bluuebunny/crossref_metadata_2025 huggingface dataset:
1437-P: Blood Pressure (BP) Trajectories and 32-Year Cardiovascular Disease (CVD) Incidence in Women and Men with Type 1 Diabetes (T1D)
Authors: MILLER RACHEL G. , ORCHARD TREVOR J. , COSTACOU TINA
Published: June 2024

While women have lower BP compared to men, CVD risk has been shown to increase at lower BPs in T1D compared to the general population, raising the need to better understand sex-specific effects of BP on CVD risk in T1D. We thus examined associations between longitudinal systolic (SBP) and diastolic (DBP) BP trajectories and 32-year CVD incidence in the Pittsburgh Epidemiology of Diabetes Complications T1D cohort separately in women and men (n=300 and 304 free of CVD at 1986-88 baseline respectively, mean age 27, T1D duration 19 yrs). SBP and DBP were measured at baseline and 2, 4, 6, 8, 10, 18, 25, and 30 years’ follow-up (median 6 measures per person). Associations between longitudinal BPs and time to first CVD event, defined as the first instance of coronary artery disease or stroke, were assessed separately in women and men using joint models which estimate the longitudinal data process and time-to-event data process simultaneously. Models were adjusted for time-varying anti-hypertensive (AH) medication use status and baseline T1D duration, HbA1c, and other CVD risk factors (HbA1c, lipids, BMI, smoking, kidney markers). On average SBP was 5.3 mmHg lower (p<0.0001) and DBP 6.1 mmHg lower (p<0.0001) over follow-up in women vs. men. SBP increased similarly in women (0.48/yr) and men (0.46/yr) but DBP decreased faster in women (-0.28/yr vs. men -0.13/yr, p=0.02). AH rates were similar in men and women over time (p=0.25), increasing from ~10 to 70% over follow-up in both. After adjustment for time-varying AH use and baseline covariates, longitudinal SBP was similarly associated with CVD in both women (HR=1.03, p=0.001) and men (HR=1.03, p<0.001) while longitudinal DBP had a slightly stronger association in women (HR=1.06, p=0.004; men: HR=1.04, p=0.04). Our results suggest that despite being significantly lower over time, BP remains an important CVD risk factor in women with T1D. Thus, further research into sex-specific BP goals is warranted to improve CVD risk reduction.

Disclosure

R.G. Miller: None. T.J. Orchard: None. T. Costacou: None.

Funding

American Diabetes Association (7-23-ICTSWH-19); NIDDK (R01DK034818)Rossi Memorial Fund (Pittsburgh, PA)
1453-P: Islet Autoantibody–Positive General Population Individuals Have Smaller Pancreas Volume Compared with Control Individuals
Authors: TRIOLO TAYLOR M. , VIROSTKO JOHN , WILLIAMS JONATHAN M. , BRONCUCIA HALI C. , HILMES MELISSA A. , REWERS MARIAN , MOORE DANIEL J. , POWERS ALVIN C. , STECK ANDREA , STUDY GROUP MAP-T1D
Published: June 2024

Introduction & Objective: Patients with type 1 diabetes (T1D) have a decline in pancreatic volume (PV) after onset. Previous studies of PV prior to onset have focused on islet autoantibody positive (AAb+) first-degree relatives (FDR) of patients with T1D who have decreased PV. Nothing is known about PV in AAb+ individuals identified from the general population.

Methods: We analyzed 10 individuals who were identified through general population screening to be multiple AAb+, had a recent oral glucose tolerance test (OGTT) and MRI through the Multicenter Assessment of the Pancreas in T1D (MAP-T1D) study. We compared PV index (PVI) of AAb+ general population individuals to multiple AAb+ FDR (n=78; 40 Stage 1, 26 Stage 2, 12 unknown Stage), individuals with T1D (n=93), and control individuals without T1D (n=90). PVI is normalized for weight which accounts for potential confounding from age or sex.

Results: Most AAb+ general population individuals were male (8/10) and non-Hispanic white (9/10). Most (8/10) were Stage 1, and 2 were Stage 2 T1D. Age at MRI was 15.6 ± 2.8 years with a mean HbA1c 5.3 ± 0.3 %, fasting glucose 87 ± 5 mg/dl and 2-hour OGTT glucose 103 ± 32 mg/dl. AAb+ general population individuals had a lower PVI 0.75 ± 0.17 ml/kg compared to control individuals 0.96 ± 0.25 ml/kg (p=0.03). The PVI of AAb+ general population individuals was similar to that of AAb+ FDR 0.85 ± 0.26 ml/kg (p=0.21). Individuals with T1D had a lower PVI 0.60 ± 0.24 ml/kg than AAb+ FDR (p<0.0001) but not AAb+ general population individuals (p=0.14).

Conclusion: AAb+ general population individuals and AAb+ FDR individuals have smaller PVI compared to control individuals without T1D. Individuals with T1D have a smaller PVI than AAb+ FDR. More study on pancreas size prior to T1D onset may help inform future prediction and prevention studies.

Disclosure

T.M. Triolo: None. J. Virostko: None. J.M. Williams: None. H.C. Broncucia: None. M.A. Hilmes: None. M. Rewers: Advisory Panel; Sanofi. Other Relationship; Sanofi. Consultant; Janssen Pharmaceuticals, Inc. Research Support; Juvenile Diabetes Research Foundation (JDRF). Consultant; Provention Bio, Inc. Research Support; Hemsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases. D.J. Moore: None. A.C. Powers: None. A. Steck: None.

Funding

NIDDK K23 DK136931
1459-P: Risk Factors for Metabolic Syndrome in Adults with Type 1 Diabetes in a Chilean Cohort
Authors: ORREGO MAITE , GARCÍA CLAUDIA , TORO LUIS , VARGAS OSCAR , GOMEZ PATRICIA C. , CLAUDIA VILLARROEL ANA , VEGA EDITH , SANZANA MARIA G.
Published: June 2024

Introduction: Risk factors associated with Metabolic Syndrome (MS) have been identified among patients with T1D, including obesity, insulin resistance (IR), family history of T2D, years since diagnosis, insulin total daily dose (TDD), and its method of administration. At a local setting, data on the impact of these variables are scarce.

Objective: To assess risk factors related to MS in adults with T1D from a Chilean cohort.

Methodology: Descriptive observational study using electronic health records from a tertiary hospital in Chile. Included were all T1D patients over 15 years with regular follow-ups between March 2020 and September 2023. Demographic, clinical, and laboratory variables were considered. MS prevalence followed the IDF 2005 definition (BMI ≥30 kg/m2 plus two other criteria). Statistical analysis using T-test and X2 depending on variables.

Results: A total of 44 patients were identified. The mean age was 42.9 (17-80) years, with 70.4% being female (n=31). The average BMI was 26.5±5.1 kg/m2, with 22.7% having a BMI ≥30 kg/m2. Insulin pump users were 38.6% (n=17, 15 on AID and 2 on PLGS). The mean A1C was 8.4±1.9%. Among the entire cohort, 6 patients (13.6%) met MS criteria, with arterial hypertension as the second most frequent criterion (83%). Besides weight and BMI, higher TDD and prandial insulin doses, and the presence of clinical signs of IR were identified as risk factors for MS (all with p<0.01). A non-significant trend was observed in those with a family history of T2D (p=0.06) and TDD ≥0.6 IU/kg/day (p=0.08). No relationship was found with years since diagnosis or insulin administration method, although potential biases may exist.

Conclusion: The prevalence of MS in adults with T1D aligned with international reports. Higher TDD and prandial insulin doses, along with clinical signs of IR, were identified as risk factors for MS. These findings highlight the need for individualized preventive and management strategies for MS in T1D, ultimately improving overall health outcomes.

Disclosure

M. Orrego: None. C. García: None. L. Toro: None. O. Vargas: None. P.C. Gomez: None. A. Villarroel: None. E. Vega: None. M.G. Sanzana: None.
1462-P: Genetic Risk Score for Type 1 Diabetes across Ethnic Populations via Multitask Learning
Authors: LI MINGQIAN , LIN FENG , ZHANG CONGJING , VEHIK KENDRA , PARIKH HEMANG M. , ORAM RICHARD A. , QIAN XIAONING , HUANG SHUAI
Published: June 2024

Introduction: Genetic risk scores (GRS) for the prognosis of Stage 3 type 1 diabetes (T1D) are potentially biased due to the predominant race/ethnicity (European) from which they were derived. We examined the performance of the current GRS2 model in The Environmental Determinants of Diabetes in the Young (TEDDY) study across different ethnic groups and proposed a fair GRS model using multi-task learning (MTL).

Methods: Through the lens of Multi-Task Learning (MTL), we incorporated different group lasso (GL) regularization strategies and have extracted commonly shared and different group-wise features among ethnic groups based on the identified single nucleotide polymorphisms (SNPs) set utilized by the published GRS2 model. Receiver operating characteristic area under the curve (ROC-AUC) is used to test performance by ethnicity.

Results: We studied 4,918 Europeans (ethnic majority), and 2,468 non-Europeans (ethnic minority) children; 274 ethnic majority and 116 ethnic minority children developed T1D. Our MTL-based strategy resulted in an improved GRS2 for each ethnic minority group. The ROC-AUC performance for the ethnic minority population demonstrated an improvement, increasing from 0.679 to 0.713, indicating a fairer prognosis performance compared to the 0.728 of the GRS2 for the ethnic majority population, which uses the 67 SNPs as features for different ethnic groups.

Conclusion: MTL with different regularization strategies for developing fair GRS models improved T1D prognosis performance for ethnic minority groups in TEDDY. Future efforts should aim to derive fair GRS models by considering fairness metrics when searching for predictive genetic markers.

Disclosure

M. Li: None. F. Lin: None. C. Zhang: None. K. Vehik: None. H.M. Parikh: None. R.A. Oram: Research Support; Randox R & D. Consultant; Provention Bio, Inc., Sanofi. X. Qian: None. S. Huang: None.
1463-P: Genetic Heterogeneity and Clinical Subtypes of Type 1 Diabetes
Authors: SHI YU , YUE TONG , TAN HUILING , DING YU , PAN LANXIN , GUO CHUANG , LUO SIHUI , ZHENG XUEYING , WENG JIANPING
Published: June 2024

Introduction & Objective: Type 1 diabetes (T1D) is a heterogeneous disorder; however, the extent to which genetic and clinical factors distinguish T1D patient’s subgroups remains uncertain. We aimed to incorporate HLA alleles and their interactions and then develop a novel T1D Genetic Risk Score (GRS). Also, we utilized a phenome-wide association study (PheWAS) to refine T1D subtype classification.

Methods: Among 1,352 Chinese T1D cases and 1,602 healthy controls, we used logistic regression to identify HLA class I and II alleles associated with T1D risk and combined significant loci to create the GRS. We modeled interactions between alleles marking strongly associated HLA haplotypes. Then, we employed PheWAS to assess the associations between 43 phenotypes and risk genotypes.

Results: T1D patients had reduced polymorphisms in HLA alleles and attenuated linkage disequilibrium between alleles compared to controls. The HLA-DRB1*09:01-HLA-DQA1*03:02 loci were significantly associated with the risk of T1D. Additionally, HLA-B*58:01 and HLA-C*3:02 exhibited associations with T1D and linkage with the DR3 haplotype. We observed a stronger genetic risk associated with an earlier onset age, especially in childhood-onset patients (p<0.001) based on the PheWAS and GRS. A significant association was found between lower ALT (p<0.01) and higher GAD antibody titers (p<0.001) and increased genetic risk in adult-onset patients.

Conclusion: Our study characterized the HLA type and the association of genetic risk in Chinese T1D patients with different ages of onset and autoantibody titers. We translated the T1D genetic and clinical subtypes to further our understanding of the etiology of these subtypes.

Disclosure

Y. Shi: None. T. Yue: None. H. Tan: None. Y. Ding: None. L. Pan: None. C. Guo: None. S. Luo: None. X. Zheng: None. J. Weng: None.
1469-P: Genetic Variation in a Bitter Taste Receptor Gene Associates with Random and Especially Postprandial Blood Glucose
Authors: GERVIS JULIE E. , WESTERMAN KENNETH E. , MERINO JORDI , JANE CROMER SARA
Published: June 2024

Taste receptors canonically mediate taste perception and food preferences. However, the recent discovery of bitter taste receptors in the gut suggests novel functions in satiety signaling and glucose homeostasis. Given the strong genetic component to taste, we aimed to evaluate whether genetic variation in bitter taste receptor genes associates with glucose homeostasis. Among 62,181 UK Biobank participants of European genetic ancestry without diabetes and with complete genetic, diet and random glucose (RG) data, we derived common taste diplotypes conferring low (“nontaster”; 48.4%), average (“taster”; 26.3%), or high (“supertaster”; 25.3%) bitter perception from three variants in the TAS2R38 bitter taste receptor gene (rs713598, rs1726866, rs10246939; linkage disequilibrium r2>0.85). We used generalized linear models to assess their associations with RG at 0 to 12 hours (hrs) post ingestion, adjusting for demographic covariates, fasting time (hrs) and BMI (Base model), and subsequently for diet and lifestyle factors. In unadjusted analyses, RG differed significantly across taste diplotypes (P=0.03) while reported energy (kcal/d) and macronutrient (%kcal) intake and BMI were similar. In the Base model, supertasters had a small but significantly lower RG compared to nontasters (Beta=-0.014 mmol/L; 95% CI: -0.03, -0.003; P=0.015), which remained significant after further adjustment for diet and lifestyle factors (P=0.013). RG did not differ significantly between tasters and either diplotype. In sensitivity analyses stratified by fasting time, RG was 0.042 (95% CI: -0.07, -0.01; P=0.006) mmol/L lower for supertasters than nontasters in the ≤2 hr fasting window (akin to a postprandial state), but was not significantly different in later fasting windows. These data suggest taste receptors may function in glucose homeostasis independent of diet, and genetic variation in bitter taste receptor genes may particularly impact the postprandial state.

Disclosure

J.E. Gervis: None. K.E. Westerman: None. J. Merino: None. S. Cromer: Other Relationship; Johnson & Johnson Medical Devices Companies. Advisory Panel; Alexion Pharmaceuticals, Inc. Other Relationship; Wolters Kluwer Health.

Funding

American Diabetes Association (7-21-JDFM-005)
1473-P: Nuclear Mitochondrial Interaction Test—A Novel Genetic Approach to Discover Mitochondrial Contributions to Chronic Disease—Demonstration of the Role of Klotho Variants on Diabetes Risk
Authors: JUNG OH TAE , ARPAWONG THALIDA E. , KUMAGAI HIROSHI , YEN KELVIN , CRIMMINS EILEEN , COHEN PINCHAS
Published: June 2024

Introduction & Objective: Previous work showed that genetic polymorphisms of the nuclear gene Klotho (KL), were associated with longevity and altered risk of various aging-related diseases. However, genetic variations of KL specifically associated with diabetes have not been published. In this study, we assessed the association of KL SNPs with diabetes, and performed a demonstration of identifying mitochondrial genetic variants that interact with KL SNPs to modulate diabetes risk.

Methods: We used the data from 10,121 participants of the Health and Retirement Study (70.3% non-Hispanic White, 60% women), a prospective observational study including adults aged 50 year and older from the United States. First, we performed single gene-wide association scan to identify KL SNPs associated with diabetes. Next, we performed a nuclear mitochondrial interaction test (NuMIT) in which we use an identified KL SNP from the gene-wide scan to evaluate potential interactions with 85 mitochondrial SNPs in relation to diabetes. All analyses were run separately within ethnic group and by sex.

Results: The prevalence of diabetes in non-Hispanic Whites was 23.8%. A KL SNP rs9563121 was associated with lower prevalence of diabetes in non-Hispanic white women (OR 0.86; P = 0.020), but this association was not significant in men or in other ethnic groups. A NuMIT analysis identified eight mitochondrial SNPs which showed significant interactions with rs9563121 in relation to diabetes. Most strikingly, MitoG15929A diminished the potential beneficial effect of KL rs9563121 on diabetes in women. In addition, in men with the MitoG15929A variant, KL rs9563121 was associated with higher prevalence of diabetes.

Conclusion: The NuMIT approach revealed significant interactions between mitochondrial and nuclear DNA variants of KL. Furthermore, MitoG15929A may be a critical risk modifier for diabetes in a sex-dependent manner.

Disclosure

T. Oh: None. T.E. Arpawong: None. H. Kumagai: None. K. Yen: None. E. Crimmins: None. P. Cohen: None.
1476-P: Metabolomic and Genetic Diabetes Predictors in the Diabetes Prevention Program (DPP)
Authors: CHEN ZSU-ZSU , SHU RICHARD , TRIPPUTI MARK , SHI XU , AVILA JULIAN , KNOWLER WILLIAM C. , KAHN STEVEN E. , HECKMAN-STODDARD BRANDY M. , CLISH CLARY B. , PAN QING , FLOREZ JOSE C. , GERSZTEN ROBERT E. , TEMPROSA MARINELLA , RESEARCH GROUP DPP
Published: June 2024

Objective: Type 2 diabetes (T2D) can be prevented, but the risk is heterogeneous even among high-risk individuals. We aimed to create a metabolite T2D risk model and evaluate its utility compared to a genetic risk score (GRS) and traditional clinical factors in 1,635 participants with available genomics and metabolomics.

Methods: Predictors were picked using elastic net from 3,145 mass spectrometry measured metabolites in baseline fasting plasma. Predictive performance after 3.2 years follow-up was assessed using AUC and IDI of Cox models that included the metabolites, the 120-SNP GRS, and clinical factors.

Results: The composite monosaccharide measurement of glucose/fructose/galactose and a 50 carbon:1 double bond triacylglycerol (TG 50:1) were selected and minimally increased the AUC beyond the clinical model (AUC=0.71 vs AUC=0.69, Fig1A). There was no change with the addition of the GRS (AUC=0.69). When added to FPG, TG 50:1 provided the same increase in the integrated discrimination index (IDI) as with clinical triglycerides (Fig1B), but glucose/fructose/galactose provided a significant increase in IDI beyond clinical FPG.

Conclusion: Metabolites minimally improve DM prediction beyond clinical risk factors in a high-risk adult population. A glucose/fructose/galactose composite metabolite significantly improves IDI.

Disclosure

Z. Chen: None. R. Shu: None. M. Tripputi: None. X. Shi: None. J. Avila: None. W.C. Knowler: None. S.E. Kahn: Advisory Panel; AltPep, Boehringer-Ingelheim, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk A/S. B.M. Heckman-Stoddard: None. C.B. Clish: None. Q. Pan: None. J.C. Florez: Research Support; Novo Nordisk. Other Relationship; Novo Nordisk, AstraZeneca. R.E. Gerszten: None. M. Temprosa: None. D. Research Group: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (UDK048489, UDK048339, UDK048377, UDK048349, UDK048381, UDK048468, UDK048434, UDK048485, UDK048375, UDK048514, UDK048437, UDK048413, UDK048411, UDK048406, UDK048380, UDK048397, UDK048412, UDK048404, UDK048387, UDK048407, UDK048443, UDK048400)
1479-P: The Association between Race and Ethnicity and Type 2 Diabetes Is Partially Mediated by Circulating Proteins—A Meta-analysis of 2,339 Individuals from Two Multiethnic Cohorts of the TOPMed Program
Authors: SEVILLA-GONZALEZ MAGDALENA , WESTERMAN KENNETH E. , WANG NINGYUAN , JANE CROMER SARA , CHEN ZSU-ZSU , ROTTER JEROME I. , KOOPERBERG CHARLES L. , MEIGS JAMES B. , MANNING ALISA
Published: June 2024

It is critical to understand the molecular basis for well-recognized disparities in type 2 diabetes (T2D) risk. We aimed to examine plasma proteomic profile variations among self-identified racial and ethnic groups and assess the mediating impact of race- and ethnic-specific proteomic signatures on prevalent T2D.

Methods: We used proteomic data from 2339 individuals who self-identified as Non-Hispanic-White, Hispanic, or Non-Hispanic Black in the Women’s Health Initiative (N=1,400) and Multi-Ethnic Study of Atherosclerosis (N=939). To identify race- and ethnicity-specific associations we used linear models adjusting by confounders; site of recruitment, age, BMI, and eGFR. We employed structural equation modeling to examine the mediation by race and ethnic-specific proteins of the relationship between self-reported race/ethnicity and prevalent T2D. Models were stratified by sex, results were meta-analyzed and corrected for multiple comparisons (P<10-5).

Results: We tested associations for 324 proteins. A total of 138 proteins (41.04%) were associated with self-reported race/ethnicity (P<10-5). Seven proteins independently mediated the association between self-reported race/ethnicity and T2D (P<10-6). Top significant proteins included Growth/differentiation factor 8, Insulin-like growth factor-binding protein 2, and Apolipoprotein M. We identified that 8-11% of the association between self-reported race and prevalent T2D can be attributed to the direct mediating effect of race-ethnic-specific proteomic signatures.

Conclusion: More than 40% of protein levels tested varied significantly by race and ethnicity. Seven protein levels were found to significantly mediate the association between race and ethnicity and T2D prevalence. These results provide insights into the molecular pathways that contribute to racial and ethnic disparities in T2D prevalence.

Disclosure

M. Sevilla-Gonzalez: Research Support; Novo Nordisk Foundation. K.E. Westerman: None. N. Wang: None. S. Cromer: Other Relationship; Johnson & Johnson Medical Devices Companies. Advisory Panel; Alexion Pharmaceuticals, Inc. Other Relationship; Wolters Kluwer Health. Z. Chen: None. J.I. Rotter: None. C.L. Kooperberg: None. J.B. Meigs: None. A. Manning: None.

Funding

American diabetes Association (9-22-PDFPM-04); National Institutes of Health (5U24DK132733-02)
1482-P: Genome-Scale Metabolic Modeling of Type 2 Diabetes Subtypes Elucidates Unique Metabolic Reactions and Flux Activity
Authors: SMITH KIRK , EAMES ALEC , SEVILLA-GONZALEZ MAGDALENA , UDLER MIRIAM
Published: June 2024

We previously used a soft clustering approach to group type 2 diabetes (T2D)-associated single nucleotide variants (SNVs) based on their associations with phenotypes. In previous work, we demonstrated associations between the resulting five clusters and various clinical phenotypes, outcomes, and tissues. To further understand the mechanistic pathways tied to these potential T2D subtypes, here we incorporate genome-scale metabolic models (GEMs).

Cluster-specific partitioned polygenic risk scores (pPS) were generated for subjects in the GTEx database. Regression analyses of the pPS and gene expression levels identified up- and down-regulated genes for each cluster. These genes were used as constraints on a generic human GEM, thereby creating cluster-specific models. We also created individualized models for GTEx subjects, followed by statistical testing of fluxes between the top and bottom pPS decile groups of each cluster.

Over 120 reactions were significantly altered in each cluster (Wilcoxon, p<0.05), with none significant in more than two clusters. In all clusters, the majority of hits were transport reactions. However, some subsystems were more heavily altered in specific clusters, including cholesterol biosynthesis and omega fatty acid metabolism in the beta-cell and lipodystrophy clusters, respectively. Of the 145 subsystems cataloged in our GEM, 39 contained a reaction that was associated with only one cluster, such as ubiquinone synthesis for the liver-lipid cluster (p=6e-4).

By creating metabolic reconstructions of our T2D clusters, we have gained a systems-level understanding of the clusters’ unique characteristics. Our results pinpoint cluster-specific metabolic reactions with differential flux activity and may therefore potentially be useful for future precision medicine efforts.

Disclosure

K. Smith: None. A. Eames: None. M. Sevilla-Gonzalez: Research Support; Novo Nordisk Foundation. M. Udler: Other Relationship; Up-To-Date.

Funding

Doris Duke Foundation Award 2022063
1489-P: GAD65247-266 Is a Major Th1 Epitope in Japanese Patients with Acute-Onset Type 1 Diabetes
Authors: CHUJO DAISUKE , AJIMA KUMIKO , MATSUSHITA MAYA , TSUTSUMI CHIHARU , HASEDA FUMITAKA , IMAGAWA AKIHISA , HANAFUSA TOSHIAKI , KAJIO HIROSHI , SHIMODA MASAYUKI , TOBE KAZUYUKI
Published: June 2024

Introduction & Objective: Autoreactive T cell responses in type 1 diabetes (T1D) may vary depending on race. In Japan, T1D is classified into three subtypes based on disease progression: acute onset (AT1D), slowly progressive (SP1D), and fulminant (FT1D). The aim of this study was to compare the features of islet antigen-specific CD4+ T cell (Th) responses among these subtypes and determine the Th epitope in Japanese AT1D patients.

Methods: Blood mononuclear cells from 20 AT1D, 17 SP1D, and 18 FT1D patients, and 17 nondiabetics (NDs) were stimulated with GAD65, preproinsulin (PPI), IGRP, and ZnT8 peptide clusters (4-6 peptides/cluster) in the presence of IL-2. Subsequently, intracytoplasmic cytokine staining (ICS) was performed to analyze cytokine expression on specific T cells (cluster analysis). After identifying the feature of Th cell responses in each T1D subtype, another stimulation and ICS were performed using single peptides to identify Th cell epitopes (epitope analysis).

Results: In the cluster analysis, the frequencies of GAD65- and PPI-specific Th1 cells were significantly higher in AT1D patients (P = 0.007 and P = 0.004, respectively) than in NDs, whereas GAD65- and IGRP-specific Th2 cells were more prevalent in SP1D patients (P = 0.010 and P = 0.030, respectively) than in NDs. Notably, FT1D patients displayed significantly less Tr1 cells specific for all four antigens. Epitope analysis, focusing on GAD65- and PPI-specific Th1 responses in AT1D patients, revealed that 3, 16, 3, and 3 out of 20 patients displayed positive Th1 responses (stimulation index > 3.0) under GAD65115-127, GAD65247-266, PPIC19-A3, and PPIC22-A5 stimulation, respectively. In addition, the frequencies of GAD65247-266-specific Th1 cells were significantly higher than those specific for other epitopes (P < 0.001).

Conclusion: The phenotypes of islet antigen-specific Th cells were distinct among the three T1D subtypes. Furthermore, GAD65247-266 was identified as a major Th1 epitope in Japanese AT1D patients.

Disclosure

D. Chujo: Research Support; Kyowa Kirin Co., Ltd. K. Ajima: None. M. Matsushita: None. C. Tsutsumi: None. F. Haseda: None. A. Imagawa: None. T. Hanafusa: None. H. Kajio: None. M. Shimoda: None. K. Tobe: None.

Funding

Japan Society for the Promotion of Science (21K08525)
1491-P: Examination of the Humanized Antibody to SerpinB13 in Autoimmune Diabetes
Authors: ALTEKREETI MARWAH , AVDULOV SVETLANA V. , SZEPIETOWSKA BARBARA , MENG SHAWN Z. , KRYVALAP YURY , CZYZYK JAN
Published: June 2024

Studies in our laboratory suggest that a combinatorial approach with a monoclonal antibody (mAb) to serpinB13, a cathepsin L (catL) inhibitor, and a suboptimal dose of antibody to CD3, is therapeutically superior to single antibody use, when these reagents are delivered into NOD mice during the late prediabetes period. The purpose of this study was to examine whether our newly generated humanized antibody to serpinB13 (hB29) has a similar effect. Ten-week old NOD female mice were each injected with 40 micrograms of hB29 and a suboptimal dose (10 micrograms) of CD3 mAb (clone 145-2C11). Control treatments included injections with non-specific human and hamster IgG. Random blood glucose levels were assessed for eight weeks after the last antibody injection, and mice were declared diabetic following two measurements of glucose exceeding 300 mg/dL. Alternatively, eight-week old NOD females were injected with the above-mentioned doses of antibodies and sacrificed 10 days later for histological analysis of pancreatic beta-cell mass. Visiopharm software was used for the quantitative analysis of microscopic images. We found that the combination of hB29 with CD3 mAb offered a significant level of protection from diabetes, while single antibody use had no effect. This was independently confirmed by microscopic analysis, which revealed increased residual beta-cell mass in the group receiving both hB29 and CD3 mAb, compared with the group receiving nonspecific human IgG. Our data demonstrate a strong similarity between the original mouse serpinB13 mAb and our new agent, the humanized antibody, hB29. Moreover, our finding of improved preservation of beta-cell mass within a short period of time following exposure to hB29 and CD3 mAb, is consistent with our previous observations that the serpinB13 mAb-mediated rescue of catL activity is responsible for impairing leukocyte function, and for slowing the progression of pancreatic islet damage.

Disclosure

M. Altekreeti: None. S.V. Avdulov: None. B. Szepietowska: None. S.Z. Meng: None. Y. Kryvalap: None. J. Czyzyk: None.
1494-P: Gr1+ Myeloid Cell Governs Adipose Tissue Remodeling via Controlling Macrophage Infiltration
Authors: CAO YAN , CAI JINYANG , JI CHENBO
Published: June 2024

Introduction & Objective: Pathological adipose tissue remodeling contributed to the development of insulin resistance and type 2 diabetes. The aberrant myeloid phenotype has recently been implicated in driving the diabetic environment. However, the role of myeloid cells in adipose remodeling remains largely unknown.

Methods: C57BL6/J mice were i.p. injected with either Gr-1 or IgG2b isotype control antibody once a week for 2 dose to temporarily eliminate Gr-1+ myeloid cells. Metabolic status was assessed by GTT and ITT. Adipose tissues were harvested for histological, immunostaining, and RNA-seq analysis.

Results: In lean mice, elimination of Gr-1+ cells led to a reduction in gWAT weight. Histologic analysis showed smaller adipocytes, augmented collagen deposition and evaluated expression of a major ECM receptor CD44 in gWAT upon Gr-1 depletion. Ablation of Gr-1+ cells resulted in increased serum level of MCP-1 and more iNOS+CD206− M1 macrophages in gWAT. Interestingly, in spite of no difference was observed in ITT, Gr-1 ablation increased glucose clearance in mice, which was associated with enhanced glycogen deposition in liver and muscle. The KEGG enrichment analysis of RNA-seq data from gWAT revealed that genes with increased expression upon Gr-1 depletion were mainly clustered in regulation of lipolysis in adipocytes, leukocyte transendothelial migration, and ECM-receptor interaction. Besides, GSEA showed a significant enrichment of gene sets associated with TNF signaling pathway, type I diabetes mellitus and insulin resistance.

Conclusion: Acute depletion of Gr-1+ cells promoted the macrophage infiltration and polarization towards a M1 phenotype in gWAT. This pro-inflammatory milieu would contribute to metabolic dysfunction, such as adipose tissue remodeling, aggravated lipolysis and insulin resistance. Our data suggested that Gr-1+ myeloid cell might be a key regulator against pathological adipose tissue remodeling by restricting macrophage infiltration.

Disclosure

Y. Cao: None. J. Cai: None. C. Ji: None.

Funding

The Key Research and Development Program of Jiangsu Province (No. BE2021614); the Outstanding Youth Fund of Nanjing Health Science and Technology Development Project (No. JQX22009).
15-PUB: A Single-Center, Open-Label, Fixed-Sequence Clinical Study to Evaluate the Pharmacokinetic Effects of Supaglutide on Digoxin or Metformin in Healthy Subjects
Authors: JINJIE HE , JING ZHANG , ANWAR DILBAR , HAIYA WU , WANG QINGHUA , WU XIAOJIE
Published: June 2024

Introduction: Supaglutide (supa) is a novel GLP-1 receptor agonist as subcutaneous once-weekly administration for the treatment of diabetes mellitus, obesity, and nonalcoholic fatty liver disease.

Objective: This is an open label, fixed-sequence clinical study to evaluate the pharmacokinetic effects of multiple injections of supa on a single dose of digoxin or multiple doses of metformin.

Methods: 32 healthy subjects were assigned to 2 parallel groups (16 cases in each), digoxin tablets (Group A), and metformin hydrochloride tablets (Group B), both combined with supa injection.

Results: After a single oral dose of 0.25 mg digoxin in healthy subjects, the coadministration of supa injection had no effect on the AUC0-last of digoxin, a reduction in Cmax by about 24%, and an increase in the AUC0-inf by about 15% compared with that of the digoxin administration alone. After multiple BID oral administration of 500 mg metformin, coadministration of supa injection had no effect on Cmax and an increase in AUC0-inf by approximately 15%, compared to the metformin administration alone (Figure). These results suggest that coadministration of supa on digoxin and metformin exposure is not clinically significant.

Conclusion: Supaglutide injection can be used in combination with digoxin or metformin without dose adjustment.

Disclosure

H. Jinjie: None. Z. Jing: None. D. Anwar: None. W. Haiya: None. Q. Wang: None. X. Wu: None.
1508-P: The Therapy of Type 1 Diabetes Mellitus with Neo-islets, 3-D Organoids of Mesenchymal Stromal and Islet Cells, Has the Capacity to Compensate for the Very Low Procurement Rate of Pancreata and Islets and This without the Need for Antirejection Drugs
Authors: WESTENFELDER CHRISTOF , GOOCH ANNA
Published: June 2024

The current number of patients with T1DM in the US is ~1.8 million, and globally ~ 58 million. In the last 10 yrs only ~ 4,400 islet allotransplants have been performed globally, while the number of deceased Organ Donors per yr in the US is ~ 15,000 and globally ~ 36,000. This demonstrates that inadequate numbers of pancreata and islets are harvested, particularly for potentially curative islet transplants. To address this organ shortage for the biotherapy of T1DM, we have engineered “Neo-islets” (NIs), islet-sized cell clusters that are composed in a 1:1 ratio of allogeneic Mesenchymal Stromal (MSCs) and culture expanded islet cells (ICs). Importantly, islets that do not meet the quality scores for clinical transplants and that are ordinarily discarded can be used to generate the needed ICs in NIs, i.e., from one such islet donor ~ 270 therapeutic NIs doses can be produced. In contrast, islet transplants require often more than one islet donor and often repeatedly. The MSC component in NIs provides durable and local allo- and auto-immune isolation that eliminates the need for anti-rejection drugs, together with powerful anti-inflammatory, proangiogenic, and anti-apoptotic actions in autoimmune, T1DM NOD mice and dogs. NIs are administered i.p. under ultrasound guidance to sedated recipients, a minimally invasive, ~15 min procedure. NIs spontaneously engraft in the recipient’s omentum from where they physiologically deliver insulin and all other islet hormones intraportally as the pancreas does. They can be retrieved if needed, which is not possible with intraportal islet or other cell-based transplants. After a successful Pre-IND meeting with the FDA, we received approval for the conduct of the required IND-enabling POC study. With receipt of the respective IND, we will carry out our Phase I/II Clinical Trial at three collaborating institutions in California.

Disclosure

C. Westenfelder: None. A. Gooch: Employee; SymbioCellTech, LLC. Board Member; SymbioCellTech, LLC. Stock/Shareholder; SymbioCellTech, LLC.
1514-P: Is Low Birthweight Associated with Lower Adiponectin Levels? A Systematic Review and Meta-analysis
Authors: ALHAKEEM AFNAN S. , TÜRKOGLU ALEYNA , LAWAETZ TRINE W.H. , HELMS ANDERSEN TUE , BRØNS CHARLOTTE , VAAG ALLAN A.
Published: June 2024

Background: Compared to people with normal birth weight (NBW), individuals born with low and high birth weights (LBW and HBW) are at increased risk of developing type 2 diabetes. Studies have suggested that this could be due to lower levels of the insulin-sensitizing adipokine adiponectin. We performed a systematic review and meta-analysis of studies that have reported circulating levels of adiponectin in relation to birthweight across all age groups to determine the extent to which levels of adiponectin are lower in LBW and/or HBW subjects, respectively.

Methods: Searching MEDLINE, Embase and Web of Science yielded a total of 1486 studies. Two independent reviewers screened studies against inclusion criteria and among these were 67 included in the meta-analysis. Using a random-effect model, two meta-analyses were carried out to calculate the pooled effect size and corresponding 95% confidence interval. Heterogeneity was assessed using the I2-test, and subgroup and meta-regression analyses performed to identify potential sources of variation.

Results: The first meta-analysis included 24 studies comparing adiponectin levels in LBW to NBW individuals. Pooled effect size revealed a statistically significant lower level of adiponectin in LBW compared to NBW individuals (SMD= -0.55 μg/ml [95% CI: -2.75; 1.65], P=0.02). The heterogeneity of results was significant (I2=92%, P<0.01), but meta-regressions failed to identify sources of heterogeneity. The second meta-analysis included 15 studies comparing adiponectin levels between HBW and NBW subjects but failed to establish firm evidence of any significant difference in the overall effect size (SMD= -0.33 μg/ml [95% CI: -2.84; 2.17], P=0.28). Similar to the LBW analysis, significant heterogeneity was observed (I2=94%, P<0.01).

Conclusion: Despite considerable heterogeneity between studies, there is firm evidence that LBW, but not HBW, subjects exhibit lower adiponectin levels compared to individuals born with NBW.

Disclosure

A.S. Alhakeem: None. A. Türkoglu: None. T.W.H. Lawaetz: None. T. Helms Andersen: None. C. Brøns: Stock/Shareholder; Novo Nordisk A/S. A.A. Vaag: None.
1531-P: Identification of a Novel Subset of Cold-Activated Hypothalamic Neurons That Stimulate Feeding
Authors: WATTS CHRISTINA A. , DEEM JENNIFER D. , REDFORD INGRID K. , BRYAN CAELEY , PHAN BAO ANH N. , DAMIAN VINCENT , SCARLETT JARRAD M. , SCHWARTZ MICHAEL W. , MORTON GREGORY J.
Published: June 2024

Growing evidence suggests that the hypothalamus plays an important role in the coupling of thermoregulation to energy homeostasis. Based on preliminary evidence that neurons expressing tyrosine hydroxylase (TH) located in the rostral hypothalamus are activated by cold exposure, we sought in the current work to 1) map this previously unrecognized neural subpopulation and, 2) investigate its role(s) in the control of food intake. To this end, four groups of C57Bl6 mice were studied. Two of the groups either exposed to a cold (10 °C) or a warm environment (30 °C) for 90 min, while the other two were either fasted overnight or fed ad libitum (AL). Brains were then processed for immunohistochemical colocalization of cFos, a marker of neuronal activation, in TH(+) neurons. Our findings reveal that relative to mice housed in a warm environment, cold exposure increased the % of TH neurons expressing fos selectively in the periventricular hypothalamic nucleus (Pe) (22.5 ± 1.2% for cold vs. 5.0 ± 1.3% for warm, a ~4-fold increase; p<0.001). In contrast, cFos was not detectably induced in TH(+) neurons located in the caudal PVN (p=ns). Overnight fasting had a similar effect to increase the % of PeTH neurons expressing cFos (26.0 ± 3.8% for fast vs. 13.4 ± 2.5% for fed, a ~2-fold increase; p<0.05), but again was without effect in caudal PVNTH neurons. To determine whether activation of PeTH neurons is sufficient to increase food intake, TH-Cre animals received a unilateral microinjection of a Cre-inducible excitatory DREADD receptor directed to this brain area. Here, we found that relative to vehicle-treated controls, food intake was robustly increased following CNO-induced activation of PeTH neurons (0.94 ± 0.18g with CNO vs. 0.28 ± 0.09g with vehicle, a ~3-fold increase; p<0.01). These findings implicate a novel set of cold-activated hypothalamic TH neurons in the regulation of food intake.

Disclosure

C.A. Watts: None. J.D. Deem: None. I.K. Redford: None. C. Bryan: None. B.N. Phan: None. V. Damian: None. J.M. Scarlett: None. M.W. Schwartz: None. G.J. Morton: Research Support; Novo Nordisk A/S.

Funding

NIDDK-T32 Diabetes, Obesity, and Metabolism Training Grant (T32DK007247)
1532-P: Expression of Fibroblast Growth Factor-1 by Medial Hypothalamic Neurons Is Required for Normal Glucose and Energy Homeostasis
Authors: CHOI PIQUE , BRYAN CAELEY , MORTON GREGORY J. , SCHWARTZ MICHAEL W. , SCARLETT JARRAD M.
Published: June 2024

The brain is a primary target for the beneficial metabolic effects of members of the fibroblast growth factor (FGF) family. As one example, our group and others have shown that a single intracerebroventricular (icv) injection of fibroblast growth factor-1 (FGF1) induces both transient anorexia and weight loss and sustained remission of diabetic hyperglycemia in rodent models of type 2 diabetes (T2D). These pharmacological responses are mediated by FGF1’s action in the mediobasal hypothalamus (MBH), which includes both arcuate (ARC) and ventromedial hypothalamic nuclei (VMN). FGF1 is endogenously expressed in the MBH and based on both RT-PCR and western blot analysis of MBH punches from male C57Bl/6J mice, we report that Fgf1 mRNA levels were reduced by 33%, (p<0.01) and FGF1 protein levels were reduced by 39%, (p<0.01) during fasting while both were restored to baseline within 2 hours of refeeding. Given the key role played by the VMN neurons in both energy and glucose homeostasis, we sought to determine if endogenous VMN FGF1 signaling participates in these processes. We deleted FGF1 from MBH neurons by microinjecting either control AAV1-CAG-GFP or AAV1-hSyn-Cre-WPRE.hGH directed towards the bilateral MBH of adult male FGF1 floxed (FGF1fl/fl) mice. We found that although daily food intake tended to be higher following targeted deletion of FGF1, the effect did not achieve statistical significance. In contrast, this intervention caused significant weight gain (characterized by increases of both lean and fat mass), glucose intolerance, and pronounced disruption of dark/light cycle feeding, energy expenditure, and locomotion patterns. Together, these preliminary findings support the conclusion that expression of FGF1 by neurons in the MBH is required for normal energy and glucose homeostasis.

Disclosure

P. Choi: None. C. Bryan: None. G.J. Morton: Research Support; Novo Nordisk A/S. M.W. Schwartz: None. J.M. Scarlett: None.
1534-P: The Role of Differentially Located Mouse Intrapancreatic Neurons in Islet ß-Cell and Acinar Cell Function
Authors: TAMAYO ALEJANDRO M. , LEVI NOAH , MAKHMUTOVA MADINA , PEREIRA ELIZABETH , CAICEDO ALEJANDRO
Published: June 2024

In the mouse, cholinergic neurons within the pancreas are organized in ganglia that can be classified based on their location: acinar ganglia embedded in the exocrine compartments versus neuroinsular ganglia located adjacent to endocrine islets. Although they form a network within the organ, it is unclear if this anatomical segregation allows channeling external input (e.g. efferent vagal input) to the pancreas in a labeled-line manner, thus differentially affecting exocrine and endocrine function. Our study aims to test the hypothesis that pancreatic innervation can be segregated into (1) acinar ganglia that preferentially target exocrine tissues controlling digestive enzyme secretion and (2) neuroinsular ganglia that preferentially target glucoregulatory endocrine islets. To test this hypothesis, we used the chemogenetic approach to stimulate cholinergic neurons in living pancreas slices from mice expressing DREADD receptors under the control of the choline acetyltransferase promoter (ChAT-hM3Dq DREADD mice). Our results showed that only cholinergic neurons express DREADD receptors and respond to CNO stimulation with a characteristic muscarinic response. We were able to measure Ca2+ responses in different tissue compartments. Acinar cells have a stronger Ca2+ response when compared with islet cells after neuronal stimulation. Ca2+ responses in the beta cell population were sparse, localized, and only at higher glucose concentrations. Acinar and islet beta cell activation were confirmed by increases in amylase and insulin secretion after neuronal stimulation from dynamic perfusion experiments. These preliminary results showed that the chemogenetic approach to target cholinergic neurons in living pancreas slices is a powerful platform for studying the effects of local neural activation on different cell populations providing the basis for future neuromodulation experiments.

Disclosure

A.M. Tamayo: None. N. Levi: None. M. Makhmutova: None. E. Pereira: None. A. Caicedo: None.
1535-P: Type 2 Diabetes Remission after Roux-en-Y Gastric Bypass Is Related to a Reduction of Pancreatic Noradrenergic Innervation and Beta-Cell Redifferentiation
Authors: CINTI FRANCESCA , AVOLIO ADRIANA , MORCIANO CASSANDRA , GUGLIANDOLO SHAWN , CAPECE UMBERTO , MEZZA TERESA , SOLDOVIERI LAURA , CICCARELLI GEA , DI GIUSEPPE GIANFRANCO , MOFFA SIMONA , GIACCARI ANDREA
Published: June 2024

Background: β cell dedifferentiation has been identified as the process responsible for the functional "disappearance" of β cells from the islets of diabetic subjects.We recently demonstrated that the islets of diabetic subjects are about 3 times more innervated than controls, with a stepwise increase in innervation correlated with worsening glucose tolerance and a direct correlation with the dedifferentiation score. The remission of Type 2 Diabetes after bariatric surgery is well known but the mechanisms which determine it are still on debate.

Aim: to test the hypothesis that the anatomical removal of entero-pancreatic innervation induces a reduction of sympathetic innervation with the consequent re-differentiation of β cells, supporting the idea that innervation represents the key mechanism responsible for β cell dedifferentiation.

Methods: 10 obese diabetic rat Zucker FA/FA have been fasted overnight for 14 h followed by a glucose tolerance test (GTT) before and 6 weeks after the Roux-en-Y gastric bypass (RYGB) surgery (n=5) or sham (n=5). The morphological analysis of noradrenergic fibers and dedifferentiation score has been performed on the pancreas samples.

Results: total glucose level determined by area under the curve (AUC) resulted significantly reduced in the RYGB group compared to sham group (p<0.0001) confirming the remission of type 2 diabetes after bariatric surgery. The number of noradrenergic fibers resulted significantly reduced in RYGB group compared to sham group (p=0.04) as well as the dedifferentiation score (p=0.01).

Conclusions: the data confirm that noradrenergic fiber might be directly involved in the process of dedifferentiation. The procedure of RYGB seems to induce a significant reduction of noradrenergic fibers with a consequent reduction of dedifferentiation score, providing a new potential explanation for the remission of type 2 diabetes after bariatric surgery.

Disclosure

F. Cinti: None. A. Avolio: None. C. Morciano: None. S. Gugliandolo: None. U. Capece: None. T. Mezza: None. L. Soldovieri: None. G. Ciccarelli: None. G. Di Giuseppe: None. S. Moffa: None. A. Giaccari: None.