bluuebunny/crossref_metadata_2025_split huggingface dataset:
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&gt;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&lt;10-5).
Results: We tested associations for 324 proteins. A total of 138 proteins (41.04%) were associated with self-reported race/ethnicity (P&lt;10-5). Seven proteins independently mediated the association between self-reported race/ethnicity and T2D (P&lt;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&lt;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 &gt; 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 &lt; 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.