Diabetes最新文献

{"title":"719-P: Oral Disposition Index (oDI) as an Outcome Measure in Type 1 Diabetes (T1D) Clinical Trials—Evidence from Stage 1 and Stage 2 Trials","authors":"ALFONSO GALDERISI, DAVID D. CUTHBERTSON, ALESSANDRA PETRELLI, ANTOINETTE MORAN, JAY SOSENKO, LAURA M. JACOBSEN, INGRID LIBMAN, MARIA J. REDONDO, HEBA M. ISMAIL","doi":"10.2337/db25-719-p","DOIUrl":"https://doi.org/10.2337/db25-719-p","url":null,"abstract":"Introduction and Objective: Metabolic endpoints are being explored for treatment response in T1D prevention trials. Measures combining both insulin secretion and sensitivity could be more sensitive markers of treatment effect in clinical trials. Methods: We compared OGTT-derived AUC C-peptide and C-peptide index (CPI) as measures of secretion, and the oDI (AUC Insulin*Matsuda Index) as a measure of β-cell function including both secretion and sensitivity in two TrialNet trials in Stage 1 (TN18, Abatacept for 12 months) and Stage 2 (TN10, Teplizumab for 14 days) T1D. We compared measures over time and after 2 years of treatment between treated and placebo arms. Results: In TN10, Teplizumab had a greater effect on AUC C-peptide (p=0.008) and CPI (p<0.001) compared to placebo after 2 years; oDI did not differ (p=0.241). Conversely, in TN18, oDI was higher in the Abatacept arm compared to placebo (p<0.001) with no differences in AUC C-peptide (p=0.270) and CPI (p=0.194). Further, in TN18, there was a positive change in oDI from baseline in the treated arm (p<0.001), Figure 1. Conclusion: The oDI appears to be more sensitive at detecting differences in Abatacept effect in Stage 1, while C-peptide measures identifies long-term effect of Teplizumab in Stage 2. This could be due to both secretion and sensitivity playing a stronger role in Stage 1, which is better seen over a longer period of time. Disclosure A. Galderisi: None. D.D. Cuthbertson: None. A. Petrelli: None. A. Moran: Research Support; Abbott. Consultant; Abata Therapeutics. Other Relationship; Novo Nordisk. J. Sosenko: None. L.M. Jacobsen: Advisory Panel; Sanofi. I. Libman: None. M.J. Redondo: None. H.M. Ismail: Consultant; Rise Therapeutics. Funding NIDDK (K23DK129799)","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"87 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288247","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":"138-OR: Cellular and Gene Therapy Development for Severe Hypoglycemia via Direct Innovative Cell Conversion","authors":"MASAHITO MATSUMOTO","doi":"10.2337/db25-138-or","DOIUrl":"https://doi.org/10.2337/db25-138-or","url":null,"abstract":"Introduction and Objective: Direct cell fate conversion (DIVER), which bypasses pluripotent stem cells, enables somatic cells to directly transform into functional target cells. This next-generation regenerative medicine technology holds promise for severe diabetes mellitus. However, efficiency, quality, and safety improvements remain essential for clinical translation. Methods: We developed a novel DIVER protocol incorporating Ngn3, MafA, Pdx1, and a newly identified \"K-factor.\" This protocol induces pancreatic islet-like cells (DiBic) from somatic cells in a single step. The efficacy of these cells was assessed through transplantation into streptozotocin (STZ)-induced type 1 diabetic mice. Additionally, in vivo gene therapy was tested using transgenic K-factor expression. Results: Our technology achieved over 80% conversion efficiency to insulin-producing cells. Transplanted DiBic reduced blood glucose and HbA1c in diabetic mice. The in vivo gene therapy normalized hyperglycemia within days. Immunohistochemistry confirmed robust insulin production in converted cells, demonstrating K-factor's ability to induce direct somatic cell reprogramming with high efficiency. Conclusion: Our findings establish a highly efficient and reproducible DIVER technology for cellular and gene therapy applications. This platform has transformative potential for the treatment of diabetes, either as a standalone regenerative therapy or in combination with existing treatments such as insulin injections or stem cell technologies. This study represents a critical step toward the practical application of regenerative medicine for severe diabetes mellitus. Disclosure M. Matsumoto: None. Funding Japan Agency for Medical Research and development, AMED (24bm1223024h0001, 24ym0126110h0002), JSPS KAKENHI (JP24936409), JST START Project Promotion Type (JPMJSF2307), Juntendo President Special Research Program Seeds A (GP22A-004, 2022-24), Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics, KOSE Cosmetology Research Foundation","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"90 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288316","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":"1640-P: Targeting Cathepsin L for Liver Fibrosis—Mechanistic Insights and Therapeutic Potential in a Diabetic Mouse Model","authors":"MING-JIA LI, MIAOMIAO ZHAO, JIN-KUI YANG","doi":"10.2337/db25-1640-p","DOIUrl":"https://doi.org/10.2337/db25-1640-p","url":null,"abstract":"Introduction and Objective: Diabetes and non-alcoholic fatty liver disease (NAFLD) are closely linked, with type 2 diabetes markedly increasing the risk of NAFLD. Our prior research identified the lysosomal enzyme Cathepsin L (CTSL) as upregulated in diabetic patients, with high glucose levels activating CTSL function (PMID: 39150053). Notably, CTSL may cleave Collagen18A1 to generate endostatin, which activates hepatic stellate cells and accelerates fibrosis. Methods: We developed a novel CTSL inhibitor that specifically targets CTSL with minimal side effects. The role and mechanism of CTSL in liver fibrosis were investigated. Results: High glucose induced CTSL maturation in human hepatocellular carcinoma cells (Huh7). Conditioned media from glucose-treated Huh7 cells activated human hepatic stellate cells (LX-2), increasing the expression of Collagen I and αSMA. In a db/db diabetic mouse model of liver fibrosis, tissue structure and pathological changes were assessed using HE staining, fibrosis severity by Sirius red staining, and inflammation infiltration by F4/80 immunohistochemistry. Treatment with the CTSL inhibitor significantly improved liver histology, reducing fibrosis and inflammation. Conclusion: The CTSL inhibitor effectively alleviated fibrosis and inflammation in db/db diabetic mice, highlighting its potential as a therapeutic agent for NAFLD. Disclosure M. Li: None. M. Zhao: None. J. Yang: None. Funding National Natural Science Foundation of China (82341076)","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"1 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288418","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":"233-OR: Occurrence and Impact of Missing Data on CGM Metrics—Analysis of Data from Type 1 Diabetes Exercise Initiative (T1DEXI)","authors":"DONGYING ZHAN, SIMON J. FISHER, XIAOHUA D. ZHANG","doi":"10.2337/db25-233-or","DOIUrl":"https://doi.org/10.2337/db25-233-or","url":null,"abstract":"Introduction and Objective: Missing CGM data can confound clinical decision making. This study explores the impact of data missingness on CGM metrics from the T1DEXI study. Methods: Study 1: Gaps in CGM data were determined based on time intervals between consecutive readings. Study 2: To evaluate the effect of gap sizes on CGM parameters, a simulation study randomly introduced missing data with gap sizes of 1-10, 11-50, or >50 continuous missing data points while maintaining the same overall missing rate of 20.83% in all groups. CGM glucose metrics including mean, SD, CV, TAR, TIR, and TBR (see Figure B for abbreviations), were compared to a control group with no missing data. Results: In the T1DEXI CGM dataset, gaps of 1-10 account for 15.76% of all missingness but 68.47% of the frequency, gaps of 11-50 account for 41.06% of all missingness and 25.44% of the frequency, and gaps of >50 account for 43.18% of all missingness but only 6.09% of the frequency. The simulation study showed that, compared to smaller missing gaps, larger gaps resulted in higher Mean Absolute Percentage Error (Figure B). Conclusion: Small gaps in CGM data are frequent but cause minimal errors; whereas large data gaps, though less frequent are associated with large errors in CGM metrics particularly in TAR and TBR. These findings highlight the need for accurate prediction of large gaps to improve CGM data interpretation. Disclosure D. Zhan: None. S.J. Fisher: None. X.D. Zhang: None. Funding This research was supported by US National Institutes of Health (through Grants U01DK135111 and UL1TR001998), the DRC at Washington University (Grant No. P30DK020579), the University of Kentucky Diabetes and Obesity Research Priority Area and the Barnstable Brown Diabetes and Obesity Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This publication is based on the data from the Type 1 Diabetes EXercise Initiative (T1DEXI) Study that has been made available through Vivli, Inc. Vivli has not contributed to or approved, and is not in any way responsible for the contents of this publication.","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":"144288317","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":"1514-P: Presentation of Diabetic Ketoacidosis (DKA) at the Time of Diagnosis of Type 1 Diabetes Mellitus (T1DM) by Race and Ethnicity in a Large Integrated Health Care System","authors":"SATISH MUDIGANTI, PRAGATI KENKARE, DAVID KERR","doi":"10.2337/db25-1514-p","DOIUrl":"https://doi.org/10.2337/db25-1514-p","url":null,"abstract":"Introduction and Objective: DKA at the time of first presentation of T1DM is preventable. The aim of this study was to determine the proportion of individuals with a new onset T1DM, by race and ethnicity, presenting with DKA in a large integrated healthcare system based in Northern California (Sutter Health). Methods: ICD-9 and ICD-10 codes were used to identify adults and children with DKA one month either side of a new diagnosis of T1DM, between January 2016 and September 2024. T1DM cases were identified using prescription for insulin and relevant codes in the electronic health record problem list, or billing data. Testing for the difference in proportion of T1DM patients with DKA were made using the Pearson Chi-Square test. Results: Of 10,956 new T1DM patients, 699 (6.4%) had a co-diagnosis of DKA within one month of a first diagnosis of T1DM. Rates of T1DM presenting with DKA were different by race/ethnicity (p<0.0001) comparing White (5.9%) vs Hispanic (7.8%), Black (10.2%), and Asian (6.6%) patients. Across age groups, the rate of DKA within one month of a first diagnosis of T1DM was highest among those aged 18-25 years (p<0.0001). Conclusion: The risk of DKA at the first presentation of T1DM varies by race and ethnicity. As DKA is preventable, greater efforts are required to reduce this disproportionate risk especially for communities of color. Disclosure S. Mudiganti: None. P. Kenkare: None. D. Kerr: None.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"51 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288380","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":"1500-P: Global Trends in Mortality and Disability Adjusted Life Years (DALYs) of Type 1 Diabetes Mellitus in Adolescents and Young Adults (15–39y) from 1990 to 2021","authors":"MUHAMMAD USMAN HAIDER, HUSNAIN AHMAD, IFFAT A. MAGSI, MIAN ZAHID JAN KAKAKHEL, UMAR HAYAT, ISHTIAQ AHMAD","doi":"10.2337/db25-1500-p","DOIUrl":"https://doi.org/10.2337/db25-1500-p","url":null,"abstract":"Introduction and Objective: Type 1 Diabetes Mellitus (T1DM) poses a substantial global health burden, particularly among adolescents and young adults. This study examines trends in Disability-Adjusted Life Years and mortality associated with T1DM from 1990 to 2021. Methods: Data on DALYs and mortality for individuals aged 15-39 years were collected from Global Burden of Disease study and analyzed using Joinpoint regression models. APC and AAPC were calculated to identify temporal trends. Statistical significance was determined using p-values (<0.05). Results: From 1990 to 2021, T1DM caused a combined 495562 deaths and 40819490 DALYs. DALYs exhibited a slight overall decline (AAPC: -0.0657, 95% CI: -0.098 to -0.028, p = 0.0016), with the most significant reduction from 2000 to 2012 (APC: -0.8420, 95% CI: -0.946 to -0.750, p = 0.0192). However, a slight increase was noted between 2012 and 2021 (APC: 0.2190, 95% CI: 0.091 to 0.375, p = 0.0128). Mortality rates declined more pronouncedly (AAPC: -0.3514, 95% CI: -0.387 to -0.3088, p < 0.000001), with the decrease during 2000-2011 (APC: -1.4747, 95% CI: -1.841 to -1.400, p < 0.000001). Slight increases occurred during 2014-2017 (APC: 0.8121, 95% CI: 0.340 to 1.134, p = 0.0044). Conclusion: While the global burden of T1DM has generally declined, periods of increasing trends highlight the need for sustained public health efforts and research into contributing factors. Disclosure M. Haider: None. H. Ahmad: None. I.A. Magsi: None. M. Kakakhel: None. U. Hayat: None. I. Ahmad: None.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"593 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288583","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":"1208-P: Parent–Teen Agreement on Teen Diabetes Self-Efficacy (DSE) Relates to Psychosocial Well-Being","authors":"LUCAS S. MATZENBACHER, LIANE J. TINSLEY, BARBARA J. ANDERSON-THOMAS, LISA K. VOLKENING, LORI M. LAFFEL","doi":"10.2337/db25-1208-p","DOIUrl":"https://doi.org/10.2337/db25-1208-p","url":null,"abstract":"Introduction and Objective: Teens and parents may have different perceptions of teens’ DSE. We investigated how agreement on teen DSE between teens with T1D and their parents impacts psychosocial outcomes. Methods: Teens with T1D (ages 13-17) and their parents completed parallel surveys measuring DSE, diabetes family conflict, emotional responses to BG checks, diabetes distress, parent involvement, T1D care adherence, and quality of life at 0, 6, and 12 mo. Baseline teen and parent DSE scores were categorized as high or low by the median and used to classify teen-parent dyads as ‘agreement on high’, ‘agreement on low’, ‘discordant (teen higher)’, and ‘discordant (parent higher)’. Linear mixed models evaluated impact of baseline DSE agreement on psychosocial outcomes over 1 year. Results: Among 296 teens (50% female; 78% white; age 15.0±1.3 yrs; T1D duration 6.6±3.7 yrs) and their parents, agreement on low DSE was associated with worse psychosocial outcomes for teens and parents (Table) compared with agreement on high DSE. Discordance (parent higher) only affected teen outcome for lower teen self-care. When parents reported low teen DSE, parents experienced worse psychosocial outcomes regardless of teen perception. Conclusion: Agreement between teens and parents on DSE relates to psychosocial outcomes, emphasizing the importance of considering perspectives of both teens and parents in assessment of psychosocial dimensions of T1D. Disclosure L.S. Matzenbacher: None. L.J. Tinsley: None. B.J. Anderson-Thomas: None. L.K. Volkening: None. L.M. Laffel: Advisory Panel; Boehringer-Ingelheim, Sanofi, MannKind Corporation, Medtronic, Vertex Pharmaceuticals Incorporated, Tandem Diabetes Care, Inc, Insulet Corporation. Research Support; Dexcom, Inc. Advisory Panel; Sequel Med Tech. Other Relationship; Janssen Pharmaceuticals, Inc. Consultant; Arbor Biotech. Funding NIH (R01DK095273); JDRF (2-SRA-2014-253-M-B)","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"225 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288640","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":"1865-LB: Association between Bariatric Surgery and Albuminuria in Adolescents with and at Risk of Diabetes","authors":"KANCHANA PERERA, JOHN BAKER, KAREN A. PICKERING, PATRICIA J. HARRY, BRANDON J. ORR-WALKER, DAVID SIMMONS","doi":"10.2337/db25-1865-lb","DOIUrl":"https://doi.org/10.2337/db25-1865-lb","url":null,"abstract":"Introduction and Objective: Obesity is a major health issue worldwide, with a higher rate of severe obesity among adolescents in South Auckland compared to other parts of New Zealand. While bariatric surgery is an effective treatment for severely obese adults, there is limited evidence on its effectiveness for adolescents. This study will explore how intensive lifestyle changes, with or without bariatric surgery, affect Urine Albumin Creatinine Ratio (UACR), a measure of kidney function, in Māori and Pasifika adolescents. Methods: Adolescents (15-17 years old) with a BMI≥35 followed a 12-week weight loss program using a Very Low-Calorie Diet (VLCD) based on the Optifast program. After 12 weeks, eligible participants were offered bariatric surgery. Longitudinal mixed effects models were used to analyze how surgery, gender, weight change, and time affected UACR levels. Results: Out of 21 participants (12F, 9M), 6 (4F, 2M) had bariatric surgery. The analysis showed no overall effect of time or surgery alone, but there was a significant interaction effect (p<0.001). Participants who had bariatric surgery showed a decrease in log(UACR), while those who didn't have surgery showed either a stable or increasing trend. Conclusion: Bariatric surgery significantly modifies the time effect on log(UACR), leading to a greater reduction in UACR levels over time compared to non-surgery participants, potentially predicting less significant or delayed nephropathy into the future. Disclosure K. Perera: None. J. Baker: None. K.A. Pickering: None. P.J. Harry: None. B.J. Orr-Walker: None. D. Simmons: Research Support; Novo Nordisk, AMSL. Other Relationship; Abbott, Abbott, Boehringer-Ingelheim. Speaker's Bureau; Ascensia Diabetes Care.","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":"144288644","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":"1402-P: Topical Administration of Recombinant Human Thrombomodulin Analogue BB-101 in Diabetic Foot Ulcer—A Randomized, Double-blind, Placebo-controlled, Sequential Dose Escalation, Phase I, Clinical Trial","authors":"JIUN-YAN DING, PAO-WEN FAN, CHIEN CHEN LIN, GUANG-HUAR YOUNG, LING-PEL LO, SRISAKUL CHAICHUUM","doi":"10.2337/db25-1402-p","DOIUrl":"https://doi.org/10.2337/db25-1402-p","url":null,"abstract":"Introduction and Objective: Diabetic foot ulcers (DFUs) are a severe complication of diabetes mellitus, characterized by impaired wound healing and high rates of chronicity. BB-101, a recombinant thrombomodulin analogue, mimics thrombomodulin's functions, promoting angiogenesis and fibroblast migration, with potential to enhance wound healing in DFU patients. The primary objectives are to evaluate the safety and tolerability of BB-101 compared with placebo group. Secondary objectives include proportion of subjects with target ulcer that heals within the 4-week treatment period and plasma concentration of BB-101. Methods: This study was a randomized, double-blind, placebo-controlled clinical trial in type 2 DM patients with DFU classified as Wagner grade 1-3, located on the lower leg or foot, with sizes ranging from 0.5-20.0 cm² after debridement. Fifteen participants were randomly assigned to one of three treatment arms: 2 μg/mL BB-101 (low-dose), 20 μg/mL BB-101 (high-dose) or placebo applied to the foot ulcer surface for a treatment duration of 4 weeks, followed by a 2-year follow-up. Weekly photography, quantitative planimetry, and physical examinations documented the ulcer appearance, surface area, and stage. Results: As a result of BB-101 treatment, none of the serious adverse events were attributed to the treatment, and no treatment-emergent adverse events led to dose interruption or withdrawal. Patients in either the low- or high- dose group tested negative for anti-BB-101 antibodies at any visit. The low-dose group showed wound reductions from 1.38-3.03 cm² to complete closure in some cases, while high-dose treatment achieved reductions from 4.39-2.67 cm² to 0.14 cm². Both groups demonstrated consistent and increasing wound tissue proliferation and significant healing progression. Conclusion: Participants receiving BB-101 represented excellent safety profile associated with DFU, paving the way for a new era in DFU care. This study lays the groundwork for further large scale randomized clinical studies. Disclosure J. Ding: Employee; Blue Blood Biotech Corp., Sanar Biotech Corp. P. Fan: None. C. Lin: Employee; Blue Blood Biotech Corp. Consultant; Sanar Biotech Corp. G. Young: None. L. Lo: None. S. Chaichuum: None.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"70 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288184","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":"1233-P: Metabolic Consequences of GCK Mutations—Does the Source of Inheritance—Mother or Father—Matter?","authors":"YANG LIU, YIFAN ZHANG, SHUHUI JI, WENLI FENG, YADI HUANG, JINYANG ZHEN, QIANNAN MA, MING LIU","doi":"10.2337/db25-1233-p","DOIUrl":"https://doi.org/10.2337/db25-1233-p","url":null,"abstract":"Introduction and Objective: Mutations in the glucokinase (GCK) gene are the primary cause of maturity-onset diabetes of the young (MODY), and the source of inheritance—whether maternal or paternal—may influence metabolic outcomes in offspring. However, this area has not been fully explored. To address this, we employed a novel GCK heterozygous inactivating mutation model (GCKmut), characterized by mild, non-progressive fasting hyperglycemia without dyslipidemia, to investigate the differential metabolic effects of maternal and paternal inheritance on offspring metabolism. Methods: The GCKmut inherited from the father is referred to as GCKmut (paternal), abbreviated as GCKmut (P), while the mutation inherited from the mother is termed GCKmut (maternal), abbreviated as GCKmut (M). Blood glucose and body weight of GCKmut offspring were monitored every one or two weeks from postnatal day 1 (P1) to 16 weeks. At 4 weeks, glucose tolerance was evaluated by intraperitoneal injection glucose tolerance test (IPGTT), and serum insulin content was detected by ELISA. Intracellular insulin content was assessed by Western blotting. At 16 weeks, insulin sensitivity was evaluated using an intraperitoneal insulin tolerance test (IPITT). Both male and female mice were included. Results: Compared to GCKmut (M), GCKmut (P) exhibited lower birth weight and serum insulin on P1, with slightly elevated blood glucose. By the first week, their blood glucose changes disappeared, and by the third week, their weight had caught up. At 16 weeks, GCKmut (P) showed impaired glucose tolerance and reduced serum insulin compared to GCKmut (M). Nevertheless, there were no significant differences in insulin and proinsulin levels or insulin sensitivity among the groups. Results were consistent for both male and female mice. Conclusion: Paternal inheritance of the GCKmut leads to reduced birth weight in newborns and disrupts glucose homeostasis in adulthood. Disclosure Y. Liu: None. Y. Zhang: None. S. Ji: None. W. Feng: None. Y. Huang: None. J. Zhen: None. Q. Ma: None. M. Liu: None. Funding National Key R&D Program (2022YFE0131400 and 2019YFA0802502), National Natural Science Foundation of China (82220108014), Tianjin Municipal Health Commission (TJWJ2021ZD001), Tianjin Medical University General Hospital Clinical Research Program (22ZYYLCZD02), Tianjin Municipal Science and Technology Commission (23JCQNJC00680), Discipline Research Special Project of Tianjin Medical University (2024XKNFM13), Discipline Research Special Project of Tianjin Medical University (2024XKNFM09).","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":"144288254","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}