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OBJECTIVE Children identified with stage 1 type 1 diabetes are at high risk for progressing to stage 3 (clinical) diabetes and require accurate monitoring. Our aim was to establish continuous glucose monitoring (CGM) metrics that could predict imminent progression to diabetes. RESEARCH DESIGN AND METHODS In the Autoimmunity Screening for Kids study, 91 children who were persistently islet autoantibody positive (median age 11.5 years; 48% non-Hispanic White; 57% female) with a baseline CGM were followed for development of diabetes for a median of 6 (range 0.2–34) months. Of these, 16 (18%) progressed to clinical diabetes in a median of 4.5 (range 0.4–29) months. RESULTS Compared with children who did not progress to clinical diabetes (nonprogressors), those who did (progressors) had significantly higher average sensor glucose levels (119 vs. 105 mg/dL, P < 0.001) and increased glycemic variability (SD 27 vs. 16, coefficient of variation, 21 vs. 15, mean of daily differences 24 vs. 16, and mean amplitude of glycemic excursions 43 vs. 26, all P < 0.001). For progressors, 21% of the time was spent with glucose levels >140 mg/dL (TA140) and 8% of time >160 mg/dL, compared with 3% and 1%, respectively, for nonprogressors. In survival analyses, the risk of progression to diabetes in 1 year was 80% in those with TA140 >10%; in contrast, it was only 5% in the other participants. Performance of prediction by receiver operating curve analyses showed area under the curve of ≥0.89 for both individual and combined CGM metric models. CONCLUSIONS TA140 >10% is associated with a high risk of progression to clinical diabetes within the next year in autoantibody-positive children. CGM should be included in the ongoing monitoring of high-risk children and could be used as potential entry criterion for prevention trials.

Viral infections may trigger islet autoimmunity leading to type 1 diabetes (T1D) . We hypothesized SARS-CoV-2 infection is associated with presence of islet autoantibodies (IAb) in children. Between 8/2020 and 12/2021, ASK screened 47general population Colorado children aged 1-17 y for IAb to GAD, insulin, IA-2 and ZnT8 as well as antibodies to SARS-CoV-2 receptor binding domain (CoV-2 RBDAb) - a sensitive and specific marker of infection. Of those, 4172 (89%) have not previously received SARS-CoV-2 vaccine. During the study period, prevalence of CoV-2 RBDAb increased in unvaccinated from 1% to 58% and up to 100% among vaccinated. Among all children, the prevalence increased from 1% to 72% - an estimate of herd immunity (Figure) . Among the unvaccinated, prevalence of multiple or single high-affinity IAb did not differ between children positive vs. negative for CoV-2 RBDAb, respectively 1.23% (16/1297) vs. 1.00% (29/2875) , p=0.52. In multivariate logistic regression, presence of IAb was not associated with presence of CoV-2 RBDAb (OR=1.40, p=0.31) , adjusting for age, sex, race/ethnicity, and family history of T1D. While we found no association between past SARS-CoV-2 infection and islet autoimmunity, a confirmation in a larger population is warranted. Longer follow-up will help assess whether SARS-CoV2 infection accelerates progression from islet autoimmunity to diabetes. Disclosure C.Geno rasmussen: None. X.Jia: None. H.Shorrosh: None. L.Yu: None. B.I.Frohnert: Advisory Panel; Provention Bio, Inc. K.M.Simmons: Advisory Panel; Provention Bio, Inc., Consultant; Dexcom, Inc. A.Steck: None. L.Pyle: None. M.Rewers: Consultant; Janssen Research & Development, LLC, Medscape, Provention Bio, Inc., Research Support; Dexcom, Inc., JDRF, Roche Diagnostics USA. Funding JDRF 2-SRA-2021-1065-M-N

There is need for a single assay able to quantify the most biologically active metabolite, 1α,25-dihydroxy-vitamin-D3, and the recently discovered biologically distinct C3-epimers of 25OHD, in addition to traditional vitamin D metabolites. We developed a method of chromatographic separation and absolute quantification of the following ten forms of vitamin D: 3-epi-25OHD3, 25OHD3, 3-epi-25OHD2, 25OHD2, 1α,25(OH)(2)D3, 24R,25(OH)(2)D3, 23R,25(OH)(2)D3, 1α,25(OH)(2)D2, D3, and D2 by single extraction and injection. Chemical derivatization followed by liquid chromatography using a charged surface hybrid C18 column and subsequent tandem mass spectrometry was utilized to detect and quantify each metabolite. This method is remarkable as a cooled column was required to achieve chromatographic resolution of epimers. Validation of each metabolite was performed at four concentrations and revealed inter- and intraday precision and accuracy below 15% across three consecutive days of analysis. After validation, this method was applied to analyze the blood plasma from 739 samples from 352 subjects (8mo to 20yr), 79 pooled plasma samples, and 10 NIST SRM972a samples. Healthy control samples (n =357) were used to investigate developmentally associated changes in vitamin D metabolite concentrations during early life. This method yields excellent linearity (R(2) ≥0.99) across concentrations encompassing the biological range of many metabolites including 1α,25(OH)(2)D3. Concentrations of 25OHD2 and 24R,25(OH)(2)D3 were significantly (q ≤0.05) lower in infants compared to both children and adolescents. The percentage of 3-epi-25OHD3 in total 25OHD3 was significantly lower (q ≥0.009) in post-puberty subjects. Here we present a single assay capable of separating and quantifying ten vitamin D metabolites including C3-epimers of 25OHD, and quantifying 1α,25-dihydroxy-vitamin-D3 at and below concentrations observed in human plasma (LLOQ

DNA methylation may be involved in development of type 1 diabetes (T1D), but previous epigenome-wide 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.