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The identification of diabetes-relevant islet autoantibodies is essential for predicting and preventing type 1 diabetes (T1D). The aim of the current study was to evaluate a newly developed electrochemiluminescence (ECL)-GAD antibody (GADA) assay and compare its sensitivity and disease relevance with standard radioassay. The assay was validated with serum samples from 227 newly diagnosed diabetic children; 68 prediabetic children who were prospectively followed to T1D; 130 nondiabetic children with confirmed islet autoantibodies to insulin, GAD65, IA-2, and/or ZnT8 longitudinally followed for 12 ± 3.7 years; and 181 age-matched, healthy, antibody-negative children. The ECL-GADA assay had a sensitivity similar to that of the standard GADA radioassay in children newly diagnosed with T1D, prediabetic children, and high-risk children with multiple positive islet autoantibodies. On the other hand, only 9 of 39 nondiabetic children with only a single islet autoantibody (GADA only) by radioassay were positive for ECL-GADA. GADA not detectable by ECL assay is shown to be of low affinity and likely not predictive of future diabetes. In conclusion, the new ECL assay identifies disease-relevant GADA by radioassay. It may help to improve the prediction and correct diagnosis of T1D among subjects positive only for GADA and no other islet autoantibodies.

R/R was successful at increasing immunization rates in adolescents and effect sizes were comparable to those in younger children. Practices conducting R/R may benefit financially if they can generate additional well-child care visits and keep supply costs low.

MELANSON, EDWARD L., WILLIAM T. DONAHOO, FRAN DONG, THERESE IDA, AND MICHAEL B. ZEMEL. Effect of low-and high-calcium dairy-based diets on macronutrient oxidation in humans. Obes Res. 2005;13: 2102-2112. Objective: Higher calcium and dairy intakes may be associated with lower body weights, but a mechanism in humans has yet to be elucidated. We compared the effects of a dairy-based high-calcium diet and a low-calcium diet on macronutrient oxidation. Research Methods and Procedures: Subjects (10 men and nine women) consumed a low-dairy (LD, ϳone serving per day, ϳ500 mg Ca 2ϩ /d) or high-dairy (HD, ϳthree to four servings per day, ϳ1400 mg Ca 2ϩ /d) energy balance diet for 1 week. Each diet condition was performed twice. On the 7th day, subjects were studied in a room calorimeter under one of four study conditions, applied in a randomized crossover design. Within each diet condition, subjects were studied under conditions of energy balance and acute energy deficit. The deficit (Ϫ600 kcal/d) was induced only for the 24 hours that subjects resided in the room and was achieved by a combination of caloric restriction and exercise. Results: Under energy balance conditions, there was no effect of diet treatment on respiratory quotient or 24-hour macronutrient oxidation. Under energy deficit conditions, 24-hour fat oxidation was significantly increased on the HD diet (HD with deficit ϭ 136 Ϯ 13 g/d, LD with deficit ϭ 106 Ϯ 7 g/d, p ϭ 0.02). Discussion: Consumption of a dairy-based high-calcium diet increased 24-hour fat oxidation under conditions of acute energy deficit. We hypothesize that these effects are due to an increased fat oxidation during exercise.

Background & Aims Little is known about the incidence of celiac disease in the general population of children in the United States. We aimed to estimate the cumulative incidence of celiac disease in adolescents born in the Denver metropolitan area. Methods We collected data on HLA-DR, DQ genotypes of 31,766 infants, born from 1993 through 2004 at St. Joseph’s Hospital in Denver, from the Diabetes Autoimmunity Study in the Young. Subjects with susceptibility genotypes for celiac disease and type 1 diabetes were followed for up to 20 years for development of tissue transglutaminase autoantibodies (tTGA). Outcomes were the development of celiac disease autoimmunity (CDA) or celiac disease. CDA was defined as persistence of tTGA for at least 3 months or development of celiac disease. Celiac disease was defined based on detection of Marsh 2 or greater lesions in biopsies or persistent high levels of tTGA. For each genotype, the cumulative incidence of CDA and celiac disease were determined. To estimate the cumulative incidence in the Denver general population, outcomes by each genotype were weighted according to the frequency of each of these genotypes in the general population. Results Of 1339 subjects followed, 66 developed CDA and met criteria for celiac disease and 46 developed only CDA. Seropositivity for tTGA resolved spontaneously, without treatment, in 21 of the 46 subjects with only CDA (46%). The estimated cumulative incidence for CDA in the Denver general population at 5, 10, and 15 years of age was 2.4%, 4.3%, and 5.1% respectively; incidence values for celiac disease were 1.6%, 2.8%, and 3.1%, respectively. Conclusions In a 20-year prospective study of 1339 children with genetic risk factors for celiac disease, we found the cumulative incidence of CDA and celiac disease to be high within the first 10 years. Although more than 5% of children may experience a period of CDA, not all develop celiac disease or require gluten-free diets.

DNA methylation may be involved in development of type 1 diabetes (T1D), but previous epigenomewide association studies were conducted among cases with clinically diagnosed diabetes. Using multiple pre-disease peripheral blood samples on the Illumina 450 K and EPIC platforms, we investigated longitudinal methylation differences between 87 T1D cases and 87 controls from the prospective Diabetes Autoimmunity Study in the Young (DAISY) cohort. Change in methylation with age differed between cases and controls in 10 regions. Average longitudinal methylation differed between cases and controls at two genomic positions and 28 regions. Some methylation differences were detectable and consistent as early as birth, including before and after the onset of preclinical islet autoimmunity. Results map to transcription factors, other protein coding genes, and non-coding regions of the genome with regulatory potential. The identification of methylation differences that predate islet autoimmunity and clinical diagnosis may suggest a role for epigenetics in T1D pathogenesis; however, functional validation is warranted. open Scientific RepoRtS | (2020) 10:3721 | https://doi.

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OBJECTIVEWe evaluated a novel electrochemiluminescent assay for insulin/proinsulin autoantibodies (ECL-IAA) as a new marker of the onset of islet autoimmunity and as a predictor of type 1 diabetes.RESEARCH DESIGN AND METHODSThe Diabetes Autoimmunity Study in the Young (DAISY) prospectively follows children at increased genetic risk for development of islet autoimmunity (defined as presence of autoantibodies to insulin, GAD65, IA-2, or zinc transporter 8 [ZnT8]) and type 1 diabetes (general population of children and first-degree relatives). Serial serum samples from subjects who progressed to type 1 diabetes and who had their first islet autoantibodies measured by age 18 months (N = 47) were tested using ECL-IAA.RESULTSAlmost all prediabetic children tested positive for ECL-IAA (46 of 47, 98%) during follow-up. ECL-IAA was almost always the first autoantibody to appear (94% total; 21% very first [by itself]; 23% with only mIAA; 19% with another islet autoantibody [GAD or ZnT8]; and 30% with ≥2 other antibodies [mIAA, GAD, IA-2, or ZnT8]). Among the 46 subjects who were ECL-IAA positive, ECL-IAA antedated the onset of other islet autoantibodies by a mean of 2.3 years (range, 0.3–7.2 years). Both the age of appearance of autoantibody and IAA levels (but not GAD65, IA2, or ZnT8 levels) are major determinants of the age of diabetes onset.CONCLUSIONSThis new ECL-IAA assay defines more precisely the onset of prediabetic autoimmunity and may help identify events triggering islet autoimmunity, as well as allow earlier intervention for type 1 diabetes. Nearly all young children progressing to diabetes are insulin autoantibody positive.