Objective: We investigated islet autoimmunity (IA) incidence trends among Colorado children born 1993-2010 in DAISY and TEDDY and whether HLA genotype or early-life environmental exposures contributed to observed increases. Research Design and Methods: We analyzed the risk of IA among 2,734 Colorado children representing three birth cohorts (BC): BC1 (1993-1998), BC2 (1999-Aug.2004), BC3 (Sept.2004-2010). Cox models evaluated IA by BC, with time-varying coefficients, BC-HLA interaction, and stratification by type 1 diabetes family history. Mediation analyses examined age at gluten introduction, weight-for-age Z-score, and maternal smoking. Results: IA increased across BC1-BC3 (7.0%, 10.7%, 12.7%). At age one, moderate-risk HLA participants in BC2 and BC3 had, respectively, 2.57 and 6.19 times the IA risk of BC1. By age five, effects attenuated. No selected environmental exposures mediated the increased incidence. Conclusions: IA increased among Colorado children born 1993-2010, with strongest effects among moderate-risk HLA genotypes in later birth cohorts.

Introduction and Objective: Type 1 diabetes (T1D) increases the risk of depression. Pregnancy can be a particularly stressful time for women with T1D, but little is known about pregnancy-related psychosocial health in this population. We report on the prevalence of depressive symptoms and diabetes distress measured by validated surveys among pregnant and postpartum women participating in a prenatal cohort study of islet autoimmunity in children who have a first-degree relative with T1D. Methods: Women were evaluated once per trimester and again at 4-6 weeks postpartum at four U.S. centers. At each visit, women completed the Patient Health Questionnaire-8 (PHQ-8) and the Type 1 Diabetes Distress Survey (T1DDS). Scores of >5 on the PHQ-8 and ≥ 2.0 on the T1DDS were considered elevated for depressive and distressed symptoms, respectively. Results: A total of 213 women with T1D and 36 women without diabetes were enrolled. The mean age was 33 ± 3 years for women with T1D and 31 ± 4 years for women without diabetes (p>0.05). Women with T1D were 3.5 times more likely to have elevated depression scores than women without diabetes (95% CI 1.2-10.0, p=0.02). The prevalence of elevated diabetes distress was 19% in the 1st trimester, 12% in the 2nd trimester, 14% in the 3rd trimester, and 9% post-partum. Women with T1D who had elevated depressive symptoms during pregnancy were 6.9 times more likely to also report elevated T1DDS than women without elevated depression symptoms (95% CI 3.3 - 14.1, p<0.001). Hemoglobin A1c values (HbA1c) were similar during pregnancy in women with vs without depression, but were significantly higher at all time points during pregnancy in women with vs. without elevated diabetes distress (difference 0.25 ± 0.10%, p=0.01). Conclusion: In this study, women with T1D had a more than 3-fold increased prevalence of depressive symptoms during the perinatal and postpartum periods compared with women without diabetes. Moderate or greater diabetes distress during pregnancy affects nearly 1 in 5 women with T1D and is associated with higher gestational glycemia. Disclosure F. Dong: None. K. Valdez: None. C. Chartier-Logan: None. S. Polsky: Research Support; Current; Leona M. and Harry B. Helmsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases, JDRF, University of Colorado. Other - honoraria for speaking engagements; Current; Children's Diabetes Foundation. Other - honororia for speaking engagements; Current; American Diabetes Association. Board Member; Current; American College of Diabetology. Other - unpaid work to write articles for online publication; Ended; diaTribe. Research Support; Ended; Dexcom, Inc. Other - travel and lodging expenses paid for a meeting; Ended; Insulet Corporation. Other - honororia for speaking engagements; Current; AACE. C. Levy: Research Support; Current; Tandem Diabetes Care, Inc., Novo Nordisk, Abbott Diabetes, MannKind Corporation. Consultant; Current; MannKind Corporation, Tandem Diabetes Care, Inc. Research Support; Current; Deka/Sequel, Dexcom, Inc., Genti Bio. Consultant; Current; Deka/Sequel. F. Brown: Research Support; Ended; Dexcom, Inc. Other - Royalties for authorship; Current; UpToDate. E. Isganaitis: None. S. Kim: None. E. Buschur: None. J. Snell-Bergeon: None.

Background Type 1 diabetes is believed to be associated with early genetic and environmental stressors. Epigenetic age acceleration (EAA) is also associated with environmental stressors and the pathogenesis of many chronic diseases. This study explored longitudinal changes in EAA among individuals at high risk for type 1 diabetes.Methods DNA methylation was measured longitudinally in subjects from the Diabetes Autoimmunity Study in the Young cohort, 2547 children born 1993–2006 at high risk for type 1 diabetes. Data were collected before and after islet autoimmunity (IA) seroconversion, a preclinical type 1 diabetes stage. EAA was estimated from DNA methylation using an epigenetic clock appropriate for pediatric blood samples. A linear mixed model was used to test for differences in EAA between 85 type 1 diabetes cases and 85 controls, before and after IA seroconversion.Results Change in EAA significantly differed between cases and controls (p=0.02). EAA significantly decreased in cases, from pre-IA to post-IA seroconversion by 0.367 units (95% CI −0.64 to 0.09, p=0.01), but not in controls (0.045, 95% CI 0.23 to 0.32, p=0.75).Conclusion These results suggest that EAA occurs in children who develop type 1 diabetes prior to IA seroconversion, highlighting the potential role of early environmental stressors in disease pathogenesis.

CONTEXT:Increased levels of 25-hydroxyvitamin D (25OHD) have been protective against islet autoimmunity (IA), a preclinical type 1 diabetes (T1D) disease state. However, the role of 25OHD and downstream metabolites in progression from IA to T1D is not well understood. OBJECTIVE:We hypothesized that downstream vitamin D metabolites and metabolite ratios would be associated with progression from IA to T1D. METHODS:Among participants at high genetic risk for T1D who developed IA (n = 143) in the Diabetes Autoimmunity Study in the Young (DAISY), a T1D birth cohort study, we quantified vitamin D3, 25OHD2, 3-epi-25OHD3, 25OHD3, 24,25(OH)2D3, and 1α,25(OH)2D3 metabolites from plasma samples using LC-MS/MS. We calculated the vitamin D metabolite ratio (VMR) (ie, 24,25(OH)2D3/25OHD3) and the epimer ratio (3-epi-25OHD3/25OHD3). We also tested the correlation between metabolite levels and gene expression in a subset of participants (n = 53). RESULTS:A total of 57/143 progressed to T1D. Higher VMR (hazard ratio (HR) per 1 SD increase: 0.65; 95% CI: 0.49-0.88) and levels of 24,25(OH)2D3 (HR per 1 SD increase: 0.72; 95% CI: 0.55-0.94) at IA seroconversion were associated with a lower risk of progression to T1D, adjusting for seroconversion age, season, HLA-DR3/4 genotype, and ancestry. Functional enrichment analysis suggests higher VMR resulted in a gene expression pattern in whole blood characteristic of decreased activation of inflammatory pathways related to neutrophil infiltration. CONCLUSION:A higher VMR, a more functional measure of vitamin D status, was protective against T1D progression, perhaps by decreasing activation of inflammatory pathways.

IntroductionType 1 diabetes (T1D) is associated with increased risk of dementias and other neurodegenerative diseases. Plasma biomarkers of neurodegeneration and neuroinflammation hold utility in risk prediction and diagnosis of neurodegenerative disease and other neuropathology, but there remains a paucity of data in the T1D population. This study quantified plasma levels of biomarkers of neurodegeneration and neuroinflammation [phosphorylated tau-181 (pTau-181), total tau (Tau), amyloid beta 42/amyloid beta 40 (Aβ42/40), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL)], and tested associations with T1D and related characteristics.MethodsThis cross-sectional analysis of a subset of participants from the Coronary Artery Calcification in Type 1 Diabetes study included adults with and without T1D. Biomarker levels were quantified using Quanterix Simoa, then log-transformed and analyzed using linear regression models adjusted for age, body mass index (BMI), race and ethnicity, smoking status, and estimated glomerular filtration rate (eGFR). A subsequent sensitivity analysis included diabetic retinopathy (DR).Results136 adults with T1D (n=90, age 52 years, 58% female, average HbA1c 7.7%) and without T1D (n=46, age 53 years, 57% female, average HbA1c 5.4%) were included. In fully adjusted models, T1D was associated with higher pTau-181 [estimate (pg/mL) 1.221, (95% confidence interval 1.003, 1.486) p=0.046], GFAP [1.296 (1.129, 1.489), p<0.001], and NfL [1.355 (1.162, 1.579), p<0.001], relative to adults without T1D. In the sensitivity analysis, relative to adults without T1D, T1D with moderate/severe DR was associated with higher pTau-181 [1.330 (1.063, 1.663), p=0.013], GFAP [1.369 (1.653, 1.608), p<0.001], and NfL [1.495 (1.252, 1.786), p<0.001], and T1D with none/mild DR was associated with higher GFAP [1.228 (1.046, 1.442), p=0.013] and NfL [1.235 (1.037, 1.470), p=0.018]. As compared to T1D with none/mild DR, T1D with moderate/severe DR was associated with higher NfL [1.211 (1.011, 1.451), p=0.038]. Across both models, eGFR was inversely associated with pTau-181, NfL, and Tau (p<0.05 for all).DiscussionT1D is associated with a greater burden of plasma biomarkers of neurodegeneration and neuroinflammation, and microvascular complications such as DR and impaired kidney function may contribute to this burden. Further study is needed to fully characterize the interplay between these biomarkers and neuropathology in T1D.

Introduction and Objective: Detecting dysglycemia at early stages of T1D can prevent DKA and improve long-term outcomes. OGTT, currently recommended for monitoring progression, can be challenging in clinical care. HbA1c is not sufficiently sensitive, particularly in young children. We aimed to identify CGM metrics predicting progression to stage 3 T1D. Methods: 171 participants prospectively followed in the ASK and DAISY studies with CGM, OGTT and HbA1c were included. Bayesian joint models for longitudinal and survival outcomes tested associations between longitudinal trajectories of CGM metrics (mean glucose, SD glucose, CV glucose, TAR140) and HbA1c with time to progression to stage 3. Results: Participants were 2-45 yrs old, 43% male, 49% progressed to stage 3. All CGM metrics and HbA1c were strongly associated with time to progression (p<0.001). HbA1c had best model fit (HR 3.58 [95% CI 2.39-5.65] per SD) while CV glucose had greatest effect size (HR 4.75 [95% CI 2.72-10.70] per SD). In a combined model, HbA1c (p=0.005) and CV glucose (p<0.001) were associated with time to progression, while the HR for CV glucose remained higher than HbA1c (3.31 [1.72-8.11] vs 2.04 [1.24-3.41]). AUC was 0.67 for HbA1c alone, and 0.84 for combined HbA1c and CV glucose. The model allows individualized risk prediction over customized time intervals (Figure). Conclusion: CGM variability metrics independently predict progression to stage 3 T1D and should be integrated into standard monitoring protocols. Disclosure T. Vigers: None. L. Pyle: None. F. Dong: None. T. Fleury: None. M. Rewers: Consultant; Current; Sanofi. Advisory Panel; Current; Vertex Pharmaceuticals Incorporated. B. Frohnert: None. A. Steck: Consultant; Current; Sanofi. Funding Breakthrough T1D (SRA-2024-1603-SB, SRA-2024-1590-MB, 3-SRA-2024-1590-M-B), NIH (U01 DK106993, 5R01DK032493)

Introduction and Objective: Novel autoantibodies to extracellular epitopes of ZnT8 (ZnT8ecA) on the β-cell surface have been recently identified as the earliest detectable autoantibody in children followed from birth. This study aims to determine its prediction for T1D progression. Methods: ZnT8ecA were measured in the DAISY birth cohort participants (n=209) who were confirmed positive for at least one standard islet autoantibody (IAb), including IAA, GADA, IA-2A or ZnT8A. Sera collected at and before the appearance of the first standard IAb were tested for ZnT8ecA. The cut-off of ZnT8ecA assay was set at 99th percentile of 189 normal controls. ZnT8ecA as a predictor of progression to clinical T1D independent of standard IAb status, age, and HLA genotype were evaluated in a multivariate Cox regression model. Results: Of the 209 children studied, 131 (62.7%) tested positive for ZnT8ecA, including 86 at and 45 before the first standard IAb seroconversion. Children positive for ZnT8ecA were more likely than those negative to carry the HLA-DR3/4 genotype (41.8% vs. 20.5%, P = 0.0017) and progress to clinical T1D (62.6% vs 15.4%, P<0.0001) during the median follow-up of 15.2 years (IQR 9.3-19.4). In a multivariate regression analysis, controlling for age of ZnT8ecA seroconversion and HLA genotype, ZnT8ecA independently predicted progression to clinical T1D in children with a single standard IAb (HR=7.35; 95%CI 2.13-25.3), but not among those positive for multiple standard IAbs (HR=1.54; 0.62-3.79). Conclusion: We confirmed that ZnT8ecA often precedes the appearance of the standard IAbs. Importantly, testing for ZnT8ecA significantly improves T1D risk prediction in children positive for a single IAb and may improve the predictive value of IAb screening in young children. X. Jia: None. C. Zhang: None. F. Dong: None. K. Waugh: None. M. Rewers: Consultant; Sanofi. Research Support; Sanofi. D. Fu: Stock/Shareholder; Islex Therapeutics LLC. L. Yu: None. Breakthrough T1D (2-SRA-2023-1451-S-B); Diabetes Research Center (DRC) (P30 DK116073)

Increasing evidence shows that pathogenic T cells in type 1 diabetes (T1D) that may have evaded negative selection recognize post-translational modified (PTM) epitopes of self-antigens. We have investigated the profiles of autoantibodies specifically targeting the deamidated epitopes of insulinoma antigen-2 extracellular domain (IA-2ec) to explore their relationship with T1D development. We compared the characteristics of autoantibodies targeting the IA-2ec Q>E epitopes (PTM IA-2ecA) as well as those targeting the IA-2ec unmodified epitopes (IA-2ecA) in participants across different stages of T1D development and in individuals with other types of diabetes and other kinds of autoimmunity. In patients with new-onset T1D, the prevalence of PTM IA-2ecA (26.1%) was significantly higher than that of IA-2ecA (19.5%, P<0.0001). In a longitudinal newborn cohort, both IA-2ecAs were present, but rare in preclinical stage 1 T1D, and with much lower positivity in individuals with stage 3 T1D who had been closely followed from birth in a clinical study compared to patients diagnosed in routine clinical settings with overt symptoms. In participants with latent autoimmune diabetes in adults, type 2 diabetes, and celiac disease autoimmunity, we did not observe significant positivity of either IA-2ecAs. These results indicate that PTM and unmodified IA-2ecA are predominantly present in clinical new-onset T1D patients, at late stages of T1D development.

Context:Over half of all new cases of type 1 diabetes (T1D) are diagnosed in adults, yet the natural history of adult-onset T1D, particularly in nonfamilial populations, is not fully understood. Objective:This study measured the prevalence of islet autoantibodies (IA) in adults without known diabetes and irrespective of T1D family history from Colorado (USA). Methods:The Autoimmunity Screening for Kids study screened for IAs to insulin, glutamic acid decarboxylase (GADA), islet antigen-2, and zinc transporter 8 in 1087 adults without known diabetes [mean age 40.7 years with range 19.6-63.9 years, 63% non-Hispanic White (NHW), 10% with family history of T1D in a first-degree relative, and 78% female] from Colorado. IAs were measured using radiobinding assay and electrochemiluminescence detection methods. Results:In total, 3.86% of adults screened positive for any IA, 0.55% screened positive for multiple IAs, and 1.75% were positive for a single IA by both detection methods. Compared to NHW, those with Hispanic race/ethnicity were more likely to screen positive for a single IA (relative risk 2.32, 95% confidence interval 1.40, 3.84, P = .001), but there was no difference in the risk of screening positive for multiple IAs when comparing across race/ethnicity. GADA was the most prevalent IA, found in 2.67% of adults. Conclusion:IA prevalence was high in this sample of adults without known diabetes from Colorado. Further study is needed to fully characterize the risk of progression to clinical diabetes among adults who screen positive for IAs, particularly in nonfamilial populations.

Introduction and Objective: The use of continuous glucose monitoring (CGM) in pregnancies complicated by type 1 diabetes (T1D) has been associated with decreases in adverse gestational health outcomes. We examined the association of CGM wear time during gestation with maternal HbA1c, infant birth weight centile, and rate of large-for-gestational-age (LGA) infants. Methods: Utilizing CGM data compiled from pregnant individuals with T1D (n=148) across five studies at the Barbara Davis Center, we averaged CGM wear by trimester and across gestation. Linear mixed effect models were used to examine associations between CGM wear and maternal HbA1c and infant birth weight centile. Logistic regression was used to examine CGM wear with LGA rates. Results: Average gestational age at the 1st pregnancy visit was 6w3d (Table). The average CGM wear was 90% throughout pregnancy and the rate of LGA infants was 43.5% (Table). CGM wear in gestation was negatively associated with HbA1c, such that a 10% increase in CGM wear was associated with a 0.025% decrease in HbA1c in log scale (p<0.0001). Increased CGM wear was not associated with infant birth weight centile (p=0.21) or with rate of LGA infants (p=0.27). Conclusion: Higher CGM wear was associated with lower maternal HbA1c, but not fetal growth in this cohort. Larger studies are needed to see if dose-response relationships of CGM wear with maternal glycemia and fetal outcomes exist. M.P. Klein: None. S. Maclean: None. F. Dong: None. J.K. Snell-Bergeon: Stock/Shareholder; GlaxoSmithKline plc. S. Polsky: Research Support; Dexcom, Inc., Hemsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases, Juvenile Diabetes Research Foundation (JDRF). Consultant; Medtronic.

OBJECTIVE:Multiple studies have reported an inverse association between self-reported smoking during pregnancy and offspring type 1 diabetes (T1D) risk. We investigated the association between DNA methylation (DNAm) smoke exposure scores, parental self-reported smoking, and islet autoimmunity (IA) and T1D risk in children at high risk of T1D. RESEARCH DESIGN AND METHODS:We used longitudinal data from the Diabetes Autoimmunity Study in the Young cohort, including 205 IA case and 206 control participants (87 and 88 were T1D case and control participants, respectively), matched by age, race/ethnicity, and sample availability. DNAm profiles were obtained from cord or peripheral blood using the Infinium Human Methylation 450K or EPIC BeadChip. Three published DNAm smoking scores were calculated at every time point. To estimate in utero smoke exposure, participant-specific intercepts were derived from mixed-effects models of longitudinal DNAm scores. These intercepts strongly correlated with cord blood scores (r = 0.85-0.95; n = 179), indicating their utility as proxies for in utero smoke exposure. Associations with IA/T1D were evaluated using logistic regression, adjusting for HLA-DR3/4, first-degree relative status, and sex. RESULTS:Multivariable models showed both maternally reported smoking during pregnancy and higher DNAm smoking scores to be associated with lower risk of IA and T1D. Maternal smoking showed a strong inverse association with IA (odds ratio [OR] 0.24; 95% CI 0.10-0.54). Rauschert and McCartney DNAm scores showed consistent inverse associations with both outcomes (OR 0.65-0.83 for SD increase). CONCLUSIONS:Our study supports existing literature indicating in utero smoke exposure is associated with reduced IA and T1D risk. Further research is essential to uncover the underlying mechanisms.