American Diabetes Association Research Articles (Page 10)

Introduction and Objective: The choroid plexus (ChP), located in each ventricle of the brain, is recognized as a potential site for leptin transport via short- and long-form leptin receptor (LepR). However, knowledge of how LepR in the ChP regulates leptin transport and energy metabolism remains limited. We investigated the role of LepR in Foxj1-expressing ChP cells in leptin transport and body weight regulation. Methods: Mice lacking LepR in Foxj1-expressing cells (Foxj1-Cre; LepRloxP/loxP) and LepRloxP/loxP mice were fed chow or high-fat diet (HFD). Foxj1 is enriched in ChP epithelial cells. We evaluated body weight, fat mass, serum hormones, food intake, leptin-stimulated food intake, and hypothalamic Stat3 phosphorylation. The interaction between LepR and LRP1 was measured by PLA. Leptin uptake and release were determined in cultured cell lines. Results: Foxj1-Cre-driven LepR deletion reduced LepR expression in ChP by ~80%. On a chow diet, deletion of LepR in Foxj1-expressing cells of the ChP modestly increased body weight and fat mass due to hyperphagia with elevated serum insulin and leptin but normal glucose. Importantly, leptin’s ability to suppress food intake and enhance hypothalamic pStat3 was significantly impaired in these mice. Under HFD, LepR deficiency further exacerbated weight gain and adiposity. Mechanistically, we found that leptin induces the physical interaction between LepR and LRP1 in the ChP. In vitro study demonstrated that leptin uptake and release were significantly reduced in ChP-derived Z310 epithelial cells lacking LepR. Conversely, LepR overexpression in Neuro-2a cells markedly increased leptin uptake and release. Conclusion: These findings suggest that LepR in Foxj1-expressing cells is required to regulate leptin transport, affecting feeding and body weight homeostasis. Thus, our study uncovers a new cellular mechanism in which LepR in the ChP functions as a key mediator of leptin transport, maintaining metabolic homeostasis. Disclosure K. Rodrigues: None. W. Yang: None. J. Young: None. M. Lee: None. F. Timzoura: None. V. Prevot: None. Y. Kim: None. Funding American Diabetes Association (1-25-PDF-49); RO1DK1230023RO1DK129946-03

Introduction and Objective: Prior research identified genetic variants for macronutrient preference in adults, but whether these genetic differences affect early life food intake and metabolic phenotypes is unknown. We examined the associations of polygenic scores (PS) for macronutrient preference with dietary behaviors, BMI trajectories from 3-17y and insulin resistance at 17y. Methods: We used genetics, dietary intake and anthropometrics collected at ages ~3, 7, 12, and 17y, and glycemic data measured at 17y among non-Hispanic White children from US prebirth cohort Project Viva. Dietary behaviors from questionnaire included consumption of sugar-sweetened beverages (SSBs) and fast-food. Macronutrient preference PS were calculated from prior large genome-wide study in adults. We estimated odds ratios (OR) for frequent fast-food (>=1 meal/wk) and SSB intake (>1 serving/wk) with generalized estimating equations from 3-17y, and beta coefficients for BMI z-score with linear mixed models from 3-17y. We used linear regressions to examine associations of PS with homeostatic model assessment for insulin resistance (HOMA-IR). We adjusted models for child’s age, sex, and 3 genetic principal components. Results: Among 516 children, each SD increment in PS for carbohydrate preference was associated with a higher likelihood of frequent fast-food (OR 1.13 for >=1 meal/wk, 95% CI: 1.02 to 1.26) and SSB (OR 1.15 for >1 serving/wk, 95% CI: 1.03 to 1.28) intake on average from 3-17y. Each SD increase in the protein preference PS was associated with lower likelihood of frequent SSB intake (OR for >1 serving/wk: 0.89, 95% CI: 0.79 to 0.99). We did not find significant associations between macronutrient PS with BMI z-score or HOMA-IR. Conclusion: Our findings suggest that genetic predisposition for carbohydrate and protein preference could influence SSB and fast-food intake patterns in children, which could heighten their future risk for diabetes. Disclosure S. Harnois-Leblanc: None. K. Switkowski: None. J. Young: None. I.M. Aris: None. S.L. Rifas-Shiman: None. E. Oken: None. J.E. Gervis: None. K.E. Westerman: None. H.S. Dashti: None. M. Hivert: None. J. Merino: None. Funding American Diabetes Association (7-23-PDFT2DY-03); National Institutes of Health (R01034568, R24ES030894)

Introduction and Objective: Hepatic stellate cells (HSCs) play a key role in developing insulin resistance. While Rho-kinase 1 (ROCK1) activation in hepatocytes promotes obesity-induced insulin resistance, the physiological role of ROCK1 in HSCs remains unclear. This study investigated the importance of ROCK1 in HSCs in the context of obesity-related metabolic dysfunction. Methods: Mice lacking ROCK1 in HSCs (Lrat-Cre; ROCK1 loxP/loxP ) were fed a high-fat diet (HFD) for 22 weeks. Metabolic assessments included glucose and insulin tolerance tests, serum insulin, and lipids profiles. Gene expression of key molecules involved in hepatic inflammation, fibrosis, and muscle function were also determined. Results: Hepatic ROCK1 expression increased notably in HFD-fed mice. ROCK1 deficiency in HSCs prevented HFD-induced obesity, resulting from decreased lean mass but not fat mass. Lrat-Cre; ROCK1 loxP/loxP mice were insulin sensitive, evidenced by a significant decrease in blood glucose levels after insulin injection, while glucose tolerance remained normal. Serum insulin was decreased, but blood glucose was unaltered. Hepatic TG content increased with the upregulated lipogenic genes (ACC and ChREBP) in Lrat-Cre; ROCK1 loxP/loxP mice, but serum lipid profiles were unchanged. No changes in hepatic inflammatory or fibrosis markers were observed. Interestingly, despite reduced lean mass, skeletal muscle showed increased expression of genes linked to differentiation and functionality (Myl2, Myl4, Myog, IGFBP5, Desmin, Mef2c) and decreased expression of atrophy markers (MuRF1, atrogin-1), likely contributing to the insulin-sensitive phenotype. Conclusion: These data suggest that ROCK1 in HSCs is a key mediator that regulates insulin sensitivity and muscle functionality during overnutrition, highlighting ROCK1’s significance in HSCs-muscle communication. Identifying HSC-derived factors that affect muscle function is under investigation. Disclosure K. Rodrigues: None. L. Zhang: None. J. Young: None. M. Lee: None. Y. Lim: None. W. Yang: None. P. Hirsova: None. Y. Kim: None. Funding American Diabetes Association (1-25-PDF-49); RO1DK129946

Introduction and Objective: Recent advances in single-cell technologies have uncovered intricate cellular heterogeneity, yet its biological implications remain unclear. Key questions include whether functional heterogeneity exists and its impact on tissue activity. Brown and beige adipocytes (BAs) are thermogenic cells critical for energy homeostasis, and a decline in thermogenic activity is linked to age-related metabolic disorders. We previously identified a BA subpopulation with low uncoupling protein 1 (UCP1) expression (BA-L) that coexists with the classical high UCP1-expressing BAs (BA-H). Methods: Utilizing multiple lineage-tracing and gene knockout mouse models, single-cell RNA sequencing, and tissue imaging. Results: Here, we report that BA-Ls have spatial proximity to interleukin-1 beta (IL-1β) positive cells, as IL-1β is “cooling down” the thermogenesis of surrounding BAs, stabilizing these cells in the low-thermogenic states. Specifically, IL-1β stabilizes hexose-6-phosphate dehydrogenase (H6PD) protein from degradation, which promotes glucocorticoid receptor (GR) signaling to suppress UCP1 expression via GR target regulator of G-protein signaling 2 (RGS2). Cold exposure reduces IL-1β levels, depending on the sympathetic innervation, leading to H6PD degradation, and thus converting BA-Ls into BA-Hs to enhance thermogenesis. Rising environmental temperatures trigger the opposite events. BA-specific, inducible deletion of GR during cold exposure prevents the switch of BA-Hs to BA-Ls when the environmental temperature rises, leading to persistent thermogenesis. Critically, IL-1β level is elevated in aged BAT, leading to low BA-H/BA-L ratio and cold intolerance. Suppressing GR in aged mice restores the BA-H/BA-L ratio and increases thermogenesis. Conclusion: Our findings unveil a spatiotemporal regulation of BA heterogeneity governing thermogenesis that integrates neural and immune signals and a fundamental mechanism of thermogenic fat tissue aging. Disclosure A. Song: None. Y. Wang: None. G. Wang: None. J. Yu: None. L. Jiang: None. Y. Zhu: None. Q. Wang: None. Funding National Institutes of Health (R01AG063854); National Institutes of Health (R01HD096152); National Institutes of Health (R01DK128907); California Institute for Regenerative Medicine (DISC0-15689); American Diabetes Association Junior Faculty Development Award (1-19-JDF-023)

Introduction and Objective: The impact of psychiatric interventions on glycemic control in pediatric and adolescent patients with type 2 diabetes mellitus (T2DM) has not been assessed using machine learning methods. We investigated the integration of psychiatric interventions in the management of T2DM, emphasizing the need for psychosocial support, as recommended by the 2024 American Diabetes Association and 2022 International Society for Pediatric and Adolescent Diabetes guidelines. Methods: We applied machine learning on a dataset from Inha University Hospital, Korea, involving 111 pediatric patients with T2DM to predict the optimal timing for psychiatric intervention to enhance glycemic control. Results: The analysis revealed that early psychiatric interventions contributed to more stable glycemic control with a slight improvement in HbA1c levels, indicating the effectiveness of these interventions. Advanced analytical techniques identified patient subgroups that benefited from early intervention, although age did not significantly affect the outcomes. Conclusion: This study serves as a foundation for future research utilizing datasets in the field of medicine, emphasizing the role of machine learning in predicting disease prognosis and adopting a multifaceted approach to analyze factors influencing disease outcomes. It advocates a shift towards leveraging comprehensive data analysis to enhance our understanding of diseases, thereby fostering more informed, predictive, and personalized disease management strategies. This aspiration pioneered the application of machine learning to explore the breadth of data to advance patient care. Disclosure J. Park: None. S. Kim: None. J. Lee: None. S. Kim: None.

Introduction and Objective: Although the bi-directional relationship between diabetes and oral health has been well documented, there is a lack of theory-informed, evidence-based behavioral oral self-care interventions for PWD. Guided by the Health Belief Model (HBM), we developed the DiaOral web-based program, a di gital technology-assisted oral health education and self-care intervention to be administered via primary care for racially and socioeconomically diverse PWD. This study aims to identify self-perceived needs in oral self-care practices among PWD and to obtain their feedback about the prototype of the newly developed DiaOral program. Methods: We conducted a qualitative study of 15 semi-structured interviews among patients in a large healthcare system. Participants were recruited from among PWD in racially/ethnically diverse zip codes in urban/suburban communities. The interview focused on respondents' oral self-care practices in relation to their diabetes. Also, examples of DiaOral modules were presented and feedback was solicited on the content and images. The reflective thematic analysis method was used to code, discuss, and review the transcript, attributes, and meaning of the themes according to constructs of the HBM to the point of consensus among the research team. Results: Three major themes and 27 sub-themes emerged from the thematic analyses. Each sub-theme was categorized into one HBM construct. Three major themes are 1) lack of knowledge on optimal oral care, 2) low perceived importance of preventive care and oral health in diabetes, 3) limited self-efficacy for performing effective oral self-care. After viewing the DiaOral prototype on paper, all participants expressed satisfaction with the content and their confidence and interest in using the DiaOral program. Conclusion: Thematic analyses confirmed theoretical constructs of HBM. HBM guided DiaOral program modules were acceptable and accessible to diverse PWD. Next steps will be to refine the DiaOral program and subsequently to test its efficacy in PWD. Disclosure Y. Zhang: None. S. Leveille: None. K. Berger: None. R.M. Cohen: Research Support; Dexcom, Inc. Stock/Shareholder; Abbott. Research Support; National Institute of Diabetes and Digestive and Kidney Diseases. T. Bakas: None. Funding American Diabetes Association (11-22-JDFHD-06)

Introduction and Objective: Activation of innate immune signaling is recognized as a critical factor in the pathogenesis diabetic nephropathy (DN). We previously observed that podocyte-specific expression of the stress response protein REDD1 (Regulated in Development and DNA Damage 1) is required for podocyte injury and function deficits in DN. Given that podocytes are thought to play an immune modulatory role in kidney disease, we investigated the hypothesis that diabetes-induced REDD1 expression in podocytes contributes to mitochondrial injury leading to a DNA-driven immune response. Methods: REDD1fl/fl and podocyte-specific NPHS2-cre REDD1 knockout mice were fed a high fat diet to induce diabetes. Kidneys were removed after 16 weeks of diabetes, and analyzed for immune cell infiltrates using flow cytometry. Protein and mRNA expression in isolated glomeruli were determined. Similar analyses were carried out in wild-type or CRISPR REDD1 KO human podocyte cultures exposed to 150 µM palmitate. Results: Podocyte-specific REDD1 deletion prevented diabetes-induced albuminuria, activation of NF-κB, and expression of pro-inflammatory factors. Similarly, in cultured human podocytes, we observed that palmitate exposure increased mitochondrial injury, membrane depolarization, and mtDNA leakage in cells expressing REDD1, which was concomitant with increased activation of the cGAS-STING pathway and NF-κB mediated inflammation. Importantly, podocyte-specific REDD1 deletion prevented mitochondrial dysfunction, STING activation and proinflammatory macrophage infiltration in kidneys of diabetic mice. Conclusion: Overall, the findings provide new insight into the role of podocyte REDD1 expression in regulating renal pathology and function in diabetes and support the possibility that therapeutics targeting podocyte REDD1 could be beneficial in suppressing innate immune response activation in DN. Disclosure S. Sunilkumar: None. S. Moothedath Subrahmanian: None. M.D. Dennis: None. Funding American Diabetes Association (11-23-PDF-24); National Institutes of Health (R01 EY032879), Juvenile Diabetes Research Association (1-INO-2024-1538-A-N)

Introduction and Objective: The American Diabetes Association recommends annual eye exams for adults with Diabetes Mellitus Type 2 (T2DM); however, barriers to timely screening persist. This study assesses the diabetic eye care continuum among patients with T2DM at the University of California, San Francisco (UCSF) and Irvine (UCI). Methods: Electronic health records at UCSF and UCI were queried to identify adult patients with T2DM seen by a primary care provider (PCP) from 2020 through the end of 2022. We estimated the proportion of screening-eligible patients referred to a specialist and those who completed a screening visit within 12 months as well as those diagnosed with and treated for DR. Significant predictors of referrals and screening visits were identified using adjusted logistic regression. Targeted Maximum Likelihood Estimation (TMLE) estimated the impact of an automated referral system. Results: The patient population needing diabetic eye screening included 2,612 patients with T2DM at UCSF and 5,661 at UCI. UCSF had higher 1-year rates of referrals (53.6% vs. 37.4%) and eye screening visits (21.0% vs. 13.4%) (p<0.001). DR diagnosis prevalence was 3.6% at UCSF and 3.4% at UCI, with treatment rates at 0.7% and 1.0%, respectively. Referrals (OR 57.3[47.5-77.2]), previous eye diseases (OR 6.6[5.8-7.4]), and Charlson comorbidity index (OR 1.2[1.1-1.9]) were associated with higher screening rates. A higher Area Deprivation Index (OR 0.8[0.8, 0.9]) was associated with a lower likelihood of screening visits. TMLE suggested screening rates could improve to 34% at UCSF and 24% at UCI with automated referrals. Conclusion: Most patients with T2DM did not receive timely diabetic eye disease screening. Implementing an automated referral system could significantly boost screening rates, but gaps may persist. Further research is needed to understand these gaps and design interventions to improve eye health. Disclosure A. Ayati: Research Support; Genentech, Inc. S. Ko: Employee; Genentech, Inc. N.G. Bonine: None. D. Tabano: Employee; Genentech, Inc. N. Malik: Employee; Genentech, Inc. S. Azzam: None. C. Ben-David: None. M. Wang: Research Support; BeiGene, Amgen Inc. F. Brodie: Consultant; Genentech, Inc. Research Support; Genentech, Inc. Advisory Panel; Genentech, Inc, Apellis. M. Mehta: Research Support; Genentech, Inc. Speaker's Bureau; Astellas Pharma Inc. Consultant; Ani. Research Support; Zeiss. Stock/Shareholder; Eyedaptic. Speaker's Bureau; Apellis. Research Support; jCyte. V. Rudrapatna: Research Support; Genentech, Inc, Merck & Co., Inc, Janssen Pharmaceuticals, Inc, Stryker, Mitsubishi Tanabe Pharma Corporation, Blueprint Medicines, Beigene. Consultant; Ironwood, Natera. Advisory Panel; ZebraMD, DataUnite, Acucare.

Introduction and Objective: Obesity is characterized by hypoxia and mitochondrial dysfunction in adipocytes, which contribute to metabolic complications. This study aims to investigate the interplay between adipocyte hypoxia and the mitochondrial unfolded protein response (UPRmt), with the goal of identifying potential therapeutic targets or strategies for obesity treatment. Methods: We utilized an In Vivo Imaging System (IVIS) to assess hypoxia in adipose tissue following acute high-fat diet (HFD) exposure. The expression levels of hypoxia-related and UPRmt-related genes were measured using qPCR. Additionally, we generated adipocyte-specific hypoxia-inducible factor-1α (HIF1A) knockout (KO) mice to evaluate the effects of HIF1A deletion on adipose UPRmt, together with body weight, glucose metabolism, and mitochondrial function after acute or chronic HFD exposure. Finally, adipose metabolomic analyses were performed to characterize mitochondrial metabolism alterations. Results: Acute HFD exposure (3 and 7 days) significantly enhanced hypoxia signals in white adipose tissues, accompanied by upregulation of hypoxia-related and UPRmt-related genes. Adipocyte-specific HIF1A KO mice exhibited increased body weight and impaired glucose metabolism following acute HFD. These mice also demonstrated elevated UPRmt activation, increased oxidative stress, and a reprogramming of mitochondrial metabolism in white adipose tissues. Conclusion: Our findings suggest that HIF1A negatively regulates UPRmt in adipocytes and highlight hypoxia as a potential therapeutic avenue for obesity treatment. Ongoing studies aim to provide stronger evidence for the link between HIF1A and UPRmt and explore the therapeutic potential of modulating the hypoxia-UPRmt axis in obesity management. Disclosure F. Wang: None. P.M. Huynh: None. A. Rivera: None. Y. An: None. Funding American Diabetes Association (11-23-PDF-23)

Introduction and Objective: Culturally tailored DSMES and RT-CGM support patients with T2DM. Our objective was to assess how culturally tailored DSMES influenced nutrition and activity and if RT-CGM use enhanced DSMES's effects in Latino populations. Methods: Latino adults with T2DM on no insulin or basal insulin only, were randomized 1:1 to receive virtually delivered education only (blinded CGM) or with cyclic RT-CGM. The primary outcome was HbA1c at 12-weeks; secondary outcomes included lifestyle modifications assessed by questionnaires. Results: Eighty one participants (41 RT-CGM and 40 blinded) completed lifestyle questionnaires at baseline and 12-weeks. The nutrition short summary score showed overall improvement (-1.76 (2.43) RT-CGM, -1.33 (3.58) blinded, (p=0.5)). RT-CGM reduced fast food or snack consumption by 34% vs. 19% for blinded. Sugared beverages decreased by 23% for RT-CGM vs. 26% for blinded. Vegetable and fruit consumption increased by 36% and 20% for RT-CGM and 23% and 26% for blinded, respectively. Physical activity days for vigorous and moderate exercise increased by 1.00 (3.18) and 0.86 (2.27) for RT-CGM vs. 0.14 (1.45) and 0.67 (2.40) for blinded. Walking for 10 minutes/day increased 0.3 (3.1) for RT-CGM and 1.0 (3.7) for blinded. Among RT-CGM users, 81% felt CGM made them read labels more, 83% limited or excluded rice, and 78% were more likely to go for a walk. 97% of RT-CGM participants felt that CGM led to a healthier lifestyle. Conclusion: Culturally tailored DSMES facilitates healthy lifestyle changes. CGM appeared to promote increased physical activity and it may improve lifestyle modifications when combined with DSMES. Disclosure J. Vidovic: None. D. Gil Menchaca: None. E. Jones: None. P. Berberian: None. L. Wright: Advisory Panel; Genentech, Inc. A. Vasconcelos: None. B.A. Comstock: None. N.M. Ehrhardt: Advisory Panel; Novo Nordisk. Research Support; Dexcom, Inc. Advisory Panel; Bayer Pharmaceuticals, Inc. Research Support; Novo Nordisk. Advisory Panel; Dexcom, Inc. Research Support; Boehringer-Ingelheim. Funding American Diabetes Association (11-21-ICTSHD-51)

Introduction and Objective: Diabetic foot infection (DFI) is a common and significant complication of diabetes, with racial, ethnic, and age disparities potentially influencing clinical outcomes. We analyzed 7,769 patients evaluated for DFI at Parkland Health (PHHS), a large tertiary county system, and UT Southwestern (UTSW), a university center, to examine demographic differences between these adjacent healthcare facilities. Methods: The study population included 6,187 PHHS and 1,582 UTSW patients that were seen between 2013 to 2024. Each patient underwent biopsy, surgical resection, or amputation with accompanying histopathology. Results: UTSW patients were predominantly Non-Hispanic White, while PHHS patients were mainly Hispanic White. Slightly more females were seen at UTSW (33%) compared to PHHS (30%). PHHS patients tended to be younger, with most aged 51-60 years, compared to 61-70 years at UTSW. A subset of 3,181 subjects also had microbial cultures associated with their histopathology (2,271 PHHS and 910 UTSW patients). The top five pathogens observed at both facilities included S. aureus, S. agalactiae, MRSA, P. aeruginosa, and E. faecalis, with S. aureus being the most frequently identified microbe. Conclusion: These findings highlight how institutions in close geographical proximity can serve demographically distinct populations, emphasizing the need to consider these differences to tailor care and advance personalized medicine. Disclosure A. Sherwood: None. P.A. Crisologo: None. L.A. Lavery: Consultant; Limflow, enerenesis Medical, Clyra Medical technologies, Blue Sky, Tissue Health Plus. Stock/Shareholder; Xilas Medical. Consultant; Altrazeal. O.K. Oz: None. Funding American Diabetes Association (11-22-ICTSPM-05)

Introduction and Objective: Computer vision offers an opportunity to automatically analyze foot images to segment diabetic foot ulcers (DFU) and determine clinically relevant characteristics. Although diabetic foot complications take a disproportionate toll on communities of color, these communities are underrepresented in dermatologic image datasets, which may propagate health disparities. Are current state-of-the-art foot ulcer recognition algorithms effective for Black patients living with diabetes (compared to patients with white or pale skin)? Methods: We collected the first known repository of DFU images from patients of color. We train and evaluate five state-of-the-art foot ulcer segmentation models (HarDNet-DFUS, Mask R-CNN, MobileNetV2, U-Net, SegNet) on our dataset, and compare to metrics reported for white or pale skin. Results: Our dataset consists of 3,483 foot images (including 1,652 instances of a DFU or pre-ulcerative lesion) from 248 patients. Images were collected from a diabetes clinic in a safety net hospital in the Southern United States and patients were predominantly (over 80%) Black. The five state-of-the-art ulcer recognition models result in insufficient performance on this new dataset. The best performing baseline model (Mask R-CNN) has been reported to achieve a Dice score (i.e., similarity coefficient indicative of model performance) of 90.2% on a dataset of foot images collected from white patients but achieves a Dice score of only 37.4% on our dataset. Conclusion: Current ulcer recognition models provide lower performance on wound images collected from patients of color. Larger, more diverse datasets will be crucial for the next generation of recognition models. Our work supports more equitable technological interventions for diabetic foot care to improve patient self-monitoring and clinician delivery of care for communities of color. As automated wound recognition may improve clinician delivery of care, it is vital to advance equity for those who face the greatest disease burden. Disclosure C. Baseman: None. Z. Leng: None. T. Ploetz: None. G. Santamarina: None. M.C. Schechter: None. M. Fayfman: Research Support; Abbott, Dexcom, Inc. R.I. Arriaga: None. Funding American Diabetes Association (11-22-ICTSHD-09)

Introduction and Objective: Sex differences in risk factors for macrovascular disease have been reported in T1D but similar data for PDR and ON by sex are limited. We thus aimed to assess sex-specific associations between longitudinal risk factors for 30-year PDR and ON in the Pittsburgh Epidemiology of Diabetes Complications (EDC) T1D cohort (baseline mean age 27, T1D duration 19 yrs). Methods: Participants free of each complication at 1986-88 baseline (PDR: n=218 women, 215 men; ON: n=223 women, 216 men) were followed prospectively for incidence of PDR (grade ≥60 in 1+ eye on fundus photos or laser photocoagulation) and ON (albumin excretion rate ≥300µg/min in 2 of 3 timed urine samples). Risk factors were collected at baseline, 2, 4, 6, 8, 10, 18, 25, and 30 years; T1D duration-adjusted risk factor associations with time to event were assessed by sex using multivariable joint models which estimate longitudinal and time to event data processes simultaneously. Results: Over 30 yrs 124 (57%) women and 127 (59%) men developed PDR; 41 (18%) women and 53 (25%) men developed ON. As shown in Table 1 HbA1c and blood pressure were associated with PDR in both sexes. For ON, risk factors except HbA1c differed by sex. Conclusion: While HbA1c and blood pressure are important risk factors for PDR regardless of sex, sex-specific clinical targets may be needed to reduce kidney damage in T1D. Disclosure R.G. Miller: None. T.J. Orchard: None. T. Costacou: None. Funding American Diabetes Association (7-23-ICTSWH-19); National Institutes of Health (R01-DK034818); Rossi Memorial Fund

Introduction and Objective: Type 2 diabetes (T2D), affecting 537 million individuals globally, disproportionately impacts Latin American populations, who experience higher rates of diabetic complications. Despite large-scale genomic studies identifying T2D-associated variants enriched in this population, many lie in non-coding regions, complicating the identification of causal genes. Existing genomics resources like GTEx were developed using data from primarily European populations, and do not cover Latin American associated variants. To address this, the LAGTEx project is generating the largest expression QTL resource from four insulin-sensitive tissues—subcutaneous and visceral adipose (SAT, N=301, VAT, N=309), liver (N=213), and skeletal muscle (N=90)—totaling 913 tissue samples from 360 participants of Latin American ancestry. Methods: Bulk RNA sequencing data was generated from SAT, VAT, liver, and muscle, and genotypes were collected from 360 participants of Latin American ancestry. Genotypes were imputed using the TOPMED reference panel and RNA-seq counts were normalized using the DESeq2 median ratio method to account for differences in sequencing depth and library composition. FastQTL was used to identify eQTLs that link genetic variants to gene expression variation, adjusting for covariates like age, sex, BMI, and batch. Results: We present results from our pilot analysis of 51 liver samples. We identified 23,424 eQTLs associated with variation in the expression of 440 genes. Effect sizes were consistent with those reported in GTEx liver eQTLs (rho: 0.754, p<2.2x10-300). Our results replicate the isoform-specific effects of a previously identified Latin American specific T2D protective splice acceptor variant in IGF2, with carriers showing reduced expression of IGF2 isoform 2. Conclusion: LAGTEx covers an important gap to assess gene expression effects of Latin American enriched variants in insulin target tissues, enhancing understanding of ancestry-specific genetic regulation of metabolic traits. Disclosure H. Wadhwa: None. L. Szczerbinski: None. F.M. Barajas-Olmos: None. K. Taylor: None. H. Garcia-Ortiz: None. C. Contreras-Cubas: None. A. Martínez-H: None. V. Kaur: None. A. Huerta: None. A. Janucik: None. A.J. Kretowski: None. M. Claussnitzer: None. I. Cebola: Research Support; Novo Nordisk, Gilead Sciences, Inc. Other Relationship; Ochre Bio. Research Support; British Heart Foundation, Wellcome Trust, Royal Society, NIHR Imperial Biomedical Research Centre, National Centre for the Replacement, Refinement & Reduction of Animals in Research. L. Orozco: None. J. Mercader: None. Funding American Diabetes Association (11-22-ICTSPM-16); FNIH (RFP6); NHGRI (U01HG011723); National Institute Of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health (R01DK137993, U01 DK140757); Medical University of Bialystok (MUB) grant from the Ministry of Science and Higher Education (Poland)

Introduction and Objective: Chronic disease behavioral interventions have become widespread across healthcare sectors. While success of these interventions is largely dependent on their implementation, there is an absence of train-the-trainer (TTT) protocols and evaluations to serve as frameworks for behavioral interventions. Therefore, the objective of this study was to develop and evaluate the effectiveness of a theory-based TTT protocol at training researchers to deliver a clinical culinary medicine intervention for at-risk youth with T1D in a public health setting utilizing a mixed methods approach. Methods: A multi-component TTT protocol was developed and implemented to research assistants (RAs) of the intervention. A 24-item survey assessing key TTT constructs (T1D knowledge, disparities; health literacy, cultural sensitivity; research ethics, study design) was completed by RAs at baseline and post-test. Six additional qualitative questions gathered RA feedback on the TTT protocol at post-test. Results: Eighteen RAs completed the baseline and post-test surveys (100%), with significant improvements from baseline to post-test across all key TTT constructs (T1D knowledge (p<0.001); T1D disparities (p<0.001); health literacy, cultural sensitivity (p= 0.02); research ethics, study design (p<0.001)). Post-training feedback indicated strong preference (94.4%) for the multi-component approach but the in-person training day 2 (knowledge application with role play, demonstrations) best prepared RAs for their role. Conclusion: The TTT framework is an effective training model for clinical and public health diabetes interventions. Utilizing a multi-component approach with in-person knowledge application appears to resonate best with trainees and can serve as a model to integrate into chronic disease behavioral interventions in the clinical and public health sector to enhance chronic disease intervention efficacy and patient outcomes. Disclosure C.R. McManus: None. Funding American Diabetes Association (11-21-JDFHD-13)

Introduction and Objective: This study assessed the prevalence of food insecurity and examined its associations with body mass index (BMI), body weight, and healthy eating among overweight Chinese Americans at high risk for diabetes. Methods: We analyzed baseline data from a randomized controlled trial of 150 overweight Chinese Americans at risk for diabetes in New York City. Food insecurity was measured using the San Francisco Chinese Food Security Module, and higher scores indicated higher food insecurity. Healthy eating was measured by the Starting the Conversation scale. Weight and height were measured during the in-person baseline visit. Regression analyses were conducted to examine whether food insecurity (independent variable) was associated with three dependent variables: BMI, weight, and healthy eating, respectively while adjusting for age and gender. Results: Our sample (n = 150) had a median age of 49 years [IQR 39-62] and a mean BMI of 27 (SD 3.69). The majority were female (82.7%), had ≤ high school education (54%), and reported annual household incomes of ≤ $25,000 (37.3%). Approximately a quarter (25.4%) of participants reported varying levels of food insecurity (12.7% marginal, 8.7% low, 4.0% very low food security). After adjusting for age and gender, food insecurity was negatively associated, but not statistically significant, with BMI (β = -0.18, p = 0.22) and weight (β = -1.1, p = 0.23) and showed no association with healthy eating (β = -0.013, p = 0.87). Conclusion: Nearly 25% of Chinese Americans at high risk for diabetes face food insecurity, underscoring the need for targeted strategies to address this issue within the community. We observed a trend of negative association between food insecurity and weight, indicating that a large-scale study may be needed to confirm the result. Disclosure X. Yang: None. J. Liu: None. Y. Shi: None. Y. Zhao: None. O.Z. Friedman: None. H. Song: None. H. Li: None. Y. Jiang: None. I.H. Ong: None. Y. Xiao: None. Y. Cheung: None. H. Wang: None. Y. Bai: None. R. Zhao: None. L. Hu: None. Funding American Diabetes Association (7-22-ICTSN-08)

Introduction and Objective: While it is known that adults with diabetes mellitus (DM) have twice the risk of developing dementia, and discrimination has been shown to be associated with dementia in some older adult populations, it is unknown whether this association is mediated by loneliness. Therefore, the aims of this analysis were to: 1) understand whether there is a differential association between discrimination and dementia in older adults with DM in high- and middle-income countries; and 2) understand whether loneliness is a mediator of this relationship. Methods: Data for adults with DM aged 50+ in Europe (n=10622, 2017-Survey of Health, Aging and Retirement), 45+ in India (n=8857, 2017-2019-Longitudinal Aging Study), and 50+ in Brazil (n=1780, 2019-2021-The Longitudinal Study of Aging) were analyzed. Logistic regression models were used to investigate the relationship between discrimination and loneliness, loneliness and self-reported dementia, and discrimination and dementia. A final mediation model with discrimination and loneliness as independent variables and dementia as the dependent variable was run. Results: The prevalence of dementia was 0.85%, 3.8%, and 5.2% in India, Europe, and Brazil respectively. The prevalence of discrimination was 6.7% in Europe, up to 5.4% in Brazil, and up to 7.4% in India. There was no association between discrimination and dementia in older adults with DM in Europe and Israel (OR:1.04; 95%CI:0.66,1.66), nor was there an association between loneliness and dementia in India (OR:1.73; 95%CI: 0.89,3.35). However, amongst older adults in Brazil with DM, loneliness was found to fully mediate the relationship between medical care discrimination and dementia. Conclusion: There was a differential relationship between discrimination and dementia in high- and middle-income countries; and loneliness was found to fully mediate this relationship only for older adults with DM in Brazil. Disclosure A.Z. Dawson: None. J. Price: None. J.S. Williams: None. M.N. Ozieh: None. Funding American Diabetes Association (11-22-JDFHD-01); National Institutes of Health (1R21DK135965-01)

Introduction and Objective: T2D has a strong genetic basis, making PRSs useful for risk prediction. Most PRSs exclude rare variants (minor allele frequency [MAF] <0.01) due to data limitations in genome-wide association studies (GWAS). We used the current largest rare variant GWAS meta-analysis to develop a rare variant PRS (rvPRS) to improve T2D risk prediction. Methods: We developed rvPRSs using multi-ancestry GWAS data from 51,256 cases and 370,487 controls with rare variant imputation or whole-genome sequencing (MAF ≥ 5x10-5) and applied them to 7,382 cases and 8,885 controls of Latin American ancestry. We generated 84 PRSs with varying linkage disequilibrium clumping parameters (R2 and window size) and p-value thresholds. Ensemble learning weighted each PRS by predictive performance and applied these weights to variant effects. Model performance was assessed using adjusted Area Under the Receiver Operating Characteristic Curves (AAUC), adjusting for principal components, sex, age, and body mass index (BMI). We compared the rvPRS to a common variant PRS (cvPRS) derived from a European-based GWAS of 201,262 cases and 1,285,672 controls. Results: Our rvPRS (MAF ≥ 5x10-5) captured a higher proportion of rare variants (82% MAF <0.01 in Latin American ancestry vs. 38% in the cvPRS). Combining rvPRS and cvPRS (rv_cvPRS) improved prediction accuracy (AAUC = 0.68 vs. 0.66 for cvPRS alone), particularly at extreme PRS scores. Individuals at the 95th percentile of the rv_cvPRS had an odds ratio (OR) of 5.7 (4.3-7.4, p = 3.7x10-36) compared to 3.7 (2.9-4.7, p = 1.2x10-26) for the cvPRS. The rvPRS enhanced prediction for known rare variant carriers. Carriers of the HNF4A variant (p.Arg114Trp, OR = 7.9) had an average rvPRS corresponding OR of 3.1 compared to an average cvPRS corresponding OR of 0.82. Conclusion: Incorporating rare variants to PRSs substantially improved T2D prediction, particularly identifying individuals at high genetic risk driven by large-effect rare variants. Disclosure K. Taylor: None. A. Huerta: None. X. Wang: None. M. Vora: None. J. Kim: None. M. Ng: None. H. Zhang: None. J. Mercader: None. Funding American Diabetes Association (11-22-ICTSPM-16); National Human Genome Research Institute (U01HG011723); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK137993 and U01 DK140757); Medical University of Bialystok (MUB) grant from the Ministry of Science and Higher Education (Poland)

BackgroundThe relationship between health-related lifestyle trajectories and prediabetes risk among adults with normoglycemia remains unclear. We investigated this issue using data from a cohort of working individuals.MethodsThis cohort study included 10,773 workers (8986 men) aged 30–64 years in Japan, with normoglycemia in 2009, followed until 2017 using annual health checkup data. The trajectories of health-related lifestyles were identified during 2006–2009 using group-based trajectory modeling; we calculated the health-related lifestyle index in each year using five lifestyle factors: smoking, alcohol use, exercise, sleep duration, and body weight control (0–5 points; higher score indicated healthier lifestyles). Prediabetes was defined by fasting plasma glucose and hemoglobin A1c based on the American Diabetes Association criteria; the onset was assessed from 2009 to 2017. Cox regression with adjustment for demographic, health-related, and work-related factors was used to evaluate the association of lifestyle trajectories and prediabetes risk.ResultsFive trajectories of health-related lifestyles are identified. Maintaining or improving health-related lifestyles are linked to lower prediabetes risks. Compared with a persistently very unhealthy pattern, the adjusted hazard ratios (95% confidence intervals) are 0.92 (0.84, 0.99), 0.82 (0.71, 0.95), 0.83 (0.76, 0.90), and 0.74 (0.67, 0.83) for “persistently very unhealthy”, “persistently unhealthy”, “improved from unhealthy to moderately healthy”, “persistently moderately healthy”, and “persistently mostly healthy” trajectories, respectively.ConclusionsParticipants with healthier lifestyle trajectories tend to have a lower risk of developing prediabetes. The prediabetes risk at the trajectory of improved from unhealthy lifestyles is lower than that of persistently unhealthy lifestyles.

Introduction and Objective: Diabetes is the most common cause of renal failure accounting for ~50% of cases in the US. In the last 5 years, several new therapies have become available to halt the progression of CKD. Current guidelines from the American Diabetes Association recommend treatment and surveillance of CKD based on the stage of disease. Whether these guidelines are followed by primary care providers, who are increasingly managing diabetes, is unclear. Methods: We performed a retrospective analysis of patients at the Temple University Hospital Internal Medicine Clinic between January 1, 2022- December 31, 2023. We included patients with an ICD10 diagnosis of either type 1 or 2 diabetes and two visits within the two-year study period. We excluded those with no prescription of anti-glycemic therapy within 12 months of the first study visit and those with type 1 diabetes diagnosed <5 years prior. Comparisons between groups were performed with one-way ANOVAs and chi-square tests. Results: We found that 73.3% of patients had at least one serum creatinine and 37.6% of patients had both one serum creatinine and urine albumin/creatinine ratio completed in the first year of the study period. In those with CKD and albuminuria, ACE/ARBs, GLP1RA, SGLT2i, and MRAs were prescribed to 79.3%, 58%, 48.8%, and 13.7% of patients, respectively. ACE/ARBs were prescribed earlier than other medications (p<0.0001). The average number of renoprotective medications prescribed increased with CKD stage (p=0.0009) and albuminuria (p=0.042). Although differences were observed between races with respect to CKD stage (p<0.0001), there was no difference in the number (0.096) and type of medications prescribed (p=0.54). Conclusion: Compared to prior studies, we saw higher rates of screening and medications prescribed, specifically GLP1RA and SGLT2i. However, these results may draw attention to lower rates of ongoing assessment for albuminuria amongst those on evidence-based therapy. Disclosure V. Rao: None. J. Turella: None. A.D. Rao: Advisory Panel; Corcept Therapeutics. Consultant; Spruce Biosciences.