CONTEXT:Youth-onset type 2 diabetes (T2D) is characterized by accelerated β-cell decline and early treatment failure, and there is an urgent need to improve the understanding of molecular drivers of loss of glycemic control (LOGC). OBJECTIVE:To identify multiprotein signatures associated with loss of glycemic control (LOGC) in youth-onset T2D. DESIGN:Longitudinal observational study with a mean follow-up of 10.8 ± 3.8 years using data from the TODAY study, with external validation in three youth cohorts and one adult-onset T2D cohort. SETTING:Multicenter clinical research study. PARTICIPANTS:Participants from the TODAY study (N = 374; age 14 ± 2 years; 37% male), of whom 72% experienced LOGC over 10.8 ± 3.8 years. INTERVENTIONS:None. MAIN OUTCOME MEASURE:LOGC, defined as HbA1c ≥ 8% for ≥6 months or inability to discontinue insulin after acute metabolic decompensation. RESULTS:Plasma proteomics quantified 7604 aptamers representing 6596 proteins using the SomaScan 7 K platform. Sixty-seven proteins were associated with LOGC after false discovery rate correction and multivariable adjustment. Key proteins included plexin-B2 (HR: 1.46 [95% CI: 1.29-1.66]) and semaphorin-6A (HR: 1.31 [1.18-1.47]), which were also associated with glycemic outcomes in independent youth and adult cohorts. Enrichment analyses implicated pathways related to axon guidance, immune response, inflammation, and metabolism. CONCLUSIONS:Novel proteins involved in axon guidance, immune response, inflammation, and metabolism associated with LOGC in youth-onset T2D with proteins demonstrating consistent associations across the lifespan and proteomic platforms.

Introduction and Objective: Advanced cystic fibrosis transmembrane conductance regulator (CFTR) modulators such as elexacaftor-tezacaftor-ivacaftor (ETI) have transformed outcomes in people with CF (pwCF). Their effect on the natural history of glucose intolerance remains unclear. We evaluated longitudinal changes in insulin secretion and sensitivity by leveraging 3-hr frequently sampled oral glucose tolerance tests (fsOGTT) collected across two studies in pwCF (GEM-CF and EnVision-GT, 2016-2023). Methods: We conducted a secondary retrospective analysis of fsOGTTs including glucose and insulin. Longitudinal changes in insulin secretion were compared pre- vs post-ETI initiation with the following estimates: insulinogenic index (IGI), insulin:glucose incremental area under the curve (iAUC) within 30 min (iAUC30) and 180 min (iAUC180). Matsuda index was used to estimate insulin sensitivity and was used derive the oral disposition index (oDI). Analysis used mixed-effects models to account for within-participant correlation of repeat measures. Results: 13 participants had ≥2 fsOGTTs pre-ETI and at least ≥1 fsOGTT post-ETI. Median age=10.8 years (IQR 7.4-14.5), 47% female. Median time between first and last fsOGTT=3.16 years (IQR 2.99-3.76). The rates of change for IGI and oDI pre vs post-ETI were not significantly different (Table). Conclusion: In our small sample of pwCF, we did not find significant differences in insulin secretion or oDI change before vs after ETI initiation. Disclosure M. Maher: None. T. Vigers: None. A. Moheet: None. A. Granados: None. K. Larson Ode: None. C.L. Chan: None. Funding Cystic Fibrosis Foundation (CHAN16GE0, LARSON18A0, MAHER24B0), Colorado REDCap NIH support (UL1 TR002535)

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)

BACKGROUND: Routine surveillance cultures are critical in the care of patients with cystic fibrosis (CF) and are used in clinical decision-making. Due to the improved health of people with CF (pwCF) and the increased use of telehealth for clinical care, there is a strong interest in providing remote care, including remote respiratory specimen collection. RESEARCH QUESTION: Are self-obtained respiratory samples feasible and acceptable for pwCF and are the results comparable with clinic-obtained samples (COSs)? STUDY DESIGN AND METHODS: pwCF $ 1 year of age were enrolled at 6 CF centers (4 pediatric and 2 adult). Two oropharyngeal samples were obtained (order randomized): 1 COS per each CF center's practice and 1 self-obtained sample (SOS) after standardized education. The SOS was randomized to immediate vs delayed processing, for transport mimicry. Cohen kappa was used to assess agreement between sample types. Surveys were completed to determine feasibility and acceptability. RESULTS: A total of 164 pwCF were enrolled. Self-collection was feasible (99% successful SOSs) and acceptable with 88% rating the collection as very easy or easy and 100% being willing to collect another sample if clinically recommended. The overall agreement between COSs and SOSs for any CF pathogen detection was 78.7% (kappa, 0.583; 95% CI, 0.432-0.734), suggesting moderate agreement. Agreement for methicillin-susceptible Staphylococcus aureus detection was 87.9% (kappa, 0.748; 95% CI, 0.594-0.902), suggesting substantial agreement. Statistical analyses were not completed for other bacterial organisms due to low detection. Order of sample collection, time to processing, participant age, or collection by self or parent/guardian did not impact agreement. INTERPRETATION: Our results indicate that self-collection is feasible and acceptable for pwCF. Agreement between sample types suggest that self-collection may offer an alternate option for microbiology surveillance.

Background Long-acting reversible contraception (LARC) devices, including the levonorgestrel IUD and etonogestrel implant, are safe and effective contraceptive and menstrual management options for adolescents and young adults (AYA). Little is known regarding the LARC experience of AYA with polycystic ovary syndrome (PCOS). Methods The Clinical Adolescent Polycystic Ovary (CALICO) database is a retrospective, national, multi-center longitudinal data set of adolescents diagnosed with PCOS per 2023 international guidelines. Individuals were defined as “ever users” of LARC if they underwent placement of an implant or levonorgestrel IUD following PCOS diagnosis. Those never using a LARC device were used as a comparator cohort. Univariate comparisons were performed using t-tests for continuous variables and Pearson's Chi-squared test for categorical variables. For each continuous outcome, we fit a linear mixed effects model with random effects for participant and time, and an interaction effect between time and LARC status. To evaluate the effect of starting LARC on each outcome, we also fit a linear spline model with a single knot at LARC start. If models did not converge, only the random effect for participant was included. Results Among the 857 AYA with PCOS included in this analysis, 42 were ever-LARC users. Ever- and never-LARC users with PCOS were similar in terms of age at diagnosis, race, gender identity, insurance status, and sexual activity (Table). Patients self-reporting Hispanic ethnicity were less likely to use LARC (p=0.01). AYA with PCOS who never used LARC gained an average 0.11kg more per month following their PCOS diagnosis compared to ever-users of LARC (p=0.007). Weight gain over time changed after LARC insertion. On average, LARC users gained 2.3kg per year prior to LARC insertion and 0.7kg per year thereafter (p=0.05). No differences in changes in hemoglobin, lipid parameters (HDL, LDL), or blood pressure over time were seen between ever- and never-users of LARC (p>0.05 for all). Conclusions LARC provides excellent menstrual management and contraception for AYA, including those with PCOS. Our findings suggest that weight gain following LARC insertion in patients with PCOS may be lower on average than in those who never use LARC. No negative impact on measured metabolic parameters was observed. Further analyses will evaluate differences in bleeding profile, glucose control, and quality of life between LARC users and non-users.

Disclosure: C.M. Burt Solorzano: None. H. Vanden Brink: None. T. Vigers: None. G. Carey: None. M. Garant: None. A.B. Sopher: None. R. Shah: None. C. Branstetter: None. A. Coren: None. L.C. Torchen: None. J. Snell-Bergeon: None. D.H. Geller: None. M.G. Cree: None. T. CALICO Consortium: None. Introduction: PCOS is a prevalent endocrinopathy characterized by anovulation and hyperandrogenism in adolescence with increased risk of comorbidities, such as insulin resistance, Type-2 Diabetes, and Metabolic Dysfunction–Associated Steatotic Liver Disease. Estrogen-containing contraceptives (EC) and metformin are recommended therapies for PCOS, but their metabolic impact in youth is unclear. This longitudinal analysis studied the effect of EC and metformin on adolescent PCOS metabolic outcomes.Methods: Participant data (n=899) was extracted from the CALICO Database, which represents 17 US sites of adolescents with PCOS diagnosed using the 2018 international guidelines. Participants taking weight loss, continuous progesterone-only, or atypical antipsychotic medications were excluded. Outcomes were High Density Lipoprotein (HDL), Triglycerides (TG), alanine aminotransferase (ALT), HbA1c, and Systolic Blood Pressure (SBP). Linear mixed effects models evaluated the differences in metabolic outcomes over time between Ever EC Users (pill, patch, or ring, n=458) vs Never EC Users (n=441) and Ever Metformin Users (n=503) vs Never Metformin Users (n=396). All models were adjusted for age, race, and insurance status. EC models were adjusted for metformin use, and vice versa. Full models were adjusted for baseline weight; secondary models were conducted by weight subgroup (BMI 5-84%, BMI 85-94%, BMI ≥95%). Analyses were performed using R version 4.4.2. Results: No differences in trajectory of HbA1c, ALT, or SBP were observed between EC users vs non-users (p>0.05). EC users experienced greater increase in HDL over time versus non-users (0.05 [-0.03, 0.13] mg/dL/month vs -0.04 [-0.11, 0.04] mg/dL/month, P=0.03). For metformin-users vs non-users, no differences in trajectory of HbA1c, ALT, SBP, or HDL were observed (P>0.05). Metformin use was associated with a greater increase in TG over time versus non-users (0.68 [0.08, 1.28] vs 0.08 [-0.45, 0.60], P=0.03). When evaluating data by BMI category, HDL increased more slowly over time in metformin users with a BMI 85-94% versus non-users (0.35 [-0.16, 0.86] vs 0.61 [0.09, 1.12] mg/dL/month, P=0.01]). HDL also increased over time in EC users with BMI ≥ 95% versus non-users (0.11 [0.02, 0.19] vs 0.01 [-0.02, 0.19] mg/dL/month, P=0.025). Individuals with BMI 5-84% showed no differences in metabolic outcomes in medication users vs non-users.Conclusions: EC and metformin use were associated with different lipid trajectories among adolescents with PCOS, which varied by BMI. Use of estrogen-containing medications may be beneficial in adolescents for PCOS to increase HDL, particularly among adolescents with obesity. Any use of metformin or ECs did not significantly affect the trajectory of glycemic control, liver function, or blood pressure outcome measures when compared to never users, even in those with elevated BMI. Presentation: Monday, July 14, 2025

Background Psychological vulnerability is a significant but under-explored comorbidity of polycystic ovary syndrome (PCOS). A recent meta-analysis of adolescents and young adults with PCOS found increased rates of depressive and anxiety symptoms. Other data has demonstrated heightened body image dissatisfaction, disordered eating, and bulimic risk. The study objective was to assess the prevalence of mental health disorders in an ethnically diverse, nationally representative sample of adolescents with PCOS. Methods The Clinical Adolescent Polycystic Ovary (CALICO) Database includes data from adolescents with PCOS per 2023 international guidelines from 15 US sites. The main study outcomes were the prevalence of mental health disorders (anxiety, depression, binge or restrictive eating disorders, and ADHD) documented at the time of diagnostic visit for PCOS. Prevalence data was compared to the national prevalence of each mental health disorder respectively. Descriptive statistics included medians (interquartile range, IQR) and counts (percentages). Results Among 787 individuals included in the current analyses, median age at PCOS diagnosis was 15.3 years (IQR, 14.2, 16.4), median BMI was 33.6 (IQR, 28.2, 38.8) and median BMI percentile was 98.3 (IQR 95.4, 99.2). 65.7% were Caucasian, 34.6% Hispanic, 20.5% African American, 3.5% Asian, and 10.3% other race. 50.3% had public insurance. Depression screening with a standardized tool was documented in 30 (3.8%) of patients at the PCOS diagnostic visit. At the time of the PCOS diagnostic visit, 16% had a prior diagnosis of anxiety, 19% depression, 0.8% binge eating disorder, 0.2% restrictive eating disorder, and 6.8% ADHD. These rates of mental health disorders were lower than national prevalences for each condition (e.g. anxiety 32%, depression 29%, binge eating disorder 1.6%, restrictive eating disorder 0.3%, and ADHD 9%). Ninety-nine (12.6%) patients were reported as currently receiving anti-depressants or anti-anxiety medication, with 30 (3.8%) receiving ADHD medication. Conclusions In this nationally representative sample of adolescents with PCOS, we found lower rates of mental health disorders than in the general population. Given prior data demonstrating higher rates of psychological burden in this population, patients are likely being under-diagnosed prior to PCOS diagnosis, and a minority received standardized screening at diagnostic visit. Our findings underscore the need for a full mental health evaluation at the time of PCOS diagnosis. A recommended standardized screening protocol for this population would likely benefit clinical care.

RATIONALE:The introduction of elexacaftor/tezacaftor/ivacaftor (ETI), a highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, to younger ages and the COVID-19 pandemic have significantly reduced pulmonary exacerbations requiring hospitalization among children with CF. OBJECTIVE:To assess demographic and clinical characteristics of children and young adults with CF hospitalized for pulmonary exacerbations before and after pediatric ETI approval. METHODS:A retrospective chart review was conducted at five United States CF Foundation-accredited care centers. Hospitalization data from children and young adults with CF in 2018 and 2022 were analyzed. RESULTS:Hospitalizations decreased from 471 cases (241 individuals) in 2018 to 163 cases (110 individuals) in 2022. The racial distribution shifted, with more hospitalized patients identifying as people of color in 2022 (28% vs. 14%; p = 0.018). A greater proportion of hospitalized children in 2022 had two non-F508del mutations compared with children hospitalized in 2018 (38% vs. 19%) and were less likely to be infected with methicillin-resistant Staphylococcus aureus (MRSA). Comparing 2022-2018, children on CFTR modulator therapy, including ETI (76%), showed reduced infections with Pseudomonas aeruginosa and Achromobacter xylosoxidans. CONCLUSIONS:The decline in hospitalizations for pulmonary exacerbations likely reflects the benefits of ETI therapy, as a higher proportion of children and young adults hospitalized in 2022 had two non-F508del mutations and were not eligible for ETI. A greater percentage of those hospitalized in 2022 identified as belonging to minority racial groups, highlighting ongoing health disparities in the ETI era. Additionally, there were notable changes in the microbiological characteristics between 2018 and 2022.

RATIONAL:Remote health-monitoring technologies such as cough monitors can track longitudinal changes in health status in children with cystic fibrosis (cwCF). We assessed the feasibility of a bedside cough monitor and hypothesized that cwCF would have a higher baseline cough frequency compared to healthy controls (HC), which would increase during pulmonary exacerbations (PEx). METHODS:Cough monitors capturing continuous audio data during pre-set sleep times were provided for 3 months. Data were analyzed over 3 s intervals using a proprietary algorithm (CurieAi, Santa Clara, CA) to identify cough events. Multivariable modeling was used to compare baseline cough frequency (coughs per night) between cwCF and HC. RESULTS:We enrolled 40 children (20 cwCF and 20 HC; median [range] age 11 years [2-18]) between February and August 2024. Most participants were White, 3 (7.5%) identified as Hispanic and/or Latino. CwCF were all treated with elexacaftor/tezacaftor/ivacaftor (ETI); baseline median (range) ppFEV1 was 107% (86%-124%). Data were captured over 82% of nights in the study period (median of 75.5 nights per participant, range 4-106). CwCF were more likely to cough at least once during the night compared to HC (IRR = 0.279, p = 0.02), and cough at a higher, albeit non-statistically significant rate (IRR = 1.805, p = 0.082). We could not determine whether cough frequency changed during PEx due to limited data collection surrounding reported PEx. CONCLUSIONS:A passive cough monitor detected nighttime cough in cwCF and HC. CwCF with preserved lung function have more nights with cough than HC despite being on elexacator/tezacaftor/ivacaftor (ETI).

OBJECTIVE:A number of disease-modifying therapies have been introduced for people with cystic fibrosis (CF) over the past two decades. The cumulative effects of this changing landscape on cystic fibrosis-related diabetes (CFRD) are unclear. We examined trends in CFRD epidemiology over time using data from the U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR). RESEARCH DESIGN AND METHODS:CFFPR data from 2003 to 2018 were queried to determine annual screening, incidence, and prevalence rates of CFRD. Individuals with incident CFRD were compared with individuals without CFRD. Survival analyses were performed to estimate the cumulative hazard of CFRD given predictors of interest over the 15 years of study. Data were also grouped into three time periods (2003-2008, 2009-2013, and 2014-2018) to investigate whether the hazard of developing CFRD varied over time. RESULTS:CFRD screening rates increased from 2003 to 2018, particularly in 10- to 18-year-olds. Although screening rates increased in adults, overall rates remained low. In 10- to 18-year-olds, the incidence of CFRD was stable over time, while incident cases in adults steadily decreased, approaching incident rates in adolescents. Despite this, the prevalence of CFRD has gradually increased in adults, likely reflecting increased longevity. Age, female sex, Black race, severe mutation class, liver disease, poorer lung function, pancreatic insufficiency, enteric feeds, and low and high BMI were all risk factors associated with CFRD. CONCLUSIONS:Findings support the need for the development of tailored CFRD screening algorithms and increased subspecialists to care for a growing population of adults with CF and CF-associated comorbidities.

Disclosure: Z.V. Hurt: None. T. Vigers: None. A. Granados: None. A. Moheet: None. K. Larson Ode: None. C.L. Chan: None. Continuous glucose monitoring (CGM) is increasingly used in cystic fibrosis (CF) to aid cystic fibrosis related diabetes (CFRD) screening and clinical decision making. However, evidence based data to guide interpretation of CGM findings in this population are limited. A recent paper (Scully et al, JCEM, 2022) proposed CGM cutoffs of >17.5% time spent >140 mg/dL and >3.4% time >180 mg/dL for diagnosis of CFRD, finding them highly sensitive (87%, 90%) and specific (95% for both). We aimed to examine these thresholds in an independent cohort derived from the EnVision Multicenter Glucose Tolerance (EnVision-MGT) study (NCT: 03650712). EnVision-MGT is a 4 site multicenter study that enrolled people with CF ≥6 years from 2019-2023, without known diabetes. All participants underwent oral glucose tolerance testing (OGTT). CGM data was collected in a subset of participants. In this study, we included participants who had both CGM and OGTT results available. We then dichotomized participants by the CGM cutoffs proposed by Scully et al and compared OGTT results and hemoglobin A1c levels (HbA1c). Descriptive statistics were applied. Fischer’s exact and Wilcoxon rank sum tests were used to compare groups, and p<0.05 was considered significant. Continuous data are presented as median (IQR) and categorical data by N or percent. Data were available in 134 unique CF participants: 50% male, age = 17 [13,27] years. Based on fasting (FPG), 1 hour (1hG) and 2 hour (2hG) OGTT glucoses, 29% had normal glucose tolerance (NGT), 5.2% had impaired fasting glucose (IFG), 16% had indeterminant glucose tolerance (INDET), 49% had impaired glucose tolerance (IGT), and 0% had CFRD. Grouped by CGM time spent >140mg/dL, 12/134 (9%) participants had >17.5% time >140. Of these, 1=NGT, 1=INDET, and 10=IGT. Compared to those with <17.5% time spent >140 mg/dL, HbA1c was higher (5.7% (5.5, 6.3) vs. 5.5% (5.3, 5.7), p=0.008), FPG did not differ, 1hG was higher (245mg/dL (213, 273) vs 188mg/dL (154, 224), p=0.002), and 2hG was higher (184mg/dL (152, 230) vs 134mg/dL (101, 167), p=0.002). Grouped by CGM time spent >180mg/dL, 22/134 (16%) had >3.4% time >180 mg/dL. Of these, 4 (18%) had NGT, 4 (18%) had INDET and 14 (64%) had IGT. Compared to those with <3.4% time spent >180 mg/dL, HbA1c was higher (5.7% (5.4, 6.2) vs 5.5% (5.3, 5.7), p=0.029), and 1hG was higher (218mg/dL (190, 273) vs 187mg/dL (155, 224), p=0.011). There were no differences by FPG, and 2hG were not different (163mg/dL (110, 220) vs. 134mg/dL (103, 166), p=0.050). Nine and 16% of 134 people with CF without CFRD by OGTT criteria were classified as CFRD by Scully criteria, giving a specificity of 91 and 84%. These thresholds identified individuals with higher HbA1c, 1hG and/or 2hG on OGTT. However, CGM has not yet been linked to CF outcomes. Thus, prospective, longitudinal studies are still needed to determine whether CGM predicts clinical outcomes as well as, or better than, OGTT in people with CF. Presentation: Monday, July 14, 2025

INTRODUCTION:Evaluation for respiratory pathogens is a key component of cystic fibrosis (CF) care but is often lacking during remote visits. We aimed to address the impact of shipping and home collection of respiratory samples on CF pathogen identification and the feasibility of home collection in children with CF. METHODS:Participants were enrolled during a routine well clinic visit. Three respiratory samples (clinic obtained with immediate processing per CF center guidelines, clinic obtained with delayed processing, and a home sample obtained within 1 week of clinic visit) were collected and concordance between CF pathogens was evaluated using Fleiss' Kappa comparisons. Survey to assess feasibility and acceptability was completed, and descriptive statistics were used to report results. RESULTS:Fifty children were enrolled, and home samples were returned by 46 (92%). Fleiss' Kappa value for methicillin-susceptible Staphylococcus aureus was 0.676, suggesting substantial agreement. No significant differences were seen in pathogen detection between immediately processed (gold standard) and delayed processed or home collected samples. Home collection was acceptable based on participant survey responses related to ease of collection and shipping, and willingness to repeat a home collection. No significant barriers to collection or shipping were identified. CONCLUSION:Good concordance between CF pathogens identified on culture between the three sample types and good accuracy between pairwise comparisons were observed in children with CF. Home collection of respiratory samples for culture in children with CF was feasible and acceptable based on high sample return rate and survey responses.

Background Elexacaftor/tezacaftor/ivacaftor (ETI) has been highly effective for improving pulmonary disease and nutritional outcomes. However, the effect of this therapy on glycemic control in people with cystic fibrosis related diabetes (CFRD) is unclear. This study aimed to examine real-world effects of ETI on glycemia as captured by hemoglobin A1c (HbA1c) in people with pre-existing CFRD. Methods Retrospective chart review was performed at 4 US CF centers. Individuals with CFRD included in the study started ETI before December 2020, and had an HbA1c within 1 year before and up to 2 years after ETI initiation. A sub-analysis comparing CGM data and insulin dosing within the year before and after ETI was performed. Summary statistics were calculated and within-subject results compared. Results A total 175 individuals with CFRD had HbA1c data before and after ETI. Mean (±SD) age was 32.4 (±12.4) years, 49.1 % female. HbA1c were compared a median (IQR) of -40 (-93, 0) days before and 290 (107, 441) days after ETI initiation. Median (IQR) HbA1c decreased from 6.4 % (5.8, 7.2) to 6.0 % (5.5, 6.8), p<0.001. A subgroup of 13 individuals had CGM and basal insulin data for comparison. No changes were observed in CGM metrics, however, basal insulin dose in these patients decreased (p=0.03). Conclusion Findings suggest clinical improvements in glycemia following ETI initiation in people with CFRD. Further studies are required to better understand the mechanisms by which ETI may modulate insulin and glucose dynamics in individuals with existing CFRD.

Background Adolescents with polycystic ovary syndrome (PCOS) are a heterogeneous population with variable phenotypes. We describe the clinical and biochemical characteristics of a regionally and racially diverse cohort of adolescents, at the time of PCOS diagnosis, in the United States. Methods These data derive from the retrospective Clinical Adolescent Polycystic Ovary (CALICO) Database, including data from 15 U.S. sites of adolescents diagnosed with PCOS per 2023 international guidelines. Data from the initial PCOS diagnostic encounter were included. Sample size differs with each variable due to documentation and clinical practice differences across sites. To harmonize differences in hormonal assays, these variables are reported as the percentage of the upper limit of normal (%ULN) for each assay. Data were divided by overweight/obesity status (BMI >85%ile). Continuous variables were compared using linear model ANOVA or t-tests and categorical variables were compared using Pearson's Chi-squared test. Results This cohort includes 839 youth from across the U.S. (34.1% from the Southeast, 25.7% from the Midwest, 21% from the West, 16.2% from the Northeast, and 3% from the Southwest) who were of diverse race/ethnicity (65.5% Caucasian, 20.4% Black, 34.5% Hispanic). The median age of menarche was 11.5 years (IQR, 11, 12.5) and median age of PCOS diagnosis was 15.3 years (IQR, 14.2, 16.4). Menstrual patterns included primary amenorrhea in 9.3%, < 21 days between periods in 5.0%, and >45 days between periods in 85.6% of individuals. Hirsutism severity was documented in 48.7% of encounters with 34.4% reporting no hirsutism and 8.3% reporting severe hirsutism. Facial acne severity was documented in 65.4% of encounters with 26.2% reporting mild acne and 6.6% reporting severe acne. Biochemical markers including free and total testosterone, DHEA-S, FSH and LH were assessed in >60% of encounters at time of diagnosis. When stratified by overweight/obese status, those with overweight/obesity had significantly higher free testosterone but lower SHBG, androstenedione and LH. There were no significant differences by weight status in total testosterone, DHEA-S, FSH or AMH (Table 1). Conclusions In this study, we characterize the presentation of adolescents at time of PCOS diagnosis in the U.S. with data collected from a geographically, ethnically and racially diverse cohort of individuals. Weight status significantly impacted the levels of some biochemical markers used in the diagnostic evaluation of PCOS.

BACKGROUND In type 1 diabetes (T1D), impaired insulin sensitivity may contribute to the development of diabetic kidney disease (DKD) through alterations in kidney oxidative metabolism.METHODS Young adults with T1D (n = 30) and healthy controls (HCs) (n = 20) underwent hyperinsulinemic-euglycemic clamp studies, MRI, 11C-acetate PET, kidney biopsies, single-cell RNA-Seq, and spatial metabolomics to assess this relationship.RESULTS Participants with T1D had significantly higher glomerular basement membrane (GBM) thickness compared with HCs. T1D participants exhibited lower insulin sensitivity and cortical oxidative metabolism, correlating with higher insulin sensitivity. Proximal tubular transcripts of TCA cycle and oxidative phosphorylation enzymes were lower in T1D. Spatial metabolomics showed reductions in tubular TCA cycle intermediates, indicating mitochondrial dysfunction. The Slingshot algorithm identified a lineage of proximal tubular cells progressing from stable to adaptive/maladaptive subtypes, using pseudotime trajectory analysis, which computationally orders cells along a continuum of states. This analysis revealed distinct distribution patterns between T1D and HCs, with attenuated oxidative metabolism in T1D attributed to a greater proportion of adaptive/maladaptive subtypes with low expression of TCA cycle and oxidative phosphorylation transcripts. Pseudotime progression associated with higher HbA1c, BMI, and GBM, and lower insulin sensitivity and cortical oxidative metabolism.CONCLUSION These early structural and metabolic changes in T1D kidneys may precede clinical DKD.TRIAL REGISTRATION ClinicalTrials.gov NCT04074668.FUNDING University of Michigan O’Brien Kidney Translational Core Center grant (P30 DK081943); CROCODILE studies by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (P30 DK116073), Juvenile Diabetes Research Foundation (JDRF) (2-SRA-2019-845-S-B), Boettcher Foundation, Intramural Research Program at NIDDK and Centers for Disease Control and Prevention (CKD Initiative) under Inter-Agency Agreement #21FED2100157DPG.

AIM:Type 1 diabetes (T1D) increases the risk of morbidity and mortality from cardiovascular disease, and insufficient sleep is prevalent. Emerging evidence suggests a link between sleep and cardiometabolic health, but this has not been examined across the lifespan in individuals with T1D. We aimed to examine associations between sleep and cardiometabolic health in adolescents and adults with T1D in a secondary analysis of data from a 4-week double-blind, random-order, placebo-controlled crossover trial of bromocriptine quick release (BCQR) therapy with a 4-week washout in between conditions. MATERIALS AND METHODS:Forty-two adults (19-60 years) and 42 adolescents (12-18 years) with T1D >9 months completed 1 week of home monitoring with wrist-worn actigraphy to estimate sleep duration and continuous glucose monitoring, anthropometrics, arterial stiffness, magnetic resonance imaging (adolescents only), and fasting laboratory testing at each treatment phase. RESULTS:Sixty-two per cent of adolescents and 74% of adults obtained <7 h of sleep per night at baseline. After adjustment for age, sex and diabetes duration, baseline sleep <7 h per night was associated with a higher body mass index, a higher waist circumference, a higher systolic blood pressure, worse arterial stiffness and a lower estimated insulin sensitivity (all p < .05). When examined by age group, associations between sleep duration and cardiometabolic health outcomes remained significant, predominantly for adolescents. In adolescents only, wake time was significantly later (p = .027) and time in bed was significantly longer with BCQR versus placebo (p = .049). CONCLUSIONS:Objectively measured sleep <7 h per night was prevalent in adolescents and adults with T1D and associated with poorer cardiometabolic health markers. Small changes in sleep were seen following BCQR treatment in adolescents only. Sleep may be an important and novel target for improving cardiometabolic health in individuals with T1D.