, who have a 10 times lower prevalence of DKA at diagnosis, including among minorities. [ABSTRACT FROM AUTHOR]

Purpose : The aim was to study the association between dietary intake of B vitamins in childhood and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D) by the age of 10 years. Methods: We followed 8500 T1D-susceptible children born in the U.S., Finland, Sweden, and Germany in 2004 -2010 from the Environmental Determinants of Diabetes in the Young (TEDDY) study, which is a prospective observational birth cohort. Dietary intake of seven B vitamins was calculated from foods and dietary supplements based on 24-h recall at 3 months and 3-day food records collected regularly from 6 months to 10 years of age. Cox proportional hazard models were adjusted for energy, HLA-genotype, first-degree relative with T1D, sex, and country. Results: A total of 778 (9.2) children developed at least one autoantibody (any IA), and 335 (3.9%) developed multiple autoantibodies. 280 (3.3%) children had IAA and 319 (3.8%) GADA as the first autoantibody. 344 (44%) children with IA progressed to T1D. We observed that higher intake of niacin was associated with a decreased risk of developing multiple autoantibodies (HR 0.95; 95% CI 0.92, 0.98) per 1 mg/1000 kcal in niacin intake. Higher intake of pyridoxine (HR 0.66; 95% CI 0.46, 0.96) and vitamin B12 (HR 0.87; 95% CI 0.77, 0.97) was associated with a decreased risk of IAA-first autoimmunity. Higher intake of riboflavin (HR 1.38; 95% CI 1.05, 1.80) was associated with an increased risk of GADA-first autoimmunity. There were no associations between any of the B vitamins and the outcomes "any IA" and progression from IA to T1D. Conclusion: In this multinational, prospective birth cohort of children with genetic susceptibility to T1D, we observed some direct and inverse associations between different B vitamins and risk of IA. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To characterize distinct islet autoantibody profiles preceding stage 3 type 1 diabetes RESEARCH DESIGN AND METHODS: The T1DI (Type 1 Diabetes Intelligence) study combined data from 1,845 genetically susceptible prospectively observed children who were positive for at least one islet autoantibody: insulin autoantibody (IAA), GAD antibody (GADA), or islet antigen 2 antibody (IA-2A). Using a novel similarity algorithm that considers an individual's temporal autoantibody profile, age at autoantibody appearance, and variation in the positivity of autoantibody types, we performed an unsupervised hierarchical clustering analysis. Progression rates to diabetes were analyzed via survival analysis. RESULTS: We identified five main clusters of individuals with distinct autoantibody profiles characterized by seroconversion age and sequence of appearance of the three autoantibodies. The highest 5-year risk from first positive autoantibody to type 1 diabetes (69.9%; 95% CI 60.0–79.2) was observed in children who first developed IAA in early life (median age 1.6 years) followed by GADA (1.9 years) and then IA-2A (2.1 years). Their 10-year risk was 89.9% (95% CI 81.9–95.4). A high 5-year risk was also found in children with persistent IAA and GADA (39.1%) and children with persistent GADA and IA-2A (30.9%). A lower 5-year risk (10.5%) was observed in children with a late appearance of persistent GADA (6.1 years). The lowest 5-year diabetes risk (1.6%) was associated with positivity for a single, often reverting, autoantibody. CONCLUSIONS: The novel clustering algorithm identified children with distinct islet autoantibody profiles and progression rates to diabetes. These results are useful for prediction, selection of individuals for prevention trials, and studies investigating various pathways to type 1 diabetes. [ABSTRACT FROM AUTHOR]

AimsThe Environmental Determinants of Diabetes in the Young planned biomarker discovery studies on longitudinal samples for persistent confirmed islet cell autoantibodies and type 1 diabetes using dietary biomarkers, metabolomics, microbiome/viral metagenomics and gene expression.MethodsThis article describes the details of planning The Environmental Determinants of Diabetes in the Young 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 conclusionOur design is to reduce potential bias and retain study power while reducing 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 type 1 diabetes). The resulting list of case-control matched samples for each laboratory was augmented with external quality control samples.

Context The 2 peaks of type 1 diabetes incidence occur during early childhood and puberty. Objective We sought to better understand the relationship between puberty, islet autoimmunity, and type 1 diabetes. Methods The relationships between puberty, islet autoimmunity, and progression to type 1 diabetes were investigated prospectively in children followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Onset of puberty was determined by subject self-assessment of Tanner stages. Associations between speed of pubertal progression, pubertal growth, weight gain, homeostasis model assessment of insulin resistance (HOMA-IR), islet autoimmunity, and progression to type 1 diabetes were assessed. The influence of individual factors was analyzed using Cox proportional hazard ratios. Results Out of 5677 children who were still in the study at age 8 years, 95% reported at least 1 Tanner Stage score and were included in the study. Children at puberty (Tanner Stage ≥2) had a lower risk (HR 0.65, 95% CI 0.45-0.93; P =.019) for incident autoimmunity than prepubertal children (Tanner Stage 1). An increase of body mass index Z-score was associated with a higher risk (HR 2.88, 95% CI 1.61-5.15; P <.001) of incident insulin autoantibodies. In children with multiple autoantibodies, neither HOMA-IR nor rate of progression to Tanner Stage 4 were associated with progression to type 1 diabetes. Conclusion Rapid weight gain during puberty is associated with development of islet autoimmunity. Puberty itself had no significant influence on the appearance of autoantibodies or type 1 diabetes. Further studies are needed to better understand the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Background: Type 1 diabetes (T1D) is preceded by a heterogenous pre-clinical phase, islet autoimmunity (IA). We aimed to identify pre vs. post-IA seroconversion (SV) changes in DNAm that differed across three IA progression phenotypes, those who lose autoantibodies (reverters), progress to clinical T1D (progressors), or maintain autoantibody levels (maintainers). Methods: This epigenome-wide association study (EWAS) included longitudinal DNAm measurements in blood (Illumina 450K and EPIC) from participants in Diabetes Autoimmunity Study in the Young (DAISY) who developed IA, one or more islet autoantibodies on at least two consecutive visits. We compared reverters - individuals who sero-reverted, negative for all autoantibodies on at least two consecutive visits and did not develop T1D (n=41); maintainers - continued to test positive for autoantibodies but did not develop T1D (n=60); progressors - developed clinical T1D (n=42). DNAm data were measured before (pre-SV visit) and after IA (post-SV visit). Linear mixed models were used to test for differences in pre-vs post-SV changes in DNAm across the three groups. Linear mixed models were also used to test for group differences in average DNAm. Cell proportions, age, and sex were adjusted for in all models. Median follow-up across all participants was 15.5 yrs. (interquartile range (IQR): 10.8-18.7). Results: The median age at the pre-SV visit was 2.2 yrs. (IQR: 0.8-5.3) in progressors, compared to 6.0 yrs. (IQR: 1.3-8.4) in reverters, and 5.7 yrs. (IQR: 1.4-9.7) in maintainers. Median time between the visits was similar in reverters 1.4 yrs. (IQR: 1-1.9), maintainers 1.3 yrs. (IQR: 1.0-2.0), and progressors 1.8 yrs. (IQR: 1.0-2.0). Changes in DNAm, pre- vs post-SV, differed across the groups at one site (cg16066195) and 11 regions. Average DNAm (mean of pre- and post-SV) differed across 22 regions. Conclusion: Differentially changing DNAm regions were located in genomic areas related to beta cell function, immune cell differentiation, and immune cell function. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is an autoimmune disease in which one's own immune system destroys insulin‐secreting beta cells in the pancreas. This process results in life‐long dependence on exogenous insulin for survival. Both genetic and environmental factors play a role in disease initiation, progression, and ultimate clinical diagnosis of type 1 diabetes. This review will provide background on the natural history of type 1 diabetes and the role of genetic factors involved in the complement system, as several recent studies have identified changes in levels of these proteins as the disease evolves from pre‐clinical through to clinically apparent disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess anxiety and risk perception among parents whose children screened positive for islet autoantibodies, indicating elevated risk for type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: The Autoimmunity Screening for Kids (ASK) study identified 319 children age 1 to 17 years at risk for T1D via screening for islet autoantibodies; 280 children with confirmed islet autoantibodies and their caregivers enrolled in a follow-up education and monitoring program to prevent diabetic ketoacidosis at diagnosis. Parents completed questionnaires at each monitoring visit, including a 6-item version of the State Anxiety Inventory (SAI), to assess anxiety about their child developing T1D, and a single question to assess risk perception. RESULTS: At the first ASK follow-up monitoring visit, mean parental anxiety was elevated above the clinical cutoff of 40 (SAI 46.1 ± 11.2). At the second follow-up monitoring visit (i.e., visit 2), mean anxiety remained elevated but started to trend down. Approximately half (48.9%) of parents reported their child was at increased risk for T1D at the initial follow-up monitoring visit (visit 1). Parents of children with more than one islet autoantibody and a first-degree relative with T1D were more likely to report their child was at increased risk. CONCLUSIONS: Most parents of autoantibody-positive children have high anxiety about their child developing T1D. Information about the risk of developing T1D is difficult to convey, as evidenced by the wide range of risk perception reported in this sample. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To estimate the risk of progression to stage 3 type 1 diabetes based on varying definitions of multiple islet autoantibody positivity (mIA). RESEARCH DESIGN AND METHODS: Type 1 Diabetes Intelligence (T1DI) is a combined prospective data set of children from Finland, Germany, Sweden, and the U.S. who have an increased genetic risk for type 1 diabetes. Analysis included 16,709 infants-toddlers enrolled by age 2.5 years and comparison between groups using Kaplan-Meier survival analysis. RESULTS: Of 865 (5%) children with mIA, 537 (62%) progressed to type 1 diabetes. The 15-year cumulative incidence of diabetes varied from the most stringent definition (mIA/Persistent/2: two or more islet autoantibodies positive at the same visit with two or more antibodies persistent at next visit; 88% [95% CI 85–92%]) to the least stringent (mIA/Any: positivity for two islet autoantibodies without co-occurring positivity or persistence; 18% [5–40%]). Progression in mIA/Persistent/2 was significantly higher than all other groups (P < 0.0001). Intermediate stringency definitions showed intermediate risk and were significantly different than mIA/Any (P < 0.05); however, differences waned over the 2-year follow-up among those who did not subsequently reach higher stringency. Among mIA/Persistent/2 individuals with three autoantibodies, loss of one autoantibody by the 2-year follow-up was associated with accelerated progression. Age was significantly associated with time from seroconversion to mIA/Persistent/2 status and mIA to stage 3 type 1 diabetes. CONCLUSIONS: The 15-year risk of progression to type 1 diabetes risk varies markedly from 18 to 88% based on the stringency of mIA definition. While initial categorization identifies highest-risk individuals, short-term follow-up over 2 years may help stratify evolving risk, especially for those with less stringent definitions of mIA. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To study the interaction among HLA genotype, early probiotic exposure, and timing of complementary foods in relation to risk of islet autoimmunity (IA). RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,676 children with increased genetic risk of type 1 diabetes. We used a Cox proportional hazards regression model adjusting for potential confounders to study early feeding and the risk of IA in a sample of 7,770 children. RESULTS: Any solid food introduced early (<6 months) was associated with increased risk of IA if the child had the HLA DR3/4 genotype and no probiotic exposure during the 1st year of life. Rice introduced at 4–5.9 months compared with later in the U.S. was associated with an increased risk of IA. CONCLUSIONS: Timing of solid food introduction, including rice, may be associated with IA in children with the HLA DR3/4 genotype not exposed to probiotics. The microbiome composition under these exposure combinations requires further study. [ABSTRACT FROM AUTHOR]

Given the differential risk of type 1 diabetes (T1D) in offspring of affected fathers versus affected mothers and our observation that T1D cases have differential DNA methylation near the imprinted DLGAP2 gene compared to controls, we examined whether methylation near DLGAP2 mediates the association between T1D family history and T1D risk. In a nested case–control study of 87 T1D cases and 87 controls from the Diabetes Autoimmunity Study in the Young, we conducted causal mediation analyses at 12 DLGAP2 region CpGs to decompose the effect of family history on T1D risk into indirect and direct effects. These effects were estimated from two regression models adjusted for the human leukocyte antigen DR3/4 genotype: a linear regression of family history on methylation (mediator model) and a logistic regression of family history and methylation on T1D (outcome model). For 8 of the 12 CpGs, we identified a significant interaction between T1D family history and methylation on T1D risk. Accounting for this interaction, we found that the increased risk of T1D for children with affected mothers compared to those with no family history was mediated through differences in methylation at two CpGs (cg27351978, cg00565786) in the DLGAP2 region, as demonstrated by a significant pure natural indirect effect (odds ratio (OR) = 1.98, 95% confidence interval (CI): 1.06–3.71) and nonsignificant total natural direct effect (OR = 1.65, 95% CI: 0.16–16.62) (for cg00565786). In contrast, the increased risk of T1D for children with an affected father or sibling was not explained by DNA methylation changes at these CpGs. Results were similar for cg27351978 and robust in sensitivity analyses. Lastly, we found that DNA methylation in the DLGAP2 region was associated (P < 0.05) with gene expression of nearby protein-coding genes DLGAP2, ARHGEF10, ZNF596, and ERICH1. Results indicate that the maternal protective effect conferred through exposure to T1D in utero may operate through changes to DNA methylation that have functional downstream consequences. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a chronic autoimmune disease that attacks the insulin-producing b cells of the pancreatic islets. Autoantibodies to b cell proteins typically appear in the circulation years before disease onset, and serve as the most accurate biomarkers of T1D risk. Our laboratory has recently discovered novel b cell proteins comprising hybrid proinsulin:islet amyloid polypeptide peptides (IAPP). T cells from a diabetic mouse model and T1D patients are activated by these hybrid peptides. In this study, we asked whether these hybrid molecules could serve as antigens for autoantibodies in T1D and prediabetic patients. We analyzed sera from T1D patients, prediabetics and healthy age-matched donors. Using a highly sensitive electrochemiluminescence assay, sera were screened for binding to recombinant proinsulin:IAPP probes or truncated derivatives. Our results show that sera from T1D patients contain antibodies that bind larger hybrid proinsulin:IAPP probes, but not proinsulin or insulin, at significantly increased frequencies compared to normal donors. Examination of sera from prediabetic patients confirms titers of antibodies to these hybrid probes in more than 80% of individuals, often before seroconversion. These results suggest that hybrid insulin peptides are common autoantigens in T1D and prediabetic patients, and that antibodies to these peptides may serve as valuable early biomarkers of the disease. [ABSTRACT FROM AUTHOR]

The etiology of type 1 diabetes (T1D) foreshadows the pancreatic islet beta‐cell autoimmune pathogenesis that heralds the clinical onset of T1D. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen‐2 (IA‐2A), and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden, and the United States) observational study, children were identified at birth for the T1D high‐risk HLA haploid genotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8, and DQ4/DQ8. The TEDDY study was preceded by smaller studies in Finland, Germany, Colorado, Washington, and Sweden. The aims were to follow children at increased genetic risk to identify environmental factors that trigger the first‐appearing autoantibody (etiology) and progress to T1D (pathogenesis). The larger TEDDY study found that the incidence rate of the first‐appearing autoantibody was split into two patterns. IAA first peaked already during the first year of life and tapered off by 3–4 years of age. GADA first appeared by 2–3 years of age to reach a plateau by about 4 years. Prior to the first‐appearing autoantibody, genetic variants were either common or unique to either pattern. A split was also observed in whole blood transcriptomics, metabolomics, dietary factors, and exposures such as gestational life events and early infections associated with prolonged shedding of virus. An innate immune reaction prior to the adaptive response cannot be excluded. Clarifying the mechanisms by which autoimmunity is triggered to either insulin or GAD65 is key to uncovering the etiology of autoimmune T1D. [ABSTRACT FROM AUTHOR]

Objective: To distinguish among predictors of seroconversion, progression to multiple autoantibodies and from multiple autoantibodies to type 1 diabetes in young children.Research Design and Methods: Genetically high-risk newborns (n = 8,502) were followed for a median of 11.2 years (interquartile range 9.3-12.6); 835 (9.8%) developed islet autoantibodies and 283 (3.3%) were diagnosed with type 1 diabetes. Predictors were examined using Cox proportional hazards models.Results: Predictors of seroconversion and progression differed, depending on the type of first appearing autoantibody. Male sex, Finnish residence, having a sibling with type 1 diabetes, the HLA DR4 allele, probiotic use before age 28 days, and single nucleotide polymorphism (SNP) rs689_A (INS) predicted seroconversion to IAA-first (having islet autoantibody to insulin as the first appearing autoantibody). Increased weight at 12 months and SNPs rs12708716_G (CLEC16A) and rs2292239_T (ERBB3) predicted GADA-first (autoantibody to GAD as the first appearing). For those having a father with type 1 diabetes, the SNPs rs2476601_A (PTPN22) and rs3184504_T (SH2B3) predicted both. Younger age at seroconversion predicted progression from single to multiple autoantibodies as well as progression to diabetes, except for those presenting with GADA-first. Family history of type 1 diabetes and the HLA DR4 allele predicted progression to multiple autoantibodies but not diabetes. Sex did not predict progression to multiple autoantibodies, but males progressed more slowly than females from multiple autoantibodies to diabetes. SKAP2 and MIR3681HG SNPs are newly reported to be significantly associated with progression from multiple autoantibodies to type 1 diabetes.Conclusions: Predictors of IAA-first versus GADA-first autoimmunity differ from each other and from the predictors of progression to diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To examine whether iron intake and genetically determined iron overload interact in predisposing to the development of childhood islet autoimmunity (IA) and type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In The Environmental Determinants of Diabetes in the Young (TEDDY) study, 7,770 genetically high-risk children were followed from birth until the development of IA and progression to T1D. Exposures included energy-adjusted iron intake in the first 3 years of life and a genetic risk score (GRS) for increased circulating iron. RESULTS: We found a U-shaped association between iron intake and risk of GAD antibody as the first autoantibody. In children with GRS ≥2 iron risk alleles, high iron intake was associated with an increased risk of IA, with insulin as first autoantibody (adjusted hazard ratio 1.71 [95% CI 1.14; 2.58]) compared with moderate iron intake. CONCLUSIONS: Iron intake may alter the risk of IA in children with high-risk HLA haplogenotypes. [ABSTRACT FROM AUTHOR]

Background: Studies of the role of iron in the risk of type 1 diabetes (T1D) have been inconsistent. Given that iron generates reactive oxygen radicals, which can lead to oxidative damage and apoptosis in the beta cells of the pancreas, we examined whether iron intake was associated with the risk of progressing to T1D in individuals with islet autoimmunity (IA), the pre-clinical phase of T1D. Methods: DAISY is a prospective cohort following 2,547 children at increased risk for IA and progression to T1D. IA is defined as at least two consecutive serum samples positive for at least one autoantibody (insulin, GAD, IA-2, or ZnT8). We measured dietary intake at the time of IA seroconversion in 175 children with IA, and of these, 64 progressed to T1D. We used Cox regression to examine the association between energy-adjusted iron intake and progression to T1D, adjusting for HLA-DR3/4 genotype, race/ethnicity, age at seroconversion, presence of multiple autoantibodies at seroconversion, and multiple vitamin use. In addition, we tested whether this association was modified by vitamin C or calcium intake. Results: In children with IA, high iron intake (as defined as above the 75th percentile, > 20.3 mg/day) was associated with decreased risk of progression to T1D compared to moderate iron intake (as defined by the middle 25-75th percentiles, 12.7-20.3 mg/day) (adjusted hazard ratio (HR): 0.35; 95% confidence interval (CI): 0.15, 0.79). The association between iron intake and T1D was not modified by vitamin C nor calcium intake. In a sensitivity analysis, the removal of six children who had been diagnosed with celiac disease prior to IA seroconversion did not affect this association. Conclusion: Higher iron intake at the time of IA seroconversion is associated with a lower risk of progression to T1D, independent of multivitamin supplement use. Further research that includes plasma biomarkers of iron status is needed to investigate the relationship between iron and the risk of T1D. [ABSTRACT FROM AUTHOR]

Background/Objective. Growth and obesity have been associated with increased risk of islet autoimmunity (IA) and progression to type 1 diabetes. We aimed to estimate the effect of energy-yielding macronutrient intake on the development of IA through BMI. Research Design and Methods. Genetically at-risk children (n = 5,084) in Finland, Germany, Sweden, and the USA, who were autoantibody negative at 2 years of age, were followed to the age of 8 years, with anthropometric measurements and 3-day food records collected biannually. Of these, 495 (9.7%) children developed IA. Mediation analysis for time-varying covariates (BMI z-score) and exposure (energy intake) was conducted. Cox proportional hazard method was used in sensitivity analysis. Results. We found an indirect effect of total energy intake (estimates: indirect effect 0.13 [0.05, 0.21]) and energy from protein (estimates: indirect effect 0.06 [0.02, 0.11]), fat (estimates: indirect effect 0.03 [0.01, 0.05]), and carbohydrates (estimates: indirect effect 0.02 [0.00, 0.04]) (kcal/day) on the development of IA. A direct effect was found for protein, expressed both as kcal/day (estimates: direct effect 1.09 [0.35, 1.56]) and energy percentage (estimates: direct effect 72.8 [3.0, 98.0]) and the development of GAD autoantibodies (GADA). In the sensitivity analysis, energy from protein (kcal/day) was associated with increased risk for GADA, hazard ratio 1.24 (95% CI: 1.09, 1.53), p = 0.042. Conclusions. This study confirms that higher total energy intake is associated with higher BMI, which leads to higher risk of the development of IA. A diet with larger proportion of energy from protein has a direct effect on the development of GADA. [ABSTRACT FROM AUTHOR]

Objective: Increased level of glycated hemoglobin (HbA1c) is associated with type 1 diabetes onset that in turn is preceded by one to several autoantibodies against the pancreatic islet beta cell autoantigens; insulin (IA), glutamic acid decarboxylase (GAD), islet antigen‐2 (IA‐2) and zinc transporter 8 (ZnT8). The risk for type 1 diabetes diagnosis increases by autoantibody number. Biomarkers predicting the development of a second or a subsequent autoantibody and type 1 diabetes are needed to predict disease stages and improve secondary prevention trials. This study aimed to investigate whether HbA1c possibly predicts the progression from first to a subsequent autoantibody or type 1 diabetes in healthy children participating in the Environmental Determinants of Diabetes in the Young (TEDDY) study. Research Design and Methods: A joint model was designed to assess the association of longitudinal HbA1c levels with the development of first (insulin or GAD autoantibodies) to a second, second to third, third to fourth autoantibody or type 1 diabetes in healthy children prospectively followed from birth until 15 years of age. Results: It was found that increased levels of HbA1c were associated with a higher risk of type 1 diabetes (HR 1.82, 95% CI [1.57–2.10], p < 0.001) regardless of first appearing autoantibody, autoantibody number or type. A decrease in HbA1c levels was associated with the development of IA‐2A as a second autoantibody following GADA (HR 0.85, 95% CI [0.75, 0.97], p = 0.017) and a fourth autoantibody following GADA, IAA and ZnT8A (HR 0.90, 95% CI [0.82, 0.99], p = 0.036). HbA1c trajectory analyses showed a significant increase of HbA1c over time (p < 0.001) and that the increase is more rapid as the number of autoantibodies increased from one to three (p < 0.001). Conclusion: In conclusion, increased HbA1c is a reliable time predictive marker for type 1 diabetes onset. The increased rate of increase of HbA1c from first to third autoantibody and the decrease in HbA1c predicting the development of IA‐2A are novel findings proving the link between HbA1c and the appearance of autoantibodies. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is an autoimmune disease, characterized by the presence of autoantibodies to protein and non-protein antigens. Here we report the identification of specific anti-carbohydrate antibodies (ACAs) that are associated with pathogenesis and progression to T1D. We compare circulatory levels of ACAs against 202 glycans in a cross-sectional cohort of T1D patients (n = 278) and healthy controls (n = 298), as well as in a longitudinal cohort (n = 112). We identify 11 clusters of ACAs associated with glycan function class. Clusters enriched for aminoglycosides, blood group A and B antigens, glycolipids, ganglio-series, and O-linked glycans are associated with progression to T1D. ACAs against gentamicin and its related structures, G418 and sisomicin, are also associated with islet autoimmunity. ACAs improve discrimination of T1D status of individuals over a model with only clinical variables and are potential biomarkers for T1D. Type I diabetes is characterized by autoantibodies directed against protein or non-protein self-antigens. Here the authors profile glycan reactive anti-carbohydrate antibodies (ACA) in a longitudinal and cross-sectional childhood diabetes cohort and associate clusters of ACA with disease progression. [ABSTRACT FROM AUTHOR]

Background: Type 1 diabetes (T1D) is the most frequent chronic autoimmune disease in childhood and adolescence, its incidence is increasing particularly in toddlers and preschool children, and up to 60% of young patients present with diabetic ketoacidosis (DKA), a severe and life-threatening complication. So far, the majority of screening efforts have been performed in the at-risk group, i.e., relatives of people with T1D; anyhow, around 90% of young patients who eventually develop T1D do not have a family history. Summary: Some studies in Europe and the USA have clearly shown that a public health screening of children (with positive autoantibodies) is effective in reducing the prevalence of DKA by more than 10 times, decreasing the rate of hospitalization and its costs, providing psychological, emotional, and social support to children and their families. In addition, several treatments and trials are available for children with stage 2 and stage 3 T1D. There is still room for improvement of sensitivity, specificity, positive and negative predictive value in a population screening program; anyhow, there is vivid debate on the opportunity for a screening program in the general population of children at risk for developing T1D. Key Messages: This paper, endorsed by the European Society for Paediatric Endocrinology (ESPE), discusses the issues of a screening program in the general population with the hope that uncertainties and difficulties in this field will be overcome by better screening methods, improved cost-effectiveness, reliable treatments for secondary prevention, and relevant delay in clinically evident T1D in children and adolescents. [ABSTRACT FROM AUTHOR]

Objective: Biomarkers predicting risk of type 1 diabetes (stage 3) among children with islet autoantibodies are greatly needed to prevent diabetic ketoacidosis and facilitate prevention therapies.Research Design and Methods: Children in the prospective The Environmental Determinants of Diabetes in the Young (TEDDY) study (n = 707) with confirmed diabetes-associated autoantibodies (GAD antibody, IA-2A, and/or insulin autoantibody) and two or more HbA1c measurements were followed to diabetes or median age 11.1 years. Once confirmed autoantibody positive, HbA1c was measured quarterly. Cox models and receiver operative characteristic curve analyses revealed the prognostic utility for risk of stage 3 on a relative HbA1c increase from the baseline visit or an oral glucose tolerance test (OGTT) 2-h plasma glucose (2-hPG). This HbA1c approach was then validated in the Type 1 Diabetes TrialNet Pathway to Prevention Study (TrialNet) (n = 1,190).Results: A 10% relative HbA1c increase from baseline best marked the increased risk of stage 3 in TEDDY (74% sensitive; 88% specific). Significant predictors of risk for HbA1c change were age and HbA1c at the baseline test, genetic sex, maximum number of autoantibodies, and maximum rate of HbA1c increase by time of change. The multivariable model featuring a HbA1c ≥10% increase and these additional factors revealed increased risk of stage 3 in TEDDY (hazard ratio [HR] 12.74, 95% CI 8.7-18.6, P < 0.0001) and TrialNet (HR 5.09, 95% CI 3.3-7.9, P < 0.0001). Furthermore, the composite model using HbA1c ≥10% increase performed similarly to an OGTT 2-hPG composite model (TEDDY area under the curve [AUC] 0.88 and 0.85, respectively) and to the HbA1c model in TrialNet (AUC 0.82).Conclusions: An increase of ≥10% in HbA1c from baseline is as informative as OGTT 2-hPG in predicting risk of stage 3 in youth with genetic risk and diabetes-associated autoantibodies. [ABSTRACT FROM AUTHOR]

Longitudinal changes in gene expression during islet autoimmunity (IA) may provide insight into biological processes that explain progression to type 1 diabetes (T1D). We identified individuals from Diabetes Autoimmunity Study in the Young (DAISY) who developed IA, autoantibodies present on two or more visits. Illumina's NovaSeq 6000 was used to quantify gene expression in whole blood. With linear mixed models we tested for changes in expression after IA that differed across individuals who progressed to T1D (progressors) (n = 25), reverted to an autoantibody-negative stage (reverters) (n = 47), or maintained IA positivity but did not develop T1D (maintainers) (n = 66). Weighted gene coexpression network analysis was used to identify coexpression modules. Gene Ontology pathway analysis of the top 150 differentially expressed genes (nominal P < 0.01) identified significantly enriched pathways including leukocyte activation involved in immune response, innate immune response, and regulation of immune response. We identified a module of 14 coexpressed genes with roles in the innate immunity. The hub gene, LTF, is known to have immunomodulatory properties. Another gene within the module, CAMP, is potentially relevant based on its role in promoting β-cell survival in a murine model. Overall, results provide evidence of alterations in expression of innate immune genes prior to onset of T1D. [ABSTRACT FROM AUTHOR]

Context: Biomarkers that can accurately predict risk of type 1 diabetes (T1D) in genetically predisposed children can facilitate interventions to delay or prevent the disease. Objective: This work aimed to determine if a combination of genetic, immunologic, and metabolic features, measured at infancy, can be used to predict the likelihood that a child will develop T1D by age 6 years. Methods: Newborns with human leukocyte antigen (HLA) typing were enrolled in the prospective birth cohort of The Environmental Determinants of Diabetes in the Young (TEDDY). TEDDY ascertained children in Finland, Germany, Sweden, and the United States. TEDDY children were either from the general population or from families with T1D with an HLA genotype associated with T1D specific to TEDDY eligibility criteria. From the TEDDY cohort there were 702 children will all data sources measured at ages 3, 6, and 9 months, 11.4% of whom progressed to T1D by age 6 years. The main outcome measure was a diagnosis of T1D as diagnosed by American Diabetes Association criteria. Results: Machine learning–based feature selection yielded classifiers based on disparate demographic, immunologic, genetic, and metabolite features. The accuracy of the model using all available data evaluated by the area under a receiver operating characteristic curve is 0.84. Reducing to only 3- and 9-month measurements did not reduce the area under the curve significantly. Metabolomics had the largest value when evaluating the accuracy at a low false-positive rate. Conclusion: The metabolite features identified as important for progression to T1D by age 6 years point to altered sugar metabolism in infancy. Integrating this information with classic risk factors improves prediction of the progression to T1D in early childhood. [ABSTRACT FROM AUTHOR]

Aims/Hypotheses: Physical inactivity may contribute to islet autoimmunity and progression to clinical type 1 diabetes. To test this hypothesis, we evaluated physical activity, assessed by accelerometer, as an independent risk factor for progression to clinical diabetes among genetically at risk for type 1 diabetes children and youth with islet autoimmunity. Methods: Accelerometer data were obtained for 95 children and youth participating in the diabetes autoimmunity study in the young who had islet autoimmunity. Islet autoimmunity was defined as the presence of islet autoantibodies to insulin, glutamic acid decarboxylase, tyrosine phosphatase‐like protein IA‐2, or zinc transporter 8. Results: During prospective follow‐up for up to 7 years, 13 of the 95 participants progressed to clinical diabetes. In multivariable survival analysis, none of the physical activity parameters examined predicted a higher risk of developing diabetes. In survival analysis with time‐varying physical activity parameters, none of the physical activity parameters over time were associated with the risk of developing type 1 diabetes. Conclusions/Interpretation: It does not appear that low‐physical activity is a risk factor for progression from islet autoantibodies to diabetes in children and youth at high‐genetic risk for type 1 diabetes. [ABSTRACT FROM AUTHOR]

Most screening programs to identify individuals at risk for type 1 diabetes have targeted relatives of people living with the disease to improve yield and feasibility. However, ∼90% of those who develop type 1 diabetes do not have a family history. Recent successes in disease-modifying therapies to impact the course of early-stage disease have ignited the consideration of the need for and feasibility of population screening to identify those at increased risk. Existing population screening programs rely on genetic or autoantibody screening, and these have yielded significant information about disease progression and approaches for timing for screening in clinical practice. At the March 2021 Type 1 Diabetes TrialNet Steering Committee meeting, a session was held in which ongoing efforts for screening in the general population were discussed. This report reviews the background of these efforts and the details of those programs. Additionally, we present hurdles that need to be addressed for successful implementation of population screening and provide initial recommendations for individuals with positive screens so that standardized guidelines for monitoring and follow-up can be established. [ABSTRACT FROM AUTHOR]