bluuebunny/crossref_metadata_2025 huggingface dataset:
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 < 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 <.001), 1-hour c-peptide level (9.60 vs 7.75 ug/dL, p <.001) and gestational diabetes (14 vs 9.5%, p <.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<0.0001, FDR<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<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 <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<0.004). These defects in insulin signaling were also associated with a 35% (p<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 (<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<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<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)
214-OR: Results from the Promoting Resilience in Stress Management (PRISM) Intervention—A Multisite Randomized Controlled Trial (RCT) for Teens with Type 1 Diabetes (T1D)
Authors: YI-FRAZIER JOYCE P. , HILLIARD MARISA E. , O'DONNELL MAEVE B. , ZHOU CHUAN , ELLISOR BRITNEY M. , GARCIA PEREZ SAMANTHA , ROJAS YULIANA , MALIK FAISAL , DESALVO DANIEL , PIHOKER CATHERINE , BRADFORD MIRANDA , SCOTT SAMANTHA R. , ROSENBERG ABBY
Published: June 2023

Introduction: PRISM is a resilience resources intervention that teaches stress-management, goal setting, reframing, and benefit finding. We tested the efficacy of PRISM on glycemic control, diabetes distress, resilience, and quality of life.

Methods: This 2-site (Seattle WA, Houston TX) 1:1 RCT of PRISM vs. usual care (UC) included teens 13-18y with T1D≥12m and diabetes distress (PAID-T) scores ≥30. A1C, distress (PAID-T), diabetes resilience (DSTAR), and diabetes quality of life (T1DAL) were assessed at baseline (BL), 6m and 12m. Regression analyses used treatment arm as the primary predictor, controlling for additional covariates (Table).

Results: Teens (n=172) were 56% female, race = 73% White, 15% Black, 4% Asian, 8% other, ethnicity = 19% Hispanic, BL A1C 8.7% ± 2.0%. No differences were evident between PRISM and UC in A1C, distress, resilience, quality of life at 6 months post-baseline. However, at 12 months, participants in the PRISM arm experienced improvements in distress, resilience, and quality of life versus UC (Table).

Conclusions: Resilience promotion through PRISM had multiple psychosocial benefits for a diverse sample of teens with T1D by 12-months. Integrating resilience skill-building with medical intervention may optimize diabetes outcomes.

Disclosure

J.P.Yi-frazier: None. C.Pihoker: None. M.Bradford: None. S.R.Scott: None. A.Rosenberg: None. M.E.Hilliard: None. M.B.O'donnell: None. C.Zhou: None. B.M.Ellisor: None. S.Garcia perez: None. Y.Rojas: None. F.Malik: None. D.Desalvo: Consultant; Dexcom, Inc., Research Support; Insulet Corporation.

Funding

National Institutes of Health (R01DK121224)
224-LB: Shared Genetic Architecture of Complication of Diabetes
Authors: SALEM RANY M. , CAO STEVEN , RICHARD ERIN L.
Published: June 2023

Introduction: Approximately 1 in 10 Americans have diabetes (~37 million), 90-95% of which is type 2 diabetes (T2D). T2D is the leading cause of kidney disease (DKD), retinopathy, neuropathy, peripheral vascular disease (PVD), stroke, and coronary heart disease (CHD). Inherited variation is known to contribute to the risk of T2D complications, however, the relationship between and role of genetic variants on risk across complications is not fully understood.

Method: We used data from our recently completed genomic investigations of a broad set of 18 diabetic complications, which included ~64K T2D subjects across five race-ethnic groups (Admixed Americas-, African-, East Asian-, European- and South Asian-ancestry samples) from 24 studies retrieved from dbGaP and UKBB biomedical repositories. Using these GWAS summary statistics, we calculated the genetic correlation between complication pairs with Z-scores (beta/SE) to investigate their relationship and guide post hoc pleiotropy analysis.

Results: Genetic correlation analysis revealed four clusters of complications that shared strong correlation. Pleiotropy analysis identified three novel pleiotropic loci for T2D complications at SNX17 (Albuminuria, CHD & PVD), UBE2E2 (Albuminuria & end-stage kidney disease) and GCKR (Albuminuria, DKD, retinopathy, fatty liver disease, CHD & PVD).

Conclusion: These findings support the hypothesis of shared heritability between diabetic complications. Additional work is needed to increase genetic discovery of pleiotropic variants across diabetic complications.

Disclosure

R. M. Salem: Other Relationship; Travere Inc. S. Cao: None. E. L. Richard: None.

Funding

Foundation for the National Institutes of Health; National Institutes of Health (R00HL122515)
228-LB: Metformin Alleviates Aging-Associated Metabolic Disorders through Intestinal AMPK-Mediated Gut Microbiome Alteration
Authors: ZHANG ERYUN , HUANG WENDONG
Published: June 2023

The biguanide drug metformin combats age-related disorders and improves health span and is currently the first FDA approved drug to be tested for its age-targeting effects in the large clinical trial. However, the underlying molecular mechanisms remain unclear. AMPK is a key nutrient sensor for maintaining cellular energy status and a known therapeutic target of metformin to treat T2D. Despite current understandings of its well-established roles in regulating glucose metabolism in various tissues, the functions of AMPK in the intestine remain largely unexplored. Our previous study uncovered a novel link between intestinal AMPK activation and energy metabolism through modulating the anti-microbial peptide (AMP)-controlled gut microbiota. We therefore ask whether intestinal AMPK also mediates metformin effects on aging-associated metabolic improvement. In this study, we showed that AMPKα1 deficiency in the intestine resulted in weight gain, impaired glucose tolerance and insulin resistance in aged mice. Interestingly, metformin administration ameliorated these aging-associated metabolic disorders in aged wild type but not intestinal AMPK α1 KO mice, which indicated that the beneficial effects of metformin were dependent on the intestinal AMPKα1 in aging animals. Moreover, we found that metformin treatment significantly altered the abundance of several gut bacterial genera in aged-AMPKα1fl/fl but not intestinal AMPK α1 KO mice. Mechanistically, we identified several key anti-microbial peptides were upregulated by metformin treatment in an intestinal AMPK-dependent manner in aged mice.

In summary, our findings provide a new mechanistic underpinning by which intestinal AMPK regulates aging metabolism, which may shed light on not only the ongoing large clinical trials of metformin in aging patients, but also general drug discoveries utilizing enteral drug administration to treat aging-associated metabolic diseases.

Disclosure

E. Zhang: None. W. Huang: None.
229-LB: Generation of Human CAR-Treg Cells for Inducing Immunological Tolerance against Diabetogenic T Cells in Human Pancreatic Islets
Authors: IMAM SHAHNAWAZ , IMTIAZ RAFIQI SHAFIYA , JAUME JUAN C.
Published: June 2023

We have developed pancreatic beta-cell, antigen-specific, Chimeric Antigen Receptor (CAR) T regulatory cells (Tregs) and explored their therapeutic potential against type 1 diabetes (T1D)/Latent Autoimmune Diabetes of Adult (LADA) in human pancreatic tissues ex-vivo. Two human Glutamic Acid Decarboxylase 65 kD isoform (GAD65) B-cell paratopes known to bind to two immunodominant regions in the N-terminal (CAR-N) and Middle (CAR-M) regions of human GAD65 were selected for assembly onto T cell receptors of Tregs. We first show that GAD65-CAR Tregs had a superior proliferation index (3 times than naïve Tregs) and were able to suppress diabetogenic, T cells in-vitro and this suppression was significantly superior to naïve Tregs at 2:1 (Tresp vs Treg) ratio (p<0.004). Further, in ex vivo co-culture experimentation with pancreatic islets, confocal images demonstrated homing of GAD65-CAR Tregs to pancreatic islets as early as 24 hrs. With live immunofluorescence imaging and flow cytometry we demonstrated that GAD65-CAR Tregs from T1D/LADA patient were able to suppress diabetogenic cytotoxic T lymphocytes (CTLs) (p<0.04) in the immune cell microenvironment in presence of heterologous pancreatic islet ex vivo. These findings verify that GAD65-CAR Tregs recognize endogenous GAD65 on isolated islets in an MHC-independent manner, are proliferative robustly and suppress autologous CTLs. Thus, GAD65-CAR Tregs can induce tolerance against T1D diabetogenic T cells and the use of GAD65-CAR Tregs can prove a promising strategy for inducing tolerance in islet transplantation to replace the immunosuppressive drugs in a safe potent manner.

Finally, homing of the GAD65-CAR Tregs to the islets, provided evidence for antigen-specific re-directionality. The robust proliferation and superior suppression of diabetogenic T cells by GAD65-CAR Tregs validate the functionality of GAD65-CAR Tregs in inducing tolerance in T1D patients and host vs graft islet rejections.

Disclosure

S. Imam: None. S. Rafiqi: None. J. C. Jaume: None.

Funding

University of Toledo
232-OR: STIM1 Interacts with G Protein–Coupled Estrogen Receptor Signaling to Maintain ß-Cell Identity in Female Mice
Authors: MCLAUGHLIN MADELINE , SOHN PAUL , KRISHNAN PREETHI , LEE CHIH-CHUN , KONO TATSUYOSHI , EVANS-MOLINA CARMELLA
Published: June 2023

Calcium (Ca2+) plays a vital role in normal β cell function, and the β cell endoplasmic reticulum (ER) serves as the dominant intracellular store of Ca2+. ER Ca2+ depletion triggers a rescue mechanism known as store-operated Ca2+ entry (SOCE), which replenishes ER Ca2+ stores through the ER-localized Ca2+ sensor stromal interaction molecule 1 (STIM1). We have demonstrated pathogenic reductions in β cell SOCE and loss of STIM1 expression in rodent and human models of type 2 diabetes (T2D) and shown that β cell-specific loss of STIM1 (STIM1Δβ) leads to obesity-induced glucose intolerance, decreased β cell and increased cell mass in female but not male STIM1Δβ mice. To test mechanisms underlying these findings, lineage tracing experiments were performed and revealed increased colocalization of tdTomato and glucagon in STIM1Δβ mice compared to control mice, suggesting dedifferentiation of β cells to ⍺ cells. RNA sequencing of islets isolated from female STIM1Δβ mice revealed reductions in G-protein coupled estrogen receptor (GPER) expression and a transcriptional signature indicative of reduced estradiol mediated signaling. To test whether GPER is required for the maintenance of β cell identity, INS-1 cells were transfected with siRNA targeted to Gper1 or treated with the GPER1 antagonist, G-15. RT-qPCR showed that markers of β cell identity were significantly reduced and Gcg expression was significantly increased in Gper1 knockdown and G-15-treated cells. Lastly, to explore the functional connection between SOCE and GPER, STIM1KO and GPER knockdown INS-1 cells were stimulated with glucose, and Ca2+ responses were evaluated. First and second phase Ca2+ responses after glucose treatment were impaired in both STIM1KO and GPER knockdown INS-1 cells compared to WT INS-1 cells, suggesting that STIM1 and GPER may be functionally linked through Ca2+ signaling. Together, these data identify a novel connection between β cell SOCE, GPER signaling, and β cell differentiation status.

Disclosure

M.Mclaughlin: None. P.Sohn: None. P.Krishnan: None. C.Lee: None. T.Kono: 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 Institute of Diabetes and Digestive and Kidney Diseases (R01DK093954, R01DK127236, U01DK127786, R01DK127308, UC4DK104166); U.S. Department of Veterans Affairs (I01BX001733)
233-OR: The Beta-Cell Specific Deletion of Complement 1q-Like-3 Secreted Protein Improves Beta-Cell Function and Glucose Homeostasis
Authors: MOSTAFIZUR RAHMAN MD , ALSHARIF HAIFA , MICHL AVA , BHATNAGAR SUSHANT
Published: June 2023

Using bioinformatics network analysis, we identified complement-1q like-3 (C1ql3) as a secreted protein that affects pancreatic islet function in obese mice. Previously, we showed that the recombinant C1ql3 protein inhibits insulin secretion stimulated by exendin-4 (an agonist for GLP-1 receptor) from human and mouse islets. Currently, we are elucidating the role of C1ql3 in pancreatic β-cell function by using mice with β-cell-specific deletion of the C1ql3 (βKO) gene on a standard chow diet. C1ql3βKO mice showed significantly improved glucose clearance after oral glucose challenge than the control mice, whereas no difference in insulin sensitivity was observed. Moreover, the plasma insulin levels were significantly increased at 15 min after the glucose challenge in the C1ql3 βKO vs. control mice. However, islets isolated from C1ql3βKO significantly increased insulin secretion stimulated by cAMP and Exendin-4 than control islets. These results suggest that the loss of C1ql3 in β-cells increases insulin secretion to improve glucose tolerance. Adenovirus-mediated overexpression of C1ql3 in islets showed increased ER stress and decreased expression of genes involving β-cell function and maintenance. In pathophysiological conditions, increased C1ql3 expression coupled to secretion was observed from both T2D donor islets and obese mouse islets. Interestingly, reduction in C1ql3 secretion is inversely correlated with increased glucose-stimulated insulin secretion from islets of C1ql3βKOLeptinob/ob compared to Leptinob/ob control mice. These findings suggest that the loss of β-cell C1ql3 maintains ER stress and increases insulin secretion to maintain glucose homeostasis. Our work shows that an autocrine regulation of the C1ql3-signaling pathway contributes to β-cell dysfunction in obesity and type 2 diabetes.

Disclosure

M.Rahman: None. H.Alsharif: None. A.Michl: None. S.Bhatnagar: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK120684-01)
240-OR: Islet Allotransplantation into Prevascularized Sernova Cell Pouch—Early Results from the University of Chicago
Authors: OGLEDZINSKI MATEUSZ , GONDEK SARAH , LIN WILLIAM , MILEJCZYK KAMILA , JUENGEL BRADEN , POTTER LISA , BACHUL PIOTR J. , BASTO LINDSAY , PEREA LAURENCIA , WANG LINGJIA , TIBUDAN MARTIN , BARTH ROLF , FUNG JOHN , WITKOWSKI PIOTR
Published: June 2023

Each of 6 patients with T1DM and problematic hypoglycemia received 2 islet transplants into pre-implanted Sernova Cell Pouches (SCPs). Each procedure involved transplantation of islets into two 8-channel SCPs and one mini sentinel SCP. SCP implants and the combination of SCP with human cadaveric islets are both well tolerated with durations exceeding 3 years. Detectable islet function (≥0.3ng/ml peak serum c-peptide in mixed meal tolerance test) was achieved in 4 patients following islet transplant to SCP. It was correlated with transplanted islet mass of 300k-500k IEQ per procedure. Transplantation of islet mass <300k IEQ did not lead to detectable c-peptide secretion. C-peptide was detectable for periods ranging from days up to 12 months after the procedure. Three patients with suboptimal levels of immunosuppression due to non-compliance experienced antibody mediated rejection based on de novo donor specific antibodies (DSAs). One patient with DSAs had detectable stimulated c-peptide at 90 days post-transplant. Histological assessment of sentinel SCPs retrieved ≥90 days post-transplant revealed surviving functional islets within vascularized SCP channels via positive immunofluorescence staining of insulin, c-peptide, glucagon and somatostatin in 5 of 6 patients. Five patients received supplemental intraportal islet transplants (IPITx) and all of them remain insulin independent (>2.5Y, >1Y, 10M, 2M, 1M). The sixth patient is awaiting an IPITx in the coming months as per protocol. Safety and dose-response observations from the first cohort of 6 patients led to the implementation of 10-channel SCPs with 50% greater transplant capacity than the 8-channel configuration in a second study cohort. Two additional patients were recently implanted with 10-channel SCPs and are currently awaiting their first islet transplantation.

Disclosure

M.Ogledzinski: None. L.Wang: None. M.Tibudan: None. R.Barth: None. J.Fung: None. P.Witkowski: Advisory Panel; Vertex Pharmaceuticals Incorporated, Novartis. S.Gondek: None. W.Lin: None. K.Milejczyk: None. B.Juengel: None. L.Potter: None. P.J.Bachul: None. L.Basto: None. L.Perea: None.

Funding

Sernova; JDRF
241-OR: Preservation of Islet Graft Function and Blood Glucose Control after Total Pancreatectomy with Islet Autotransplantation in Patients with Chronic Pancreatitis and Intractable Pain—Nine-Year Follow-up
Authors: LIN WILLIAM , OGLEDZINSKI MATEUSZ , GONDEK SARAH , MILEJCZYK KAMILA , JUENGEL BRADEN , POTTER LISA , BACHUL PIOTR J. , BASTO LINDSAY , PEREA LAURENCIA , WANG LINGJIA , TIBUDAN MARTIN , BARTH ROLF , FUNG JOHN , WITKOWSKI PIOTR
Published: June 2023

Background: Total pancreatectomy is a last resort treatment for patients with chronic pancreatitis and intractable abdominal pain, however its utility has been hampered by the uncertain endocrine outcomes of islet transplantation and risk of postsurgical diabetes. Here, we present our 9-year clinical results after total pancreatectomy and islet transplantation.

Materials and Method: Forty-one patients with chronic or recurrent acute pancreatitis were treated with TPIAT over the last 9 years at the University of Chicago Medical Center. There were 15 male and 26 female with a median age of 33 (6-65) and with median BMI of 25 (17-39). Five (12%) patients were already diabetic prior to surgery. Islet isolation was performed at a local laboratory compliant with current Good Manufacture Practice regulations. Islet purification was implemented in 4 (10%) cases to reduce islet pellet volume below 20mL for intraportal infusion.

Results: All patients required opioids for pain control prior to surgery. Most of the patients (93%) reported resolution of pancreatic-type pain by postoperative year one. The number of patients requiring opioids for different type or location of pain declined over time from 13 (31%) at 1 year to 5 (12%) at 5 years after TPIAT. During TPIAT patients received on average 211,000±111,000 islet equivalents (IEQ), 2,500±1,600,). The majority of patients (95%) maintained endocrine beta cell function during follow up (serum c-peptide >0.5ng/ml). Over 40% of patients maintained long-term insulin independence: 44% (15/34) at 1-year and 45% (5/11) at 5-year follow-up.

Conclusions: TPIAT successfully provided pancreatic pain resolution of pancreatic pain and preservation of the endocrine beta cell function in majority of the patients with no mortality. Islet autotransplantation prevented diabetes in over 40% of patients.

Disclosure

W.Lin: None. L.Wang: None. M.Tibudan: None. R.Barth: None. J.Fung: None. P.Witkowski: Advisory Panel; Vertex Pharmaceuticals Incorporated, Novartis. M.Ogledzinski: None. S.Gondek: None. K.Milejczyk: None. B.Juengel: None. L.Potter: None. P.J.Bachul: None. L.Basto: None. L.Perea: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020595)
247-OR: Positive Effects of Bariatric Surgery Are Associated with Attenuation of Cellular Senescence
Authors: STEMBERKOVA HUBACKOVA SONA , HAVRLANTOVA TEREZA , SIMONIK IGOR , MRAZ MILOS , HALUZIK MARTIN
Published: June 2023

Bariatric surgery represents the most efficient approach to treatment of obesity; however, the detailed mechanism of its positive metabolic effect is still not fully understood. Cellular senescence arrests the cell cycle in damaged cells thus preventing further spreading of the damage. Persistence of senescent cells especially in adipose tissue can, however, contribute to the development of a number of chronic diseases including obesity and its complications. Reduction of adipose tissue after bariatric surgery can therefore reduce the number of senescent cells and their negative effects on organism.

17 patients with obesity (2nd grade and higher) scheduled for bariatric surgery (sleeve gastrectomy) were included into the study. Subcutaneous (SAT) adipose tissue and plasma were collected during and 6 months after surgery. The analysis of samples included RT-qPCR (mRNA transcription in SAT) and ELISA or Luminex for detection of hormones and proteins from plasma.

Our results show that bariatric surgery reduces the amount of senescent cells in adipose tissue, which results in the decrease of oxidative stress and inflammation, partially also by reduced recruitment of pro-inflammatory macrophages. In addition, we detected lower plasma levels of soluble E-selectin and ICAM-1, molecules enhancing cardiovascular damage known to be produced by senescent cells, as well as decreased expression of ACE2, whose increased expression was detected in senescent cells. Importantly, we also observed decreased expression of ADAM17 responsible for producing a soluble form of ACE2, a newly identified predictor of cardiovascular damage.

In conclusion, reduction of senescent cells in adipose tissue after bariatric surgery contributes to improvement of inflammation and metabolic parameters in patients with obesity and decreases the risk of cardiovascular complications.

Disclosure

S.Stemberkova hubackova: None. T.Havrlantova: None. I.Simonik: None. M.Mraz: None. M.Haluzik: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca.

Funding

Czech Health Science Foundation (NU22-01-00096); Programme EXCELES (LX22NPO5104); Czech Ministry of Health (IKEM, IN00023001)
250-LB: Ethnic Disparities in Insulin Secretion and Clearance in Normoglycemic Adults with Parental Type 2 Diabetes
Authors: ASUZU PEACE , PATEL AVNISHA , WAN JIM Y. , DAGOGO-JACK SAMUEL
Published: June 2023

Background: To determine the role of ethnicity vs. heredity in glucoregulation, we assessed insulin secretion in healthy Black and White offspring of parents with T2DM.

Methods: Participants were screened with 75-g OGTT, and normoglycemic enrollees underwent assessments, including anthropometry, insulin sensitivity and secretion. Basal insulin secretion (fasting insulin {FI} and HOMA-B) and dynamic secretion (insulinogenic index; corrected insulin response {CIR} from OGTT data; acute insulin response to i.v. glucose {AIR}, insulin-AUC during FSIGT, and disposition index {DI} were quantified. Insulin sensitivity (ISI) was measured with euglycemic clamp. Basal insulin clearance (molar ratio of fasting C-peptide to insulin) and dynamic clearance (molar ratio of plasma C-peptide to insulin levels during FSIGT) were determined.

Results: We studied 145 Black and 123 White adults (N=268); 72% women; mean age 44.6±10.1 y. At baseline, fasting glucose (91.0 ± 7.26 vs.93.1 ± 6.31 mg/dl, P=0.012) and ISI (0.062 ± 0.048 vs. 0.077 ± 0.04, P=.014) were lower, and BMI (31.6 ± 7.64 vs. 28.9 ± 6.79, P=.0032) higher, in Black vs. White subjects. Basal insulin secretion was similar, but all measures of dynamic secretion were higher in Black vs. White offspring (Table 1).

Conclusions: Insulin clearance is lower but dynamic insulin secretion is greater in Black versus White individuals with parental diabetes.

Disclosure

P. Asuzu: None. A. Patel: None. J. Y. Wan: None. S. Dagogo-jack: None.
260-OR: The ApoB/LDL-C Ratio Predicts Major Cardiovascular Events in Cardiovascular Disease Patients Independent of Type 2 Diabetes Status
Authors: LARCHER BARBARA , MAECHLER MAXIMILIAN , SPRENGER LUKAS , MADER ARTHUR , VONBANK ALEXANDER , PLATTNER THOMAS , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2023

A high ApoB/LDL-C ratio reflects small LDL particle size which like type 2 diabetes (T2DM) is associated with insulin resistance. Whether the ApoB/LDL ratio and the presence of T2DM are mutually independent predictors of major cardiovascular events (MACE) is unclear and is addressed in the present study. We enrolled a large high risk cohort of 1689 patients with established cardiovascular disease (1391 patients with angiographically proven stable CAD and 298 patients with sonographically proven peripheral artery disease). T2DM was diagnosed according to current ADA guidelines. Prospectively, MACE including death from cardiovascular cause, non-fatal stroke and non-fatal myocardial infarction were recorded over a mean follow-up period of 9.6±5.1 years. At baseline, the ApoB/LDL-C ratio was significantly higher in patients with T2DM (n=561) than in subjects who did not have T2DM (0.82±0.19 vs. 0.74±0.15 p<0.001). During follow-up, 668 patients suffered MACE. The Apo B/LDL-C ratio predicted MACE in univariate analysis (HR=1.12 [1.04-1.20] p= 0.002), and the event rate was higher in patients with than in those without T2DM (49.1% vs. 34.9%; p<0.001). In a multivariate adjusted Cox regression model both the ApoB/LDL-C ratio and T2DM significantly predicted MACE in a mutually independent manner, with standardized adjusted HRs of 1.17 [1.05-1.30]; p=0.005 and 1.49 [1.26-1.75]; p<0.001, respectively. We conclude that in subjects with established cardiovascular disease the ApoB/LDL-C and T2DM are mutually independent predictors of MACE.

Disclosure

B.Larcher: None. C.H.Saely: None. M.Maechler: None. L.Sprenger: None. A.Mader: None. A.Vonbank: None. T.Plattner: None. A.Leiherer: None. A.Muendlein: None. H.Drexel: None.
262-OR: Use of CGM Adhesive Kits Increase Active CGM Use among NHB and Latinx Youth with T1D
Authors: GRUNDMAN JODY , PERKINS AMANDA G. , REILLY JENNIFER K. , HOLLY SARAH L. , BOWERS STEPHANIE , CLARY LAUREN , MAJIDI SHIDEH
Published: June 2023

Introduction CGM use is lowest among minority youth in the US. This QI project aims to increase active CGM use from 39% to 70% and reduce CGM attrition from 74% to 30% among NHB and Latinx youth with T1D.

Methods We distributed CGM adhesive kits with overlay patches and adhesive wipes to youth with diabetes, with instructions on use and how to purchase. PDSA cycles were completed in an iterative process. Demographic and CGM use data (“active”, “attrition”, or “never”) were obtained over 9 months. Chi square tests compared data between NHB/Latinx youth who received versus did not receive kits at 3, 6, and 9 months from project initiation.

Results 103 kit-receiving youth (Mage 12.8±4.5, Male 51.0%, NHB 71.8%, Latinx 28.2%,T1D 81.6%) were compared with 917 youth seen in clinic over the same period who did not receive kits (Mage 14.4±4.1, Male 47.0%, NHB 70.1%, Latinx 29.9%, T1D 65.1%). CGM use rates are described in Figure 1. From baseline to follow-up, current CGM use increased and never CGM use decreased among those that received kits, while current and never CGM use rates remained relatively unchanged among non-kit receivers. At final visit, 48% of never users and 29.3% with CGM attrition prior to receiving kits became active users.

Conclusions There was a greater increase in active CGM use and decrease in never CGM use among NHB and Latinx youth who received CGM adhesive kits. QI projects can help to promote equity in use of diabetes technologies.

Disclosure

J.Grundman: Research Support; American Diabetes Association, Dexcom, Inc. A.G.Perkins: Research Support; Tandem Diabetes Care, Inc., Dexcom, Inc. J.K.Reilly: None. S.L.Holly: None. S.Bowers: None. L.Clary: None. S.Majidi: None.
268-OR: The Combined Use of SGLT2 Inhibitors and GLP-1 Receptor Agonists on the Risk of Cardiovascular Events among Patients with Type 2 Diabetes
Authors: AZOULAY LAURENT , SIMMS-WILLIAMS NIKITA , YIN HUI , LU SALLY , TREVES NIR , HOI YUN YU ORIANA
Published: June 2023

Background: While sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to have cardiovascular benefits when used individually, it remains unknown whether their combined use is associated with further reductions in cardiovascular events in the real-world setting.

Objective: To determine whether the SGLT2 inhibitor-GLP-1 RA combination is associated with a decreased risk of major adverse cardiovascular events (MACE) compared with SGLT-2 inhibitors alone.

Methods: Using the United Kingdom Clinical Practice Research Datalink linked with the Hospital Episode Statistics and Office for National Statistics databases, we identified all patients, >18 years of age, who initiated an SGLT2 inhibitor from 2013 to 2020. Using a prevalent new-user design, we matched 8980 patients initiating an SGLT2 inhibitor-GLP-1 RA combination, in a 1:1 ratio, with patients using SGLT2 inhibitors alone on time-conditional propensity scores. The primary outcome was MACE (myocardial infarction, ischemic stroke, and cardiovascular mortality). Secondary outcomes were the individual components of MACE and heart failure. Patients were followed using an on-treatment approach and Cox proportional hazards regression models were fit to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for each outcome.

Results: Compared with SGLT2 inhibitors alone, the SGLT2 inhibitor-GLP-1 RA combination was associated with a 34% decreased risk of MACE (HR: 0.66, 95% CI: 0.48-0.91). In secondary analyses, the combination was associated with a decreased risk of myocardial infarction (HR: 0.64, 95 CI: 0.42-0.98), while the other outcomes generated more modest effects with CIs including the null.

Conclusions: The results of this real-world study suggest that the SGLT2 inhibitor-GLP-1 RA combination is associated with further reductions in the risk of MACE, compared with the SGLT2 inhibitors alone.

Disclosure

L.Azoulay: Advisory Panel; Pfizer Inc., Consultant; Pfizer Inc., Speaker's Bureau; Roche Diagnostics. N.Simms-williams: None. H.Yin: None. S.Lu: None. N.Treves: None. O.Yu: Consultant; Novo Nordisk.

Funding

Canadian Institutes of Health Research (FDN143328)