Diabetes最新文献

{"title":"FXR Stimulation by Obeticholic Acid Treatment Restores Gut Mucosa Functional and Structural Integrity in Individuals With Altered Glucose Tolerance","authors":"Francesca De Vito, Raffaella Marasco, Evelina Suraci, Antonio Facciolo, Marta Letizia Hribal, Giorgio Sesti, Francesco Andreozzi, Francesco Luzza, Teresa Vanessa Fiorentino","doi":"10.2337/db25-0035","DOIUrl":"https://doi.org/10.2337/db25-0035","url":null,"abstract":"The farnesoid X receptor (FXR)–fibroblast growth factor 19 (FGF19) axis is involved in maintaining glucose homeostasis and gut tight-junction (TJ) integrity. We evaluated whether individuals with prediabetes or type 2 diabetes (T2D) have altered intestinal FXR-FGF19 signaling and barrier function and whether high-glucose (HG) exposure may cause these aberrations. Moreover, we tested beneficial effects of the FXR agonist obeticholic acid (OCA) on intestinal FXR signaling in individuals with prediabetes or T2D. Included were 60 individuals with different glucose tolerance (normal glucose tolerance [NGT; n = 25], prediabetes [n = 19], or T2D [n = 16]) who underwent ileocolonoscopy with collection of ileal mucosa biopsy specimens, which were used for expression profiling analysis of the FXR/FGF19/TJ axis and tissue culture experiments. Individuals with prediabetes or T2D displayed lower ileal levels of FXR and its target genes FGF19 and TJ proteins zonula, occludens-1, occludin, and claudin-1, along with increased proinflammatory nuclear factor-κB (NF-κB) activity and cytokines expression compared with those with NGT. HG exposure on ileal explants collected from NGT individuals hampered the FXR/FGF19/TJ axis. OCA treatment on ileal fragments of individuals with prediabetes/T2D was able to restore FGF19 synthesis and secretion, TJ expression, and counteract NF-κB activity and cytokines expression. In conclusion, OCA treatment counteracts T2D-related intestinal abnormalities in the FXR/FGF19/TJ axis. Article Highlights The intestinal farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF19) axis is involved in maintaining glucose homeostasis and gut barrier function in animals. Do individuals with prediabetes and type 2 diabetes exhibit a compromised intestinal FXR/FGF19/barrier integrity axis? Can obeticholic acid (OCA) treatment counteract diabetes-related gut mucosa dysfunction? A downregulation of ileal FXR/FGF19/tight-junctions signaling occurs in individuals with hyperglycemia. OCA-mediated FXR activation reverts diabetes-related alterations. OCA-mediated intestinal FXR activation in individuals with hyperglycemia may represent a strategy for restoring FGF19 synthesis with positive effects on gut barrier.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"37 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"1000-P: Observed Glycemic and Psychosocial Benefits in the Prospective Bigfoot Unity Real-World Study (BURST)—A Twelve-Month Analysis","authors":"JOHN TILLMAN, ROY W. BECK, WILLIAM H. POLONSKY, PETER CALHOUN, THOMAS J. MOUSE, RYAN BAILEY, RAKESH NANDAN","doi":"10.2337/db25-1000-p","DOIUrl":"https://doi.org/10.2337/db25-1000-p","url":null,"abstract":"Introduction and Objective: The Bigfoot Unity System integrates Abbott FreeStyle Libre 2 CGM data into a smart insulin pen cap and mobile app enabling clinician-directed insulin dose recommendations and real time alerts. The objective was to analyze real world, 12-month data for System users. Methods: We conducted a 12-month final analysis from the prospective BURST study (NCT05088265) and report the per-protocol results (N=125). Participants completed baseline, adverse event and patient-reported outcome surveys electronically. HbA1c data were from home kits or electronic medical records. Results: Median age was 58 years and 86% had T2D. Mean HbA1c decreased from 9.2±1.8% at baseline to 8.0±1.2% at 12 months (mean change -1.3%, 95%CI -1.6, -0.9; p<0.001). There were six severe hypoglycemia events in 4 participants (none System related), and no DKA. Diabetes Distress Scale scores decreased (mean change -0.8, 95%CI -1.0, -0.6; p<0.001) and Hypoglycemic Confidence Scale scores increased (mean change 0.5, 95%CI 0.4, 0.7; p<0.001) with System use (Table). Conclusion: Durable glycemic improvement with reduced diabetes distress and increased hypoglycemic confidence occurred using the System for 6 months and sustained through 12 months. The reduction in HbA1c occurred while meeting established hypoglycemia targets of <4 and <1% for percent time below 70 and 54 mg/dL, respectively. Disclosure J. Tillman: Employee; Abbott. R.W. Beck: Research Support; Insulet Corporation. Consultant; Insulet Corporation. Research Support; Tandem Diabetes Care, Inc, Beta Bionics, Inc, Dexcom, Inc., Bigfoot Biomedical, Inc, Abbott, embecta, Sequel Med Tech, MannKind Corporation. Consultant; Novo Nordisk, Vertex Pharmaceuticals Incorporated, Hagar, Ypsomed AG, Zucara Therapeutics, Abata Therapeutics, Eli Lilly and Company. W.H. Polonsky: Consultant; Abbott. Research Support; Abbott. Consultant; Dexcom, Inc. Research Support; Dexcom, Inc. Other Relationship; Ascensia Diabetes Care. P. Calhoun: None. T.J. Mouse: None. R. Bailey: None. R. Nandan: Employee; Abbott, Bigfoot Biomedical, Inc. Funding Abbott","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"8 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"1953-LB: Effect of Subjective Stress in Adults with Type 1 Diabetes in Free-Living Condition","authors":"MINSUN PARK, THANAKRIT JEAMJITVIBOOL, SIRINAN PRAKOT, EMILY HUERTA, MUDASSIR M. RASHID, MAHMOUD M. ABDEL LATIF, LISA SHARP, ALI CINAR, LAURIE T. QUINN","doi":"10.2337/db25-1953-lb","DOIUrl":"https://doi.org/10.2337/db25-1953-lb","url":null,"abstract":"Introduction and Objective: Stress has been shown to impact blood glucose levels, presenting significant challenges for individuals with type 1 diabetes (T1D). However, there is limited research on the relations among stress, diabetes-related worry, and glucose variability (GV) in free-living conditions. The purpose of this study was to examine the differences in diabetes-related worry and GV in a free-living environment between two groups based on subjective stress level, measured using visual analog scale (VAS). Participants were divided into two groups: high stress (VAS ≥ 7) (n = 3) and low stress (VAS <7) (n = 9). Methods: Participants completed questionnaires and wore a Dexcom G6 continuous glucose monitor (CGM), ActiGraph (GT3x_BT) for 7 days under free-living conditions. Questionnaires included Hypoglycemia Fear Survey II, Diabetes Quality of Life, Diabetes Distress Scale and stress VAS. The Mann-Whitney test was used to analyze data using SPSS 29.0. Results: Twelve people with T1D (ages: 31.73 ± 8.02 years; A1C: 6.59 ± 1.19 %; BMI: 26.00 ± 3.69 kg/m2; duration of diabetes 16.44 ± 10.35 years) participated. Individuals who reported experiencing high stress level exhibited greater diabetes-related worry (41.33 ± 5.77 vs. 26.22 ± 7.55; z = -2.130, p<.05) and higher diabetes-related regimen stress (3.13 ± .42 vs. 1.98 ± .70; z = -2.045, p<.05). However, they had a lower Low Blood Glucose Index (.85 ± .39 vs. 3.13 ± 1.98; z = -2.041, p<.05) and a lower Time Below Range (.15 ± .22 vs. 3.36 ± 3.23; z = -1.944, p<.05). Conclusion: These results suggest that subjective stress may be associated with increased vigilance in diabetes management through diabetes-related worry and regimen related stress. Further research with a larger sample size is needed to confirm these findings and determine additional glycemic effects of stress. Disclosure M. Park: None. T. Jeamjitvibool: None. S. Prakot: None. E. Huerta: None. M.M. Rashid: None. M.M. Abdel Latif: None. L. Sharp: None. A. Cinar: None. L.T. Quinn: None. Funding National Institutes of Health (5R01DK130049-02)","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"26 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"749-P: Integrated Analysis Supports Cardiovascular Safety and Risk Reduction with Pemvidutide Treatment","authors":"SHAHEEN TOMAH, JOYCE JAMES, SARAH K. BROWNE, BORJE DARPO, M S. ROBERTS, JOHN J. SUSCHAK__III, LIANG HE, JAY YANG, M. SCOTT HARRIS","doi":"10.2337/db25-749-p","DOIUrl":"https://doi.org/10.2337/db25-749-p","url":null,"abstract":"Introduction and Objective: Pemvidutide is a GLP-1/glucagon dual receptor agonist in development for the treatment of obesity and metabolic dysfunction-associated steatohepatitis. Pemvidutide reduces cardiovascular (CV) disease risk factors (excess adiposity, total and LDL cholesterol, cardio-inflammatory lipids, visceral adipose tissue, liver fat content). In this study, its effects on parameters of CV safety were assessed. Methods: Systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR) and rate pressure product (RPP) were assessed in integrated analyses across 5 clinical trials. In a separate QT study, healthy volunteers receiving single ascending doses (SAD) up to 4.8 mg and multiple ascending doses (MAD) up to 3.0 mg once weekly for 12 weeks underwent continuous ECG recordings, and Friderica-corrected QT intervals (QTcF) were assessed by linear time-matched concentration-QTc analysis. Results: In integrated analyses, reductions in SBP and DBP up to 13.0 mmHg and 6.5 mmHg, respectively, were observed without dose-related or clinically meaningful effects on RPP or HR or imbalances in cardiac adverse events. In QTc analyses, mean (90% CI) predicted placebo-corrected change in QTcF (∆∆QTcF) was <10 ms at all pemvidutide concentrations (Figure 1). Conclusion: Pemvidutide reduces SBP and DBP without clinically meaningful effects on QTc or HR and no imbalances in cardiac adverse events. Disclosure S. Tomah: Employee; Altimmune Inc. Stock/Shareholder; Altimmune Inc. J. James: Consultant; Altimmune Inc. S.K. Browne: Employee; Altimmune Inc. B. Darpo: None. M.S. Roberts: Employee; Altimmune Inc. J.J. Suschak: Employee; Altimmune Inc. L. He: None. J. Yang: Employee; Altimmune Inc. M. Harris: Employee; Altimmune Inc.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"6 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"1408-P: Metabolic Dysfunction–Associated Steatohepatitis as a Risk Factor for Worse Outcomes in Patients Admitted for Diabetic Ketoacidosis","authors":"DIEGO MATEO CORNEJO GONZALEZ, DANIEL GUIFARRO","doi":"10.2337/db25-1408-p","DOIUrl":"https://doi.org/10.2337/db25-1408-p","url":null,"abstract":"Introduction and Objective: Diabetic ketoacidosis (DKA) is a severe complication in Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). Metabolic dysfunction-associated steatohepatitis (MASH) refers to fatty liver with inflammation in patients with metabolic syndrome criteria including diabetes. We aimed to study if MASH increases mortality in DKA. Methods: Using data from the NIS from 2017 to 2021, we analyzed patients with T1D and T2D admitted for DKA to evaluate whether MASH is a risk factor for worse outcomes, including mortality. Statistical analysis was performed using logistic regression, adjusting for confounders. Risk was assessed by calculating odds ratio (OR) utilizing STATA 18. Results: 315,755 cases of DKA were identified, including 2,065 patients with T1D and MASH and 3,925 patients with T2D and MASH. MASH was identified as a risk factor for increased mortality in patients with DKA, with a higher risk in T1D (OR: 2.17; 95% CI: 1.04-4.53; P < 0.05) compared to T2D (OR: 1.45; 95% CI: 1.12-1.89; P < 0.01). Additionally, MASH was associated with other adverse outcomes including longer hospital stays (Table 1). Conclusion: MASH is associated with worse outcomes in both T1D and T2D patients admitted for DKA. Further studies are needed to explore this relationship, considering additional factors such as age, hemoglobin A1C levels, and current treatment regimens. Disclosure D. Cornejo Gonzalez: None. D. Guifarro: None.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"10 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"627-P: Learnings from Equitably Developing and Administering a Survey for the National Center for Engagement in Diabetes Equity Research (CEDER)","authors":"CLAIRE COOPER, TABIA AKINTOBI, STEPHANIE L. ALBERT, SANDRA ALBRECHT, MONA AUYOUNG, DEDRA BUCHWALD, CLAIRE K. TOWNSEND, GLORIA KIM, DAVID W. LOUNSBURY, ADITI LUITEL, KARINA D. RAMIREZ, EMMA RODGERS, SARAH A. STOTZ, RAKALE C. QUARELLS, CHAU TRINH-SHEVRIN, JENNIFER A. WONG, LAURA WYATT, JENNIFER ZANOWIAK, ARLEEN BROWN, EARLE CHAMBERS, NADIA ISLAM","doi":"10.2337/db25-627-p","DOIUrl":"https://doi.org/10.2337/db25-627-p","url":null,"abstract":"Introduction and Objective: The National Center for Engagement in Diabetes Equity Research (CEDER) fosters nationwide collaborations to increase engagement and equity in type 2 diabetes research. Co-led by community and academic partners, CEDER utilizes a partnership hub (PH) and steering committee (SC), comprising diverse members, to provide input on CEDER’s model. We describe lessons learned on how to advance equity in co-developing and co-administering CEDER’s national needs & asset assessment. Methods: CEDER staff and faculty trained in community-based participatory methods developed a survey and outreach plan from March-June 2024. Materials were shared in advance of and during 5 PH and SC meetings; two 1.5 hour listening sessions with 12 community-based and academic partners from varied geographical locations and experience with diverse populations; and were disseminated through partner networks to broaden reach/input. To increase accessibility, partners could share written or oral feedback. Feedback was iteratively synthesized and applied to improve relevance and acceptability of the materials and strategies. Results: Lessons learned were: 1) Include community members earlier in the development phase; 2) Include more iterations to incorporate feedback adequately; 3) Leverage non-traditional engagement methods, including informational videos and use of existing networks to boost participation from community-based organizations; and 4) Ensure materials language, tone, and content resonate with different audiences, which may require cultural and linguistic tailoring. Conclusion: Coordinating national efforts to assess diabetes equity research across diverse partners and underrepresented communities highlights challenges in community-partnered research. When developing materials, centers may benefit from implementing processes to better integrate and balance community participation and perspectives. Disclosure C. Cooper: None. T. Akintobi: None. S.L. Albert: None. S. Albrecht: None. M. AuYoung: None. D. Buchwald: Advisory Panel; Novo Nordisk. C.K. Townsend: None. G. Kim: None. D.W. Lounsbury: None. A. Luitel: None. K.D. Ramirez: None. E. Rodgers: None. S.A. Stotz: None. R.C. Quarells: Consultant; UCB Pharmaceutical Company. C. Trinh-Shevrin: None. J.A. Wong: None. L. Wyatt: None. J. Zanowiak: None. A. Brown: None. E. Chambers: None. N. Islam: None. Funding U2CDK137135","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"11 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"1321-P: Quantifying and Adjusting for Classification Uncertainty in Type 2 Diabetes Subtypes","authors":"TIM MORI, OANA P. ZAHARIA, KLAUS STRASSBURGER, JOHN M. DENNIS, MICHAEL RODEN, ROBERT WAGNER, OLIVER KUSS","doi":"10.2337/db25-1321-p","DOIUrl":"https://doi.org/10.2337/db25-1321-p","url":null,"abstract":"Introduction and Objective: Despite continued interest in type 2 diabetes subtypes, the challenge of uncertainty in the classification of individuals into subtypes remains. This study introduces a novel method for quantifying and adjusting for classification uncertainty in type 2 diabetes subtypes. Methods: Building on recommendations from the ADA/EASD Precision Medicine in Diabetes Initiative, we quantified individual classification uncertainty using the normalized relative entropy (NRE), computed from distances to cluster centroids. A lower NRE value indicates greater uncertainty. We examined the NRE of 859 individuals with recent-onset type 2 diabetes from the German Diabetes Study (GDS) and compared it across previously identified diabetes subtypes, defined by age, BMI, HbA1c, HOMA-IR, and HOMA-B. Predicted 10-year cardiovascular disease (CVD) risk (SCORE2-Diabetes) of the subtypes was evaluated with and without adjustment for classification uncertainty. Results: The median NRE of individuals with type 2 diabetes (age 54±10 years, BMI 31.6±6.2 kg/m2, HbA1c 6.4±0.9%) was 0.127 (95% CI: 0.119-0.135). Individuals with mild age-related diabetes (n=395) and mild obesity-related diabetes (n=316) had a median NRE of 0.155 (95% CI: 0.142-0.177) and 0.119 (95% CI: 0.107-0.131). By contrast, individuals with severe insulin-resistant diabetes (n=130) and severe insulin-deficient diabetes (n=18) had a lower median NRE of 0.086 (95% CI: 0.075-0.108) and 0.082 (95% CI: 0.071-0.109). After adjustment, the proportion of variation in SCORE2-diabetes explained by the subtypes (R2) increased from 17.4% (95% CI: 12.8-23.0) to 31.5% (95% CI: 26.4-37.1). The predicted 10-year CVD risk of the mild age-related diabetes subtype increased from 10.3% (95% CI: 9.8-10.7) to 11.6% (95% CI: 11.2-12.0). Conclusion: Classification uncertainty varied between subtypes and individuals with type 2 diabetes, and adjusting for it improved the ability of the subtypes to predict 10-year CVD risk. Disclosure T. Mori: None. O.P. Zaharia: None. K. Strassburger: None. J.M. Dennis: None. M. Roden: Research Support; Boehringer-Ingelheim. Advisory Panel; Echosens. Speaker's Bureau; Madrigal Pharmaceuticals, Inc. Advisory Panel; MSD Life Science Foundation. Board Member; Novo Nordisk. Advisory Panel; TARGET PharmaSolutions, Inc. R. Wagner: Speaker's Bureau; Boehringer-Ingelheim, Novo Nordisk. Advisory Panel; Sanofi. Speaker's Bureau; Sanofi. Advisory Panel; Lilly Diabetes. O. Kuss: None.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"28 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2182-LB: Development and Characterization of a Humanized GLP-1 Receptor Mouse Model for the Evaluation of Small-Molecule GLP1R Agonists","authors":"NINA SONNE, KRISTOPHER ABNEY, MICHAEL FEIGH, HENRIK H. HANSEN, CHRISTOPHER JONES, OLIVIA OSBORN, MALENE L. RIIS, SUSANNE E. PORS, MICHELE CAVALERA, LINE F. ZACHARIASSEN, MARCO TOZZI","doi":"10.2337/db25-2182-lb","DOIUrl":"https://doi.org/10.2337/db25-2182-lb","url":null,"abstract":"Introduction and Objective: Injectable peptide-based GLP-1 receptor agonists (GLP1RAs) have emerged as effective therapies for obesity and diabetes. However, peptide-based GLP1RAs present challenges related to patient compliance and scalable production. Small-molecule GLP1RAs offer advantages in oral administration but exhibit poor activity on rodent GLP1R, complicating preclinical pharmacodynamic assessments. To improve translational relevance, we developed a humanized GLP1R (hGLP1R) mouse model using CRISPR-Cas9 gene editing, replacing the endogenous murine receptor with the human form. Methods: The hGLP1R mouse model was generated by replacing the murine GLP1R with the human GLP1R using CRISPR-Cas9 gene editing. Immunohistochemical analyses confirmed hGLP1R expression in pancreatic beta cells, brain stem, and hypothalamus. Pharmacological characterization included single-dose and chronic treatment studies evaluating the metabolic effects of semaglutide (peptide GLP1RA) and orforglipron (small-molecule GLP1RA) in both lean and DIO hGLP1R and wt mice. Additionally, 3D whole-brain imaging was performed to assess central target engagement. Results: Single-dose studies in lean hGLP1R mice showed comparable efficacy of semaglutide and orforglipron on body weight, food intake, glucose tolerance, and conditioned taste aversion. Semaglutide, but not orforglipron, also demonstrated metabolic effects in lean wt mice. Chronic semaglutide and orforglipron treatment significantly reduced body weight, whole-body fat mass, and food intake in DIO hGLP1R mice, with no effect of orforglipron observed in DIO wild-type mice. 3D whole-brain imaging confirmed activation of canonical appetite-regulating brain regions by both semaglutide and orforglipron in hGLP1R mice. Conclusion: These findings validate the Gubra hGLP1R mouse as a relevant preclinical model to advance preclinical development of small-molecule GLP1RAs for the treatment of obesity and related metabolic disorders. Disclosure N. Sonne: None. K. Abney: Research Support; TERNS Pharmaceuticals. M. Feigh: None. H.H. Hansen: None. C. Jones: Employee; TERNS Pharmaceuticals. O. Osborn: None. M.L. Riis: None. S.E. Pors: None. M. Cavalera: None. L.F. Zachariassen: None. M. Tozzi: None.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"63 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"1154-P: Increasing Awareness and Identification of Maturity-Onset Diabetes of the Young (MODY) in a Pediatric Diabetes Clinic","authors":"RAYMOND J. KREIENKAMP, JESSICA RUIZ, SARAH F. SCHLEGEL, OLIVIA R. STERNS, TARA K. MAXWELL, CHRISTINE CHERELLA, ERINN RHODES","doi":"10.2337/db25-1154-p","DOIUrl":"https://doi.org/10.2337/db25-1154-p","url":null,"abstract":"Introduction and Objective: MODY is frequently misdiagnosed, but accurate diagnosis can afford alternate management options. Prevalent barriers to MODY identification include lack of familiarity with MODY testing guidelines and insurance denial for testing. We launched a quality improvement (QI) project in 2022 at a pediatric, tertiary care center which aimed to: (1) increase the number of MODY tests ordered on pancreatic autoantibody (PAA)-negative patients diagnosed with diabetes and (2) increase provider awareness of MODY. Methods: A monthly electronic health record report was generated with patients diagnosed with PAA-negative new-onset diabetes mellitus (NODM) in the prior 3 months with an appointment scheduled in the reporting month. For each patient, a templated email was sent to the provider before the clinic visit that (1) noted the PAA-negative status, (2) outlined MODY testing criteria, and (3) provided instructions for ordering MODY testing, if indicated. The number of MODY tests ordered was tracked and analyzed on a control chart. Provider awareness of MODY and feedback on the process was assessed using 2 REDCap surveys in 5/2023 and 3/2024. Results: Among PAA-negative patients with NODM diagnosed within 365 days of a visit in the calendar year (CY) quarter, the average percentage of MODY tests ordered increased from 1.97% at baseline (CY Q3’20 - Q4’21) to 8.20% (CY Q1’22 - Q1’24). Providers indicating that they were “extremely” familiar with criteria for MODY testing increased from 0% to 17%. Among responding providers who received an email (n=6), all felt that the email increased their likelihood of sending MODY testing, with 50% describing that it did so “quite a bit” or “extremely.” Conclusion: An email to providers of PAA-negative patients with NODM was associated with an increase in MODY testing and awareness of MODY in a pediatric diabetes clinic. This simple intervention has potential for expansion to other programs to improve detection of MODY. Disclosure R.J. Kreienkamp: None. J. Ruiz: Research Support; Dexcom, Inc. S.F. Schlegel: None. O.R. Sterns: None. T.K. Maxwell: None. C. Cherella: Consultant; Intellia Therapeutics. E. Rhodes: Other Relationship; National Institutes of Health. Funding National Institute of Health (T32DK007699 (RJK, JLR))","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"49 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"825-P: AI-Based Optimization of Patient Eligibility for Oral Insulin Treatment—A Post Hoc Analysis to Identify Responders","authors":"ROY ELDOR, MIRIAM KIDRON, ROY H. WOLF, SHAY CHAIM, RAPHAEL GIAMI, BOAZ LERNER","doi":"10.2337/db25-825-p","DOIUrl":"https://doi.org/10.2337/db25-825-p","url":null,"abstract":"Introduction and Objective: In a Phase III, randomized, placebo-controlled, multi-center study in which T2DM patients were treated with oral insulin for 26 weeks, the primary endpoint defined as a decrement of 0.6% HbA1c by end of treatment was not met. A post-hoc analysis aimed to identify subpopulations with substantial clinical responses to treatment. Methods: Explainable AI (XAI) and Phase II data (n=206) collected with the same oral insulin formulation were used to train a model to estimate the expected treatment effect in the Phase III trial (n=489). The analysis also sought to identify causal interrelations among markers that could explain treatment-disease mechanisms and recommend responder profiles. Profiles were validated using real-world data (RWD) of ~2,200 T2DM patients to guarantee sufficient representation in the T2DM patient population. Results: XAI-identified demographic (e.g., age, sex), clinical (e.g., BMI), and biological (e.g., baseline HbA1c) markers provided optimal responder profiles that enabled ~1% HbA1c reduction over placebo. Profiles derived based on Phase II data were similarly accurate on Phase III data (ρ=0.96). Conclusion: Variability in response to oral insulin can be minimized by segmenting the population based on BMI and other clinical and biological markers. These findings will inform eligibility criteria for a newly planned Phase III study. Disclosure R. Eldor: Consultant; Oramed Pharmaceuticals. Speaker's Bureau; Novo Nordisk, Lilly Diabetes, Sanofi, Medtronic. Stock/Shareholder; Oramed Pharmaceuticals. Speaker's Bureau; Novartis Pharmaceuticals Corporation, Boehringer-Ingelheim. M. Kidron: Board Member; Oramed Pharmaceuticals. Employee; Oramed Pharmaceuticals. Stock/Shareholder; Oramed Pharmaceuticals. R.H. Wolf: Other Relationship; Oramed Pharmaceuticals. S. Chaim: None. R. Giami: Other Relationship; Oramed Pharmaceuticals. B. Lerner: None.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"21 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}