bluuebunny/crossref_metadata_2025_split huggingface dataset:
1771-P: STIM1 Maintains Beta-Cell Identity and Function
Authors: KONO TATSUYOSHI , SOHN PAUL , MCLAUGHLIN MADELINE , WU WENTING , POSTIC SANDRA , KRISHNAN PREETHI , LEE CHIH-CHUN , SLAK RUPNIK MARJAN , EVANS-MOLINA CARMELLA , SLAK RUPNIK MARJAN , KRISHNAN PREETHI 
Published: June 2023

Impairments in endoplasmic reticulum (ER) Ca2+ homeostasis have been linked to β cell dysfunction and diabetes development; however, the pathways mediating these effects are not fully understood. Store-operated Ca2+ entry (SOCE) replenishes ER Ca2+ levels through reversible gating of plasma membrane Ca2+ channels by the ER Ca2+ sensor, stromal interaction molecule 1 (STIM1). We found that female, but not male, mice with β cell-specific STIM1 deletion (STIM1Δβ) had reduced β cell mass, increased α cell mass, and reduced expression of markers of β cell identity. To determine the mechanisms underlying this sexually dimorphic phenotype, RNA sequencing, immunofluorescent staining, and Ca2+ imaging experiments were performed using islets from control and STIM1Δβ mice and WT and STIM1 KO INS-1 cells. RNA sequencing of islets from STIM1Δβ mice identified 55 pathways that were significantly modulated (P&lt;0.05), including “estrogen receptor signaling”, “mitochondrial dysfunction”, and “endocytosis”, and “estrogen receptor signaling”. Consistent with a role for SOCE in mitochondrial function, STIM1 KO cells decreased mitochondrial Ca2+ levels. Furthermore, we used the novel fluorescent time construct, syncollin-dsRedE5TIMER, to demonstrate an abnormal accumulation of aged insulin granules in STIM1 KO cells. Lastly, to test the relationship between STIM1 expression and glucose regulation in humans, we queried a publicly available NCBI GEO dataset derived from organ donors with and without type 2 diabetes (T2D). In this dataset, islet STIM1 expression was negatively correlated with HbA1c levels in female organ donors (n=35, r=-0.38, p=0.035), while there was no correlation in male donors. Together, these data highlight a novel role for STIM1 in the maintenance of mitochondrial function and insulin granule turnover. These findings confirm the importance of Ca2+ regulation within the β cell and highlight the significant role of sex as a biological variable in diabetes pathogenesis.

Disclosure
T.Kono: None. M.Slak rupnik: None. P.Krishnan: None. P.Sohn: None. M.Mclaughlin: None. W.Wu: None. S.Postic: None. P.Krishnan: None. C.Lee: None. M.Slak rupnik: None. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc.

Funding
National Institutes of Health (R01DK093954, R01DK127236, U01DK127786, R01DK127308, UC4DK104166); U.S. Department of Veterans Affairs (I01BX001733)
1775-P: Liraglutide Corrects Impaired Insulin Secretion in 14-3-3-ζ Overexpressing Mice
Authors: SHISHANI RAHAF , TUCKER MADELYNN , MORENO ROSALINDA , BUSTAMANTE JESSICA M. , LIM GARETH E. , CUMMINGS BETHANY 
Published: June 2023

Crosstalk between α-cells and β-cells is an important regulator of healthy islet function. α-cells display heterogeneity in their hormone profile. α-cells typically produce glucagon but, under certain conditions, can produce glucagon-like peptide-1 (GLP-1). However, the mechanisms regulating α-cell GLP-1 production are poorly understood. We found that increased β-cell GLP-1R signaling via the GLP-1 analog, liraglutide, activates α-cell GLP-1 production through a paracrine signaling pathway. We recently identified the protein 14-3-3-ζ as a key downstream mediator of this pathway. Specifically, liraglutide downregulates β-cell 14-3-3-ζ expression, which activates α-cell GLP-1 production. Consistent with this, we found that β-cell 14-3-3-ζ ablation enhances glucose-stimulated insulin secretion (GSIS). Furthermore, mice with 14-3-3-ζ overexpression (OE) have impaired GSIS. Therefore, we tested the hypothesis that liraglutide can correct the effect of 14-3-3-ζ OE to impair GSIS. Male and female wild-type (WT) or 14-3-3-ζ OE mice maintained on high-fat diet underwent an oral glucose tolerance test (OGTT) after 2 weeks of liraglutide (200 μg/kg sc twice daily) or saline treatment. Liraglutide improved glucose tolerance in WT mice and tended to improve glucose tolerance in OE mice. Saline-treated 14-3-3-ζ OE mice exhibited lower GSIS compared with WT (P&lt;0.05). Liraglutide treatment of 14-3-3-ζ OE mice normalized GSIS to match that of liraglutide-treated WT mice (Insulin secretion index [Insulin AUC/Glucose AUC] *10-9: Saline WT = 38 ± 4, Lira WT = 37 ± 5, Saline OE = 25 ± 4, Lira OE = 39 ± 7; n=7-8 per group, P&lt;0.05 Saline WT vs. Saline OE, P=0.06 Saline OE vs. Lira OE). Overall, these data suggest that liraglutide can rescue deficits in GSIS induced by 14-3-3-ζ OE.

Disclosure
R.Shishani: None. M.Tucker: None. R.Moreno: None. J.M.Bustamante: None. G.E.Lim: None. B.Cummings: None.

Funding
Hartwell Foundation; National Institute of Diabetes and Digestive and Kidney Diseases (R56DK124853)
178-LB: Association of Pregnancy Oral Glucose Tolerance Test (OGTT) Glucose Response with Metabolic Profile in Mother and Child—Hyperglycemia and Adverse Pregnancy Outcomes Follow-up Study (HAPO-FUS)
Authors: THAKER VIDHU V. , LEDUC CHARLES A. , SALEM RANY 
Published: June 2023

The glucose response shape during an OGTT, monophasic or biphasic, can characterize physiologically distinct groups with differences in insulin secretion and sensitivity. Biphasic response (glucose rebound after nadir ≥ 0.025 mmol/L) has been associated with higher insulin sensitivity and β-cell function. We aimed to identify the association of the pregnancy OGTT response shape with follow-up maternal and offspring metabolic profiles.
Method: Using HAPO-FUS study data from the NIH-NIDDK repository, monophasic glucose response was defined as 2-hr glucose - 1-hr glucose &lt; 0. Multiple linear regression assessed the relationship of glucose response shape with maternal profile at 10-year follow-up and offspring metabolic profile at 10-12 years of age. Maternal covariates include age, gestational age, field center and BMI. Child covariates include age, sex, pubertal stage, and family history of diabetes.
Results: 4,605 mothers (83.7% monophasic) and 3792 children were included. Mothers with monophasic shape were older (30.7 vs 29.8 years, p=.002), had higher BMI (26.7 vs 26.0 kg/m2, p=.003), HbA1c (4.80 vs 4.70 %, p &lt;.001), 1-hour c-peptide level (9.60 vs 7.75 ug/dL, p &lt;.001) and gestational diabetes (14 vs 9.5%, p &lt;.001). At 10-year follow-up, pregnancy monophasic response was associated with higher fasting glucose level (0.06 [0.01, 0.11], p =.01) and log HOMA-IR (0.06 [0.02, 0.10], p=.007) in mothers at follow-up. Offspring had higher cord c-peptide (0.12 [0.04, 0.21], p=.005) and body fat percent (1.35 [0.50-2.21], p =.002). Offspring insulin sensitivity (-0.17 [-0.04, -0.3], p=.01) and Matsuda index (-0.46 [-0.15, -0.76], p=.003) were lower with monophasic response.
Conclusion: Maternal glucose response profiles during pregnancy determined by both insulin secretion and whole-body insulin resistance are associated with long-term maternal and offspring metabolic profile.

Disclosure
V. V. Thaker: None. C. A. Leduc: None. R. Salem: Other Relationship; Travere Inc.

Funding
National Institutes of Health (K23DK110539)
183-OR: Metabolic Signatures of Type 2 Diabetes Subtypes in UK Biobank
Authors: XUE QIAOCHU , LI XIANG , WANG XUAN , MA HAO , HEIANZA YORIKO , QI LU 
Published: June 2023

Type 2 diabetes (T2D) is a complex disease with heterogeneous pathophysiology. Five distinct subtypes of T2D were previously identified in the UK Biobank and validated in the All of Us cohort through a novel clustering algorithm: Cluster 1-5, characterized by early-onset of T2D, late-onset of T2D, severe obesity, poor glycemic control, and poor renal function, respectively. We aim to establish the subtype-specific signatures of metabolites. Nuclear magnetic resonance spectroscopy-derived metabolomic profiling was undertaken on baseline plasma samples in 12,271 UK Biobank participants with T2D. Among a subset of 2828 participants with metabolomic data available, elastic net regularized regressions with 10-fold cross-validation were applied to identify subtype-specific metabolic signatures. Of the 168 named metabolites used in the analyses, we selected a combination of 39 metabolites most significantly associated with subtypes of T2D (P&lt;0.0001, FDR&lt;0.05). We observed subtype-specific highest levels of creatinine in the impaired renal function characterized Cluster 5 and the lowest level in Cluster 1, featured by early-onset of T2D (mean difference= 2.46 [SD=0.09], P&lt;0.0001). Cluster 4 characterized by poor glycemic control had increased levels of glucose and decreased levels of glutamine, indicating a greater level of hyperglycemia. Individuals in Cluster 3 characterized by severe obesity exhibited elevated levels of inflammation metabolites biomarker (glycoprotein acetyls) and obesity-related amino acids (tyrosine and valine). The plasma unsaturation degree of fatty acid was also lower in Cluster 3 compared to other clusters. Cluster 2 patients had lower levels of glucose and glycoprotein acetyls and higher levels of glutamine, omega-3 fatty acids, and docosahexaenoic acids. Overall, Cluster 1 and 2 had the least metabolic dysregulation among the T2D subtypes. We have identified metabolic signatures for T2D subtypes, revealing subtype-specific metabolic mechanisms for precision interventions.

Disclosure
Q.Xue: None. X.Li: None. X.Wang: None. H.Ma: None. Y.Heianza: None. L.Qi: None.
185-LB: Examining the Association between Neighborhood Socioeconomic Deprivation and Cesarean Section Rates among Women Diagnosed with Gestational Diabetes Mellitus—A Retrospective Analysis of the Maryland State Inpatient Database
Authors: AKINYEMI OLUWASEGUN A. 
Published: June 2023

Introduction: The rising cesarean section (CS) rates in patients with Gestational Diabetes Mellitus (GDM) may be influenced by social determinants of health, including neighborhood socioeconomic deprivation. Recent research has highlighted the association between higher levels of neighborhood socioeconomic deprivation and increased rates of CS among women with GDM. Understanding this relationship is crucial for addressing health disparities and improving maternal and infant health outcomes in disadvantaged communities.
Objective: To determine the association between neighborhood socioeconomic deprivation (DCI) and incidences of cesarean section among women with GDM in Maryland.
Methodology: DCI and CS rates among women with GDM. We adjusted for potential confounding variables, including age, day of admission, insurance type, race/ethnicity, and income, in our final multivariate analysis.
Results: In our study period, we identified 17,326 cases of GDM, with a CS rate of 44.3%. We found a significant correlation between the level of socioeconomic deprivation in the neighborhood and the rate of CS among women with GDM. Women with GDM residing in the poorest communities had the highest odds of CS. Prosperous, reference, Comfortable, (OR=1.08, 95% CI 0.98-1.20, p=0.13), Mid-tier, (OR=1.14, 95% CI 1.02-1.26, p=0.02), At-Risk, (OR= 1.17, 95% CI 1.02-1.34, p=0.03), and Distressed, (OR=1.29, 95% CI 1.11-1.50, p=0.001).
Conclusion: Women with GDM residing in areas with the poorest communities have the highest incidence of CS, irrespective of other risk factors.

Disclosure
O. A. Akinyemi: None.
186-LB: Association between Age at Diabetes Onset and Subsequent Risk of Cancer
Authors: TIAN JINGYAN , HOU TIANZHICHAO , CHALMERS JOHN 
Published: June 2023

Objective: Diabetes presenting at younger age has a more aggressive nature. We aimed to explore the association of age at type 2 diabetes (T2DM) onset with subsequent cancer incidence.
Research Design and Methods: The prospective population-based longitudinal cohort included 428,568 new-onset T2DM patients from 2011 to 2018. Participants were divided into four groups according to their T2DM onset age: 20-54, 55-64, 65-74, ≥75. The incidence of overall and 14 site-specific cancers was compared to the general population (100,649,346 person-years). A two-sample Mendelian randomization (MR) based on data from the UK Biobank, Pan-Cancer and FinnGen was used to explore the potential causality from age of diabetes onset to 13 cancers.
Results: A total of 18,853 and 582,643 cancer cases were reported in the cohort and general population. The age-standardized rate of overall cancer was 500.93/100,000 person-years and standardized incidence ratio (SIR) was 1.10 (95% CI: 1.09-1.12) in T2DM patients. With T2DM onset age from &lt;55 to ≥75, the SIRs of overall cancer were 1.48 (95% CI: 1.41-1.54) to 0.86 (95% CI: 0.84-0.89). Similar trends were detected in site-specific cancers and both males and females. The meta-analysis of MR results from Pan-Cancer and FinnGen showed a putative causal effect of earlier age of diabetes onset on increased overall cancer risk (OR: 0.93, 95% CI: 0.86-0.99), lymphoma, and liver cancer.
Conclusions: Our findings showed the earlier age of T2DM onset was associated with higher risk of subsequent cancers, which highlighted the necessity of stratifying management for T2DM according to the onset age.
Key words: Type 2 diabetes mellitus, Age of diabetes onset, Cancer incidence, Mendelian Randomization Analysis

Disclosure
J. Tian: None. T. Hou: None. J. Chalmers: None.

Funding
Shanghai Foundation of National Facility for Translational Medicine (TMSK-2021-506); Three-Year Action Plan of Shanghai Public Health (GWV-7)
192-OR: Lipid-Induced Insulin Resistance in Brown Adipose Tissue Is Mediated by the sn-1,2 DAG-PKCe-IRKT1150 Phosphorylation Pathway
Authors: GASPAR RAFAEL C. , HUBBARD BRANDON T. , SAKUMA IKKI , LAMOIA TRACI E. , ZHANG DONGYAN , SHULMAN GERALD I. 
Published: June 2023

While there is substantial evidence that brown adipose tissue (BAT) is insulin-responsive, it remains unclear whether BAT becomes insulin resistant with high fat diet (HFD) feeding. Here, we examined the hypothesis that the sn-1,2-diacylglycerol (DAG)/Protein Kinase C epsilon (PKCε)/insulin receptor kinase (IRK)T1150 phosphorylation pathway may trigger HFD-induced BAT insulin resistance. To address this hypothesis we first studied two groups of male Sprague Dawley rats fed either a regular chow diet (RC) or a HFD. HFD-fed rats manifested BAT insulin resistance as reflected by reduced insulin-stimulated phosphorylation of IRKT1158 (p=0.03), AKTT308 (p=0.003), PDHS232 (p=0.0002), and PDHS300 (p=0.0004) compared to RC rats during a hyperinsulinemic-euglycemic clamp (HEC). These reductions in insulin signaling occured at the level of the IRK and were associated with increased sn-1,2 diacylglycerols (p=0.03) and increased PKCε translocation (p&lt;0.004). These defects in insulin signaling were also associated with a 35% (p&lt;0.009) reduction in insulin-stimulated BAT mitochondrial pyruvate dehydrogenase/citrate synthase flux (VPDH/VCS) as assessed by LC-MS/MS and GC-MS measurements of C4C5 glutamate (m+2)/pyruvate (m+3) during a HEC where [13C6]glucose was the infusate. In order to assess the role of PKCε-induced IRKT1150 phosphorylation in this process we next studied the effects of HFD feeding in: 1) wild type mice fed a regular chow diet (WT), 2) wild type mice fed a HFD (WT-HFD) and 3) IRKT1150A knockin mice fed a HFD (IRKT1150A-HFD) and found that IRKT1150A-HFD mice have preserved levels of insulin-stimulated AKTS473 phosphorylation compared to WT-HFD mice (p=0.04).
Conclusion: These results demonstrate a critical role of the sn-1,2-DAG-PKCε-IRKT1150 phosphorylation pathway in mediating HFD-induced insulin resistance and mitochondrial dysfunction in BAT.

Disclosure
R.C.Gaspar: None. B.T.Hubbard: None. I.Sakuma: None. T.E.Lamoia: None. D.Zhang: None. G.I.Shulman: Consultant; Novo Nordisk, DiCerna Pharmaceuticals, Inc., Bayer Consumer Care AG, Kriya Therapeutics, Arrowhead Pharmaceuticals, Inc., ESPERION Therapeutics, Inc., Other Relationship; AstraZeneca, Merck & Co., Inc., Janssen Research & Development, LLC, iMetabolic Biopharma Corporation, Maze Therapeutics, 89bio, Inc., Equator Therapeutics, Inc., Generian Pharmaceuticals, Fortress Biotech, Inc., OrsoBio, Aro Biotherapeutics Company, Stock/Shareholder; Levels Health, Inc.
203-LB: Prevalence and Risk Factors of Diabetic Peripheral Neuropathy—A Population-Based Cross-Sectional Study in China
Authors: WANG WEIMIN , JI QIUHE , RAN XINGWU , LI CHENXI , XUE YAOMING , FENG BO , ZHU DALONG 
Published: June 2023

Aims: To assess the prevalence of diabetic peripheral neuropathy (DPN) and its risk factors in the type 2 diabetes mellitus (T2DM) population.
Methods: This cross-sectional study enrolled patients with T2DM between July and December 2017 from 24 provinces in China. DPN and its severity were assessed by the Toronto clinical scoring system, neuropathy symptoms score and neuropathy disability score. The prevalence of DPN and its risk factors were analyzed.
Results: A total of 14,908 patients with T2DM were enrolled. The prevalence of DPN was 67.6%. Among 10,084 patients with DPN, 4808 (47.7%), 3325 (33.0%), and 1951 (19.3%) had mild, moderate, and severe DPN, respectively. The prevalence of DPN was over 70% in patients aged ≥60 years, with low income (&lt;5000 RMB) and education level of primary school or below. The comorbidities and complications in patients with DPN were higher than in those without DPN (P&lt;0.001). Age, hypertension, duration of diabetes, diabetic retinopathy, diabetic nephropathy, glycated hemoglobin, high-density lipoprotein cholesterol, and lower estimated glomerular filtration rate were positively associated with DPN, while BMI, education level, fasting C-peptide, and uric acid were negatively associated with DPN.
Conclusions: Among patients with T2DM in China, the prevalence of DPN is high, especially in the elderly, low-income, and undereducated patients.

Disclosure
W. Wang: None. Q. Ji: None. X. Ran: None. C. Li: None. Y. Xue: None. B. Feng: None. D. Zhu: None.

Funding
Chinese Diabetes Society (2019YJ017)
205-OR: Automated Multiplex Antibody Detection by Agglutination PCR (ADAP) Compared with Gold Standard Radiobinding Assays of Autoantibodies in Type 1 Diabetes
Authors: LIND ALEXANDER , RAMELIUS ANITA , FREYHULT EVA , DE JESUS CORTEZ FELIPE , BENNET RASMUS , LARSSON HELENA E. , SEFTEL DAVID , TSAI JASON , LERNMARK ÅKE 
Published: June 2023

Autoantibody biomarkers detect asymptomatic autoimmunity and predict clinical onset of autoimmune type 1 diabetes. Single plex radiobinding assays (RBA) were compared with Antibody Detection by Agglutination PCR (ADAP), a novel minimum volume (4 μL) automated (Hamilton MicroLab STAR), multiplex autoantibody assay. Serum samples from 2,500 incident, 1-18 years of age, newly diagnosed type 1 diabetes patients and 2,500 controls, 1-50 years of age, were analysed for autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A) and ZnT8 transporter (ZnT8A). RBA for ZnT8A was against position 325 W, R and Q while ADAP was against W and R. Area Under the Curve (AUC) of the Receiver Operating Characteristics (ROC) curves for detection of type 1 diabetes patients showed 1) IAA improved with ADAP compared to RBA; Enable slightly better than CRC; 2) GADA improved with ADAP compared to RBA; no difference between Enable and CRC; 3) IA-2A improved with ADAP compared to RBA; similar performance between Enable and CRC and 4) ZnT8A showed better performance with RBA compared to ADAP; Enable better performance than CRC (Figure). The data suggest that multiplex ADAP, compared to golden standard single plex RBA, should prove useful in large scale, automated multiplex screening for asymptomatic type 1 diabetes.

Disclosure
A.Lind: None. A.Ramelius: None. E.Freyhult: None. F.Cortez: Employee; Enable Biosciences. R.Bennet: None. H.E.Larsson: None. D.Seftel: Employee; Enable Biosciences, Inc. J.Tsai: Stock/Shareholder; Enable Biosciences. Å.Lernmark: Advisory Panel; Diamyd Medical.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust (2009-04078)
209-LB: Discovery Metabolomics across a Population Scale Study Identifies a Community of Glycerolipids Associated with Incident Type 2 Diabetes
Authors: BEGZATI ARJANA , GODINEZ MACIAS KARLA P. , WATROUS JERAMIE , LONG TAO , KANTZ EDWARD , TUOMILEHTO JAAKKO , HAVULINNA AKI S. , NIIRANEN TEEMU , JOUSILAHTI PEKKA , SALOMAA VEIKKO , IDEKER TREY , JAIN MOHIT , MAJITHIA AMIT R. 
Published: June 2023

It is well appreciated that changes in metabolic pathways precede the development of overt type 2 diabetes (T2D), but a systematic and unbiased evaluation of such metabolic changes is lacking. Here, we applied a novel high-throughput untargeted liquid chromatography-mass spectrometry (LC-MS) method to the FINRISK 2002 cohort (n=8014) to identify plasma metabolite predictors of incident T2D. We analyzed LC-MS data consisting of 14,615 metabolite features from individuals without prevalent T2D to discover 171 that predicted T2D incidence at a threshold of P&lt;10-6 (Cox regression). To identify discrete molecular pathways, we performed Gaussian graphical modeling to create a network of all detected metabolite features finding that the T2D predictor metabolites were enriched in 11 distinct metabolite communities containing between 6 and 48 interconnected metabolites. Here we highlight one community consisting of 26 plasma diacylglycerols (DAGs) and closely related metabolites. One member of this community, a DAG with carbon:unsaturated bond sum composition of 36:4, predicted T2D incidence (HR = 1.22, p = 7.6×10-10) independently of insulin, glucose and HbA1c, but not 2-hour glucose as measured by OGTT. Thus, this metabolite is a novel predictor of incident T2D that can capture the metabolic dysregulation identifiable by OGTT.
In summary, we have identified multiple communities of T2D metabolite biomarkers, representative of distinct pathways that are dysregulated preceding T2D, with potentially clinical useful properties.

Disclosure
A. Begzati: None. K. P. Godinez Macias: None. J. Watrous: None. T. Long: None. E. Kantz: None. J. Tuomilehto: Stock/Shareholder; Orion pharma. A. S. Havulinna: None. T. Niiranen: Speaker's Bureau; AstraZeneca, Servier Laboratories. P. Jousilahti: None. V. Salomaa: Research Support; Bayer Inc. T. Ideker: None. M. Jain: Employee; Sapient Bioanalytics. A. R. Majithia: None.

Funding
National Institutes of Health (5R01DK129840-02)