bluuebunny/crossref_metadata_2025 huggingface dataset:
1352-P: Cardiometabolic Risk Factors Superior to FIB4 in Identifying Adults at Risk for NAFLD with Fibrosis
Authors: GODINEZ LEIVA EDDISON , SHARMA ANU , KALAVALAPALLI SRILAXMI , ORTIZ ROCHA ANDREA , VALDEZ SAENZ ENRIQUE , MOHSENI YASMINE , CUERVO PARDO NATHALY , ROSENBERG JENS T. , GRAJO JOSEPH R. , BARB DIANA , CUSI KENNETH
Published: June 2024

Introduction & Objective: A single effective screening tool for hepatic fibrosis across all age groups is currently lacking. The fibrosis-4 score (FIB-4) is the most commonly used screening tool but is less reliable in younger and older ages. The goal was to identify the best combination of cardiometabolic risk factors in all adults to guide clinical screening for hepatic fibrosis.

Methods: A total of 1420 adults with (63%) and without (37%) type 2 diabetes (T2D) without a prior history of NAFLD were recruited. A complete history, physical examination, and screening for NAFLD with laboratory tests and assessment of insulin sensitivity by HOMA-IR and Adipo-IR were performed. Clinically significant hepatic fibrosis (≥F2) was defined as a liver stiffness measurement ≥8.0 kPa by elastography, or ≥3.0 kPa by MRE, or on liver biopsy.

Results: Of those with hepatic fibrosis (n=135), 34% (n=46) were <35 or >65 years old. The presence of T2D had a sensitivity of 87% and a specificity of 39% for hepatic fibrosis. Adding obesity to T2D, lowered the sensitivity (76%) but increased specificity to 61%. The presence of T2D, obesity, and hypertension (HTN) together did not change test characteristics. Adding atherogenic dyslipidemia (non-HDL ≥130 mg/dL), however, significantly lowered sensitivity (20%). HOMA-IR and Adipo-IR were sensitive but not specific for hepatic fibrosis. The presence of any combination of ≥3 cardiometabolic risk factors (T2D, obesity, HTN, atherogenic dyslipidemia) had a sensitivity of 86% and specificity of 54% for hepatic fibrosis. The addition of FIB-4 ≥1.3 increased the sensitivity to 97% but decreased specificity to 41%. In comparison, FIB-4 ≥1.3 in those 35-65 years old had a sensitivity of 84% and specificity of 25% for hepatic fibrosis.

Conclusion: The presence of ≥3 common cardiometabolic risk factors (T2D, obesity, HTN, atherogenic dyslipidemia) is a simple yet effective clinical screening strategy for NAFLD in all adults with superior specificity compared to FIB-4.

Disclosure

E. Godinez Leiva: None. A. Sharma: None. S. Kalavalapalli: None. A. Ortiz Rocha: None. E. Valdez Saenz: None. Y. Mohseni: None. N. Cuervo Pardo: None. J.T. Rosenberg: None. J.R. Grajo: None. D. Barb: Speaker's Bureau; Novo Nordisk. Other Relationship; Inventiva Pharma. K. Cusi: Research Support; Echosens, Boehringer-Ingelheim, Quest Diagnostics, Inventiva Pharma, LabCorp, Nordic Bioscience A/S. Consultant; Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer-Ingelheim, Lilly Diabetes, 89bio, Inc., GlaxoSmithKline plc, Novo Nordisk, Siemens Healthcare Diagnostics, Sagimet Biosciences, Terns Pharmaceuticals.

Funding

National Institutes of Health (R01DK120331)
1361-P: Development and Validation of a Scoring System for Predicting the Need for Hypoglycemic Agents during Glucocorticoid Treatments
Authors: KATO AYAKA , FUWA MASAYUKI , ASANO MOTOCHIKA , MORI ICHIRO , MORITA HIROYUKI
Published: June 2024

Introduction & Objective: Glucocorticoid (GC) treatments have widely contributed to induction and maintenance therapies. However, GC-induced hyperglycemia cannot be predicted by fasting plasma glucose and HbA1c alone. The aim of the study was to identify the risk factors for GC-induced hyperglycemia and have developed and validated a novel scoring system for predicting the need for hypoglycemic agents during GC treatment.

Methods: In a developing set, 508 adults receiving prednisolone (PSL) for the first time were divided into two groups based on their treatment with or without hypoglycemic agents. Their clinical and laboratory parameters were compared, and risk factors were identified using logistic regression analysis after performing univariate analyses between the two groups. A point-addition scoring system with several categories and their coefficients in each risk factor was constructed to predict the need for hypoglycemic agents. The scoring system was then applied and validated on two validation sets, A and B.

Results: Older age and higher HbA1c percentages, body mass index, and initial PSL dosage were identified as risk factors. The sensitivity, specificity, and accuracy of the scoring system were 70.6%, 81.9%, and 77.1% in the developing set, 75.8%, 78.4%, and 77.4% in the validation set A, 79.4%, 73.9%, and 75.3% in the validation set B, respectively.

Conclusion: The scoring system is a valid and reliable tool for predicting the need for hypoglycemic agents in advance during GC treatment.

Disclosure

A. Kato: None. M. Fuwa: None. M. Asano: None. I. Mori: None. H. Morita: None.

Funding

JSPS KAKENHI (23K06864)
1367-P: Cognitive Assessment in Type 2 Diabetes—A Pilot Study in an Outpatient Clinic
Authors: LUDINGTON JANE , CHEN ROGER , GNJIDIC DANIJELA
Published: June 2024

Aim: Type 2 diabetes (T2D) is associated with an increased risk of cognitive decline which may impact diabetes self-care and outcomes. Assessment of cognitive function is not routine practice. The primary objective was to assess cognitive function in outpatients >55 years with T2D.

Method: People with T2D (> 55 years) attending a tertiary hospital diabetes outpatient clinic with no known cognitive impairment and sufficient English language skills were recruited. The Montreal Cognitive Assessment and Problem Areas in Diabetes questionnaires were completed with a trained investigator. Routine demographic and clinical data were obtained from healthcare records. Analysis was descriptive and results expressed as mean ± standard deviation. Institutional ethics approval was obtained.

Results: Forty patients were enrolled, age 71.3 ± 8.7 years, 75% male, diabetes duration was 15.4 ±8.7 years and current HbA1c 7.7% ± 1.2%. The number of medications prescribed was 8.2 ± 3.7. The PAID score was 14.2 ± 13.3. In 27/40 (67.5%) patients the MOCA score was <26/30 (23.6 ± 2.8) indicating cognitive impairment. The number of medications prescribed to this group was 8.4 ± 3.7. High risk medicines were prescribed to 23/27 (85%) of this cohort of patients.

Conclusion: Cognitive screening highlighted the prevalence of impairment in this outpatient clinic population (67.5%). Inclusion of routine cognitive screening can identify people who may benefit from additional diabetes management support and appropriate modifications to treatment regimens. This data will inform plans to implement routine screening in accordance with professional guidelines and screening principles.

Disclosure

J. Ludington: None. R. Chen: Speaker's Bureau; Abbott Diagnostics, AstraZeneca, Boehringer-Ingelheim. Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Advisory Panel; Novo Nordisk. Speaker's Bureau; Novo Nordisk. D. Gnjidic: None.
139-OR: Empagliflozin Enhances Hepatic Glucose Production and Reduces Total-Body Norepinephrine Turnover Rate—A Randomized Trial
Authors: ABDELGANI SIHAM , BASKOY GOZDE , ADAMS JOHN M. , KHATTAB AHMED , DEFRONZO RALPH A. , ABDUL-GHANI MUHAMMAD
Published: June 2024

Background/Aims: SGLT2 inhibitors cause an increase in hepatic glucose production (HGP) which returns glucose to the systemic circulation and offsets the amount of glucose excreted in the urine by ~50%. The signal which is activated by SGLT2 inhibition and causes the increase in HGP is unknown. We previously have shown that the acute administration of SGLT2 inhibitor is associated with an increase (within 4 hours) in norepinephrine (NE) turnover. The aim of the present study is to examine the long-term effect of SGLT2 inhibition on total body NE turnover.

Methods: 36 T2D and 36 nondiabetic subjects were randomized to receive empagliflozin or matching placebo (2:1 ratio) for 12 weeks. HGP and total-body NE turnover were measured with 3-3H-glucose and 3H-NE infusion before and after therapy with empagliflozin.

Results: Empagliflozin administration (day 1), caused an increase in HGP by 22% and 19% within 4 hours in T2D and nondiabetic individuals, respectively, and the increase in HGP persisted at week 12. Total-body NE turnover significantly decreased in both groups. The placebo-subtracted decrease in NE turnover was -139±35 and -165±71 ng/min (both p<0.05) in T2DM and nondiabetic individuals, respectively, at 24 hours after empagliflozin administration (day 2), and the decrease in NE turnover persisted at week 12 (p<0.01). The decrease in NE turnover strongly and inversely correlated with the increase in HGP at week 12 (r=0.64, p<0.001). However, the decrease in NE turnover at day 2 did not correlate with the increase in HGP on day 1 of empagliflozin administration (r=0.09, p=ns).

Interpretation: The long-term empagliflozin-induced stimulation of HGP cannot be explained by activation of the SNS. However, the inhibition of sympathetic activity by SGLT2i may explain the lack of increase in heart rate consistently observed in cardiovascular outcome trials with SGLT2 inhibitors.

Disclosure

S. Abdelgani: None. G. Baskoy: None. J.M. Adams: None. A. Khattab: None. R.A. DeFronzo: Advisory Panel; AstraZeneca, Novo Nordisk, Boehringer-Ingelheim, Intarcia Therapeutics, Inc., Aardvark, Renalytix, Corcept Therapeutics, Alnylam Pharmaceuticals, Inc. Research Support; Boehringer-Ingelheim, AstraZeneca, 89bio, Inc., Amgen Inc., Medality, Corcept Therapeutics. Speaker's Bureau; AstraZeneca, Corcept Therapeutics, Renalytix. M. Abdul-Ghani: None.

Funding

National Institutes of Health (2R01DK097554-06 grant to MAG)
1392-P: Morning Chronotype Reduces the Risk of PCOS—A Mendelian Randomization
Authors: ZHANG MANNA , LU JIAYI , DILIMULATI DILIQINGNA , CAI MEILI , ZHANG YUQIN
Published: June 2024

Objective: Previous observational studies have suggested a potential connection between PCOS and chronotype, and we aimed to assess the causal relationship between PCOS and chronotype.

Methods: A two-sample Mendelian randomization (MR) study was used to evaluate the causal association between PCOS and chronotype. The GWAS summary statistics for chronotype were obtained from the UK Biobank, and the GWAS summary statistics for PCOS were obtained from the FinnGen cohort on the IEU Open GWAS Project database. Inverse-variance weighted (IVW) fixed-effect method, the MR-Egger method, and a weighted median method were used for MR estimates.

Results: The primary IVW method showed a genetically determined morning chronotype had a significant negative causal relationship with the risk of PCOS. In the main IVW analysis, one unit morning chronotype decreased the incidence of PCOS by 0.86 (OR: 0.14, 95% CI: 0.02 ~ 0.86, P = 0.033). The main IVW estimate was generally consistent with the results of weighted median, weighted mode, and MR-Egger. The MR-PRESSO results showed no outlier SNPs, and the leave-one-out analysis showed that no single SNP has an influence on the overall estimates. Cochran’s Q statistics showed little evidence of heterogeneity between SNPs. There was no evidence of pleiotropy by MR-Egger regression intercept or MR-PRESSO global test (MR-Egger intercept = 0.020, P = 0.835), and symmetry of funnel plots supported the validity of our MR analysis.

Conclusion: Our findings indicate that genetically predicted morning chronotype had a significant negative prevalence in PCOS.

Disclosure

M. Zhang: None. J. Lu: None. D. Dilimulati: None. M. Cai: None. Y. Zhang: None.
1394-P: One-Year Effectiveness of Carbohydrate-Restricted Nutrition Therapy in Individuals with Prediabetes in Rural vs. Urban Areas
Authors: ATHINARAYANAN SHAMINIE J. , ADAMS REBECCA N. , VOLK BRITTANIE M. , ROBERTS CAROLINE G.P. , ZOLLER ALISON , MCKENZIE AMY L.
Published: June 2024

Availability of diabetes prevention programs is largely limited to urban (U) areas, posing a challenge to diabetes prevention in rural (R) areas. Virta Health provides carbohydrate-restricted nutrition therapy (CRNT) through continuous remote care (CRC) and has been implemented nationwide to prevent progression of prediabetes (preD). In this retrospective analysis, we aim to assess the 1-year effect of the program on cardiometabolic markers in individuals with preD from both R and U counties. A random sample of individuals with preD who remained in the program at least 1y was selected (250 from R areas and 250 from U areas). Changes in metabolic markers from enrollment (E) to 1y were assessed in a linear mixed effect model. Characteristics at E were consistent between the R and U cohorts (age=50.9 (9.4)y, BMI= 36.7 (7.7)kg/m2, HbA1c=5.8(0.3)%). HbA1c [-0.2% from E:5.7±0.0 (R), -0.2% from E: 5.8±0.0 (U); ps<0.001], weight [-9.2% from E:231.3±1.3 (R), -9.2% from E: 231.4±1.3 (U); ps<0.001], HDL-C [13.3% from E:49.5±0.6 (R), 13.1% from E:50.2±0.6 (U); ps<0.001], TG [-24.3% from E:152.2±4.2 (R), -26.9% from E:137.4±4.2 (U); ps<0.001] improved, with no differences between R and U areas. Liver enzymes [ALT at E: 28.4±0.9(R), 27.6±0.9(U) U/L; ALP at E: 79.4±1.3(R), 76.5±1.3(U) U/L ] were within normal limits and significantly decreased [ALT:-11.2% (R), -11.5%(U); ALP: -5.7% (R), -5.8% (U); ps<0.001]. Total cholesterol, LDL-cholesterol, and AST were unchanged. Individuals with preD in both R and U settings showed similar improvements in weight, HbA1c, and cardiometabolic markers. These findings demonstrate the effectiveness of this care model in improving cardiometabolic risk markers in people with preD living in both R and U areas.

Disclosure

S.J. Athinarayanan: Employee; Virta Health Corp. R.N. Adams: Employee; Virta Health Corp. Stock/Shareholder; Virta Health Corp. B.M. Volk: Employee; Virta Health Corp. Stock/Shareholder; Virta Health Corp. C.G.P. Roberts: Other Relationship; Virta Health Corp. A. Zoller: Employee; Virta Health Corp. Stock/Shareholder; Virta Health Corp. A.L. McKenzie: Employee; Virta Health Corp. Stock/Shareholder; Virta Health Corp. Employee; Abbott.
1395-P: Characteristics of Patients with Type 2 Diabetes and MetALD—Insight into a New Entity
Authors: BRIL FERNANDO
Published: June 2024

In 2023 nonalcoholic fatty liver disease was renamed metabolic dysfunction-associated steatotic liver disease (MASLD). A new entity was also defined: metabolic and alcohol related/associated liver disease (MetALD), corresponding to patients with MASLD with moderate alcohol consumption. In this study, we assessed the clinical and hepatic characteristics of patients with T2D with MetALD vs. MASLD.

Adult patients from NHANES 2017-2020 with complete data on transient elastography (TE) and alcohol intake were included. Diabetes was defined based on fasting plasma glucose, A1c, or prior history. Patients with secondary causes of liver steatosis were excluded. MASLD was defined as a controlled attenuation parameter (CAP) ≥288 dB/m. MetALD was defined based on CAP and self-reported alcohol use (i.e., females: 140-350 mg weekly and males: 210-420mg weekly).

Compared to MASLD (n=760), patients with T2D and MetALD (n=19; 2.4%) were younger (53 ± 15 vs. 59 ± 13 years, p=0.04) and predominantly male (89 vs. 53%, p=0.002). However, there were no significant differences in race or metabolic parameters, such as BMI (35.3 ± 9.5 vs. 34.6 ± 7.1 kg/m2, p=0.71), A1c (7.4 ± 2.6 vs. 7.4 ± 1.6%, p=0.91), triglycerides (p=0.72), HDL (p=0.90), or mean blood pressure (p=0.26). Despite metabolically similar, patients with MetALD had higher plasma AST (27 ± 9 vs. 22 ± 13, p=0.002), ALT (38 ± 23 vs. 27 ± 19, p=0.01), and GGT (p=0.01). Liver fibrosis by TE (7.9 ± 5.1 vs. 7.6 ± 5.2 kPa, p=0.82) and fat accumulation by CAP (353 ± 35 vs. 341 ± 33 dB/m, p=0.14) were similar between MASLD and MetALD.

Conclusions: MetALD represents a small percentage of patients with hepatic steatosis and T2D. Their metabolic profile is similar to MASLD patients, and despite higher liver biochemistries (i.e., ALT, AST, GGT), liver fibrosis and fat accumulation by imaging were similar in both groups. Thus, the clinical impact of this new definition in T2D is unclear. Future research is needed to determine if patients with MetALD behave similarly to patients with MASLD.

Disclosure

F. Bril: Consultant; Novo Nordisk.
1396-P: Association between COVID-19 Infection and Incident Diabetes in Two Distinct Cohorts—A Nationwide Commercial Claims Database and a Regional Academic Medical Center
Authors: LACY MARY E. , SMITH AARON P. , HAMMERSLAG LINDSEY R. , HEIER KORY , FIELDS ALICIA B. , TALBERT JEFFERY , FOWLKES JOHN , FISHER SIMON J. , KERN PHILIP A.
Published: June 2024

Background & Objective: The risk of new onset diabetes following infection with COVID-19 was contrasted in two distinct cohorts.

Methods: Using Merative MarketScan Commercial Claims database (MarketScan) and electronic health records from University of Kentucky HealthCare (UKHC), we created three cohorts in each database: 1) a COVID-19 infected cohort, 2) a contemporaneous cohort of individuals without COVID-19 infection, and 3) a historic pre-COVID-19 cohort (Table 1). Diabetes incidence rates and hazard ratios were contrasted between the COVID-19 cohort and two control cohorts (no-COVID & pre-COVID).

Results: Compared to the commercial database, diabetes prevalence was higher in UKHC database, reflecting an objectively sicker population (higher comorbidity index and increased hospitalizations). In both databases, diabetes incidence rates and hazard ratios were significantly higher in the COVID cohort (Table 1), compared to either pre-COVID or non-COVID cohorts.

Conclusions: Both databases demonstrate that COVID-19 was associated with 2-3-fold increased rate of incident diabetes. However, as compared to an academic medical center with a sicker patient population, relatively healthier patients in the commercial data set had lower incidence of COVID-19 associated diabetes.

Disclosure

M.E. Lacy: None. A.P. Smith: None. L.R. Hammerslag: None. K. Heier: None. A.B. Fields: None. J. Talbert: None. J. Fowlkes: None. S.J. Fisher: None. P.A. Kern: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (R01DK124626)
1399-P: Exploring Polycystic Ovary Syndrome and Leucine—A Bidirectional Mendelian Randomization Study
Authors: CAI MEILI , LU JIAYI , DILIMULATI DILIQINGNA , ZHANG YUQIN , CHEN HAIBING , QU SHEN , ZHANG MANNA
Published: June 2024

Background: Polycystic ovary syndrome (PCOS) has a certain genetic predisposition. Previous observational studies have reported alterations in the amino acid profile among women with PCOS, yet causality remains unclear. Our study aims to elucidate the causal relationship through bidirectional Mendelian randomization (MR).

Methods: Leveraging genome-wide association studies (GWAS) data from a European lineage, encompassing 1,400 blood metabolisms, a two-sample MR study was conducted to assess the causal association between PCOS and Leucine. Five models, including inverse variance weighted model (IVW), weighted median estimator model (WME), weighted model-based method (WM), and MR-Egger regression model (MER), estimated causal associations. The leave-one-out sensitivity test, MR-PRESSO, and Cochran’s Q test assessed IVs heterogeneity and pleiotropy.

Results: We found 12 metabolites (8 risk and 3 protective) that showed suggestive associations with PCOS risk. The protective metabolites included Leucine, Isovalerylcarnitine, and hydroxytryptophan. The primary IVW method revealed a negative association between genetically determined PCOS and Leucine levels (OR<0.001, 95%CI: 0.000-0.295, P= 0.018). There was no evidence of pleiotropy by the MR-Egger regression intercept or MR-PRESSO global test (MR-Egger intercept = 0.124, Global test P= 0.637). Multiple metabolic pathways were implicated, including amino acid metabolism and androgen synthesis.

Conclusion: Our MR study underscores a negative correlation between Leucine levels and increased PCOS risk. Identified metabolic products and pathways can serve as biomarkers for clinical screening and prevention, offering insights for future mechanistic exploration and drug target selection. Further observational studies and clinical trials are imperative for comprehensive understanding and validation.

Keywords: Leucine; amino acid; Mendelian randomization; polycystic ovary syndrome; blood metabolism

Disclosure

M. Cai: None. J. Lu: None. D. Dilimulati: None. Y. Zhang: None. H. Chen: None. S. Qu: None. M. Zhang: None.

Funding

National Key R&D Program of China (No.2018YFC1314100); National Nature Science Foundation of China (No. 82170861 and No.81970677); Clinical Research Plan of SHDC (No. SHDC2020CR1017B).
14-OR: Autonomous Artificial Intelligence Diabetic Eye Exams Mitigates Disparities in Screening Completion for Youth
Authors: PATEL DHRUVA , BROMBERGER LEE A. , PARIMI NEHA , BROWN ELIZABETH A. , LIU ALVIN , LEHMANN HAROLD , ABRÀMOFF MICHAEL D. , WOLF RISA M.
Published: June 2024

Diabetic retinal disease (DRD) is a complication of diabetes mellitus that can lead to vision loss; early detection through screening and treatment can prevent this. Few individuals with diabetes meet recommended DRD screening guidelines, and racial/ethnic minority youth are even less likely to undergo recommended screening. We sought to determine if implementing point of care (POC) autonomous artificial intelligence (AI) screening could mitigate disparities in diabetic eye exam completion. In ACCESS2, a preregistered prospective pre-post study design, youth with type 1(T1D) and type 2 diabetes (T2D) meeting American Diabetes Association criteria for needing a diabetic eye exam underwent POC autonomous AI diabetic eye exams at routine diabetes clinic visits. Completion rates of diabetic eye exams were compared prior to and after implementation of autonomous AI. A total of 380 youth with T1D (71.1%) and T2D (28.9%) were enrolled, mean age 15.2y, 46.8% Non-Hispanic (NH) White, with mean duration of diabetes of 6.0y, and median hemoglobin A1c of 8.1%. A greater percentage of NH White participants reported any prior diabetic eye exam (81.6 v 62.0%, p<0.001) compared to non-white and Hispanic participants. Multivariable analysis demonstrated that the strongest predictor for prior eye exam was diabetes duration. After undergoing POC autonomous AI diabetic eye exams, completion rates were 98% among non-white and Hispanic participants, and 99% among white participants. Introducing autonomous AI at the point of care enhances the accessibility and completion rates of diabetic screening eye exams, and promotes health equity for minority youth with diabetes.

Disclosure

D. Patel: None. L.A. Bromberger: None. N. Parimi: None. E.A. Brown: None. A. Liu: None. H. Lehmann: None. M.D. Abràmoff: Board Member; Digital Diagnostics. Stock/Shareholder; Digital Diagnostics. Other Relationship; Digital Diagnostics. R.M. Wolf: Research Support; Dexcom, Inc., Boehringer-Ingelheim, Novo Nordisk.

Funding

National Eye Institute (R01EY033233-03)
1424-P: Cumulative TyG Index—A Noninvasive Measure to Assess the Risk of Hyperuricemia
Authors: WU YIWEI , CHEN YAN
Published: June 2024

Objective: The aim of this study is to investigate the relationship between hyperuricemia risk and changes in the Triglyceride-Glucose (TyG) index among middle-aged and elderly Chinese individuals.

Methods: Baseline demographic, health, and physical examination data, along with blood samples, were collected from participants in both CHARLS Wave 1 and Wave 3. The TyG index was calculated, and participants meeting the inclusion criteria were grouped into four quartiles based on their cumulative TyG index. Independent factors influencing hyperuricemia were identified through the use of univariate and multivariate Cox regression models, with the lowest TyG quartile serving as the reference point. The correlation between hyperuricemia risk and cumulative TyG index was assessed using restricted cubic spline regression. Subgroup and interaction analyses were also carried out.

Results: A total of 5,600 participants (2,438 men and 3,162 women) with a median age of 57 years were included in this study. When the cumulative TyG index was less than 34.38, the risk of hyperuricemia was significantly decreased as the cumulative TyG index was reduced. Conversely, when the cumulative TyG index exceeded 34.38, the risk of hyperuricemia was seen to increase slowly with a higher cumulative TyG index. Subgroup analyses indicated that the cumulative TyG index increased the risk of hyperuricemia in various subgroups, including age, gender, hukou, education level, smoking, hypertension, body mass index (BMI), and WC. High cumulative TyG index was found to be more likely to raise the risk of hyperuricemia in individuals with low WC (< 85 cm for males, < 80 cm for females).

Conclusion: In this longitudinal study of middle-aged and elderly Chinese individuals, independent risk factors for hyperuricemia were found to include cumulative TyG index, male gender, hypertension, DBP, WC, and Cr. The cumulative TyG index, as a straightforward measure, was demonstrated to be a valuable tool for the evaluation of hyperuricemia risk.

Disclosure

Y. Wu: None. Y. Chen: None.

Funding

Natural Science Foundation of Jilin Province of China (YDZJ202301ZYTS074)
1460-P: Antibody+ (Ab+) Individuals with Marked Metabolic Heterogeneity at Screening Have Similar Evolution in the Progression to Type 1 Diabetes (T1D) with Converging Metabolic Status
Authors: SIMS EMILY K. , JACOBSEN LAURA M. , ISMAIL HEBA M. , REDONDO MARIA J. , NATHAN BRANDON M. , SOSENKO JAY
Published: June 2024

Introduction: We asked if marked OGTT metabolic heterogeneity at screening persists at T1D diagnosis.

Methods: Multiple Ab+ TrialNet Pathway to Prevention participants (n=364) who had diagnostic OGTTs ≥1 yr after screening OGTTs were stratified by median fasting glucose x fasting C-peptide (fgxfp; basic metabolic component of C-peptide HOMA-IR). Glucose and C-peptide response curves (shapes from mean OGTT glucose and C-peptide at 30, 60, 90 and 120 min; GCRCs) were derived from OGTTs at baseline and diagnosis.

Results: The fgxfp group>median (Figure: blue) had much higher baseline AUC C-peptide (p<0.001), indicated by the wider shape and rightward location of their GCRC. They subsequently had upward and leftward GCRC movement from baseline to diagnosis vs. mostly upward movement for the group

Disclosure

E.K. Sims: Consultant; Sanofi. Board Member; American Diabetes Association. Other Relationship; American Diabetes Association, Medscape. Consultant; DRI. L.M. Jacobsen: Advisory Panel; Insulet Corporation. H.M. Ismail: Consultant; Sanofi, Rise Therapeutics. M.J. Redondo: None. B.M. Nathan: None. J. Sosenko: None.
1474-P: Cross-Sectional and Longitudinal Relationships between Detailed Family History (FH) of Type 2 Diabetes Mellitus (T2DM), Hypertension (HT), and Dyslipidemia (DL) and Prevalence of Each Disorder
Authors: IKEDA IZUMI , FUJIHARA KAZUYA , TAKEDA YASUNAGA , HATTA MARIKO , WU SIJIA , KODAMA SATORU , MORI YASUMICHI , KADOWAKI TAKASHI , YAMAMOTO-HONDA RITSUKO , ARASE YASUJI , SONE HIROHITO
Published: June 2024

A FH of T2DM, HT, and DL are known risk factors; however, few studies have compared the impact of a FH of the 3 diseases in the same population. We examined the impact of a detailed FH of these conditions (i.e., in fathers, mothers, siblings and grandparents) on their prevalence and incidence in the study population. Data on 41,931 participants who underwent health checkups were examined and the results of a logistic regression and (Cox regression model in the same cohort were examined. Results of the cross-sectional study showed that odds ratios increased with the degree of a positive FH for all three diseases. Furthermore, in T2DM, the group with a three-generation positive FH was approximately 20 times larger than the control group which had no FH (Figure). In the longitudinal study, FH had a strong influence on the incidence of T2DM, HT, and DL, in that order, with a hazard ratio of 2.40 (1.93-2.98) for T2DM. A detailed FH was extremely useful for both quantitative screening for each disease and predicting the incidence of the three diseases, especially T2DM, for which a high risk was indicated in multiple generations with overlapping of positivity for a particular disease.

Disclosure

I. Ikeda: None. K. Fujihara: None. Y. Takeda: None. M. Hatta: None. S. Wu: None. S. Kodama: None. Y. Mori: None. T. Kadowaki: None. R. Yamamoto-Honda: None. Y. Arase: None. H. Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Eisai Inc., Sumitomo Dainippon Pharma Co., Ltd.
1480-P: TOPMed Metabolomics Association Analysis of Cardiovascular Disease in Participants with Type 2 Diabetes
Authors: ZHANG YIXIN , DICORPO DANIEL A. , GOODARZI MARK O. , GUO XIUQING , HAESSLER JEFFREY , HANSON PAUL A. , KOOPERBERG CHARLES L. , NGUYEN NGOC QUYNH H. , REINER ALEX , SARNOWSKI CHLOE , SEVILLA-GONZALEZ MAGDALENA , TAYLOR KENT , YU BING , DUPUIS JOSÉE , MANNING ALISA , MEIGS JAMES B. , LIU CHING-TI
Published: June 2024

Type 2 diabetes (T2D) is a prominent risk factor for cardiovascular diseases (CVD). People with T2D are twice as likely to develop heart disease or all-type stroke compared to people without T2D, though the reason behind this excess risk remains unclear. To better understand the molecular mechanisms underlying CVD in T2D, we compared the metabolomics profiles of T2D participants with or without CVD event. Using LC/MS-based metabolite data from the Trans-Omics for Precision Medicine (TOPMed) program, we collected 522 blood metabolite level measurements common to 1356 T2D participants across three TOPMed participating cohorts. We compared metabolite levels in CVD cases that occurred after T2D, versus T2D without CVD at the time of metabolite measurement. We performed cross-sectional pooled association analysis for each metabolite using a mixed effects linear model, with log-transformed and standardized metabolite level as the outcome and CVD event as the predictor, adjusting for age, sex, study population, and self-reported race/ethnicity, accounting for relatedness using a kinship matrix and a correlation-adjusted Bonferroni correction alpha level of 3.0x10-4 to define significant associations.

We identified 15 significant associations, where CVD is negatively associated with five lipids while positively associated with ten organic acids. We also replicated the effect size direction at a statistically significant level for nine organic acids in a separate TOPMed cohort with 1823 T2D participants. Most of the acids, such as gluconate, ADMA and cystine, have been previously reported as risk factors of CVD. 1-methyladenosine, our novel finding, could be a potential biomarker for CVD in T2D individuals.

Our results established metabolite associations with prevalent CVD in T2D in TOPMed. These associations will pave the way for future mechanistic studies exploring the potential utility of metabolites as therapeutic targets specific for T2D individuals at risk for CVD.

Disclosure

Y. Zhang: None. D.A. DiCorpo: None. M.O. Goodarzi: Advisory Panel; Nestlé Health Science, Organon. X. Guo: None. J. Haessler: None. P.A. Hanson: None. C.L. Kooperberg: None. N.H. Nguyen: None. A. Reiner: None. C. Sarnowski: None. M. Sevilla-Gonzalez: Research Support; Novo Nordisk Foundation. K. Taylor: None. B. Yu: None. J. Dupuis: None. A. Manning: None. J.B. Meigs: None. C. Liu: None.

Funding

National Institute of Health (NHLBI R01 HL151855); National Institute of Health (NHLBI UM1 DK078616)
1481-P: Type 2 Diabetes Is Causally Associated with Increased Risk of Pulmonary Tuberculosis—A Mendelian Randomization Study
Authors: LEE HYUNSUK , PARK SEHOON , CHOI JAEWON , PARK JONGSEOK , LEE JEONGEUN , KIM JONG-IL , SOO PARK KYONG , HEON KWAK SOO
Published: June 2024

Tuberculosis (TB) ranked as the second leading cause of mortality from infectious disease after COVID-19 in 2022, resulting in the loss of 1.3 million lives worldwide. Type 2 diabetes (T2D) is one of five risk factors of TB and an estimated 370,000 new cases were attributable to T2D in 2020. However, whether T2D is causally associated with TB is largely unknown. We aimed to infer causal relationship between T2D and pulmonary TB using a two-sample Mendelian randomization (MR) framework.

We conducted a MR analysis in the East Asian population, where pulmonary TB is endemic. Eighteen independent genome-wide significant variants of T2D from the meta-analysis of the Korean Genome and Epidemiology Study and the Taiwan Biobank (N=135,387, F-statistics=70.2) were used as instrumental variables for T2D. Outcome data for genome-wide association analysis of pulmonary TB was obtained from the Biobank Japan (N=212,453).

Summary-level MR analysis showed that higher genetic risk for T2D was significantly associated with higher risk for pulmonary TB (beta=0.324, P=3.4×10-5). This association was also significant in multiple sensitivity analyses (MR-Egger P=0.046; weighted median P=8.9×10-4; weighted mode P=0.023; MR-PRESSO P=6.7×10-4; MR-RAPS; P=9.9×10-4). Absence of horizontal pleiotropy was supported via the MR-Egger intercept test (P=0.36). Multivariable MR analysis showed that T2D’s causal effect on pulmonary TB was independent of smoking, alcohol intake, body mass index and other cardiometabolic traits. Higher genetic risk for HbA1c was also significantly associated with increased risk for pulmonary TB (43 non-erythrocytic variants, beta=0.604, P=0.029). However, genetic risk for fasting glucose showed concordant directionality but did not reach statistical significance (beta=0.266, P=0.114).

Genetically predicted T2D is significantly associated with higher risk of pulmonary TB. This MR analysis supports the causal predisposition of T2D to pulmonary TB.

Disclosure

H. Lee: None. S. Park: None. J. Choi: None. J. Park: None. J. Lee: None. J. Kim: None. K. Park: None. S. Kwak: Employee; SNUH Venture.
1486-P: Role of HLA Class I Gene Alleles and Haplotypes in Type 1 Diabetes in Kuwaiti Children
Authors: DASHTI MOHAMMED H. , ZUBBAIR MALIK MD. , NIZAM RASHEEBA , JACOB SINDHU , ALKANDARI HESSA , ALOZAIRI EBAA S. , THANGAVEL ALPHONSE T. , ALMULLA FAHD
Published: June 2024

Introduction & Objective: HLA class I genes have a role in influencing immune response and self-tolerance as they bind and present antigens to T cells. Allelic variations of these genes are associated with multifactorial autoimmune conditions including type 1 diabetes (T1D) and show variability across different ethnic groups and populations. Additionally, the amino acid variations of these genes may affect the binding and immunogenicity of insulin peptide.

Methods: We performed an association study of classical HLA class I genes between Kuwaiti T1D children (95 individuals) and adult controls (150 individuals) groups using Next-generation sequencing dataset.

Results: Significant associations were identified for alleles at HLA-A and HLA-C genes, including A*02:01 and C*07:01 were both conferred high risk for T1D. The A*24:02~B* 08:01~C*07:02 haplotype was significantly associated with the risk of developing T1D. Furthermore, we identified significant 33 amino acid positions at HLA-B and HLA-C genes that were both predisposing and protective against T1D.

Conclusion: Our results suggest that HLA class I genes and their allelic and amino acid variations play a role in modulating the risk of T1D and may have implications for disease risk management and genetic counseling in the Kuwaiti population.

Disclosure

M.H. Dashti: None. M. Malik: None. R. Nizam: None. S. Jacob: None. H. Alkandari: None. E.S. Alozairi: None. A.T. Thangavel: None. F. Almulla: None.

Funding

Kuwait Foundation for the Advancement of Sciences.
1487-P: Obesity Induces Metabolic Dysfunction in Adipose Tissue T-Cells
Authors: GUAK HANNAH , LUMENG CAREY N.
Published: June 2024

Individuals with obesity or diabetes often have impaired immune responses to infection despite elevated systemic inflammation. T cells are essential for controlling adaptive immune responses, and during chronic obesity, adipose tissue T (ATT) cells display features of exhaustion, which are characterized by impaired activation and cytokine production. How ATT cell exhaustion is generated is not well understood. We hypothesized that mitochondrial dysfunction leads to the loss of effector function in obese ATT cells. Flow cytometry-based assays were used to evaluate the effect of long-term diet-induced obesity in mouse adipose tissue. Mitochondrial dyes in conjunction with cell surface markers revealed dramatic decreases in mitochondrial mass and membrane potential by both CD8+ and CD4+ T cell populations in white adipose tissue, but not in the spleen, as early as 2 weeks of high-fat diet feeding. In addition, we performed SCENITH, an assay that determines the bioenergetic profiles of cells based on the high energetic cost of protein translation. Results from this assay showed that obese ATT cells have reduced glycolytic and mitochondrial metabolism, suggesting they have diminished metabolic activity overall. We have previously discovered that macrophages in adipose tissue of diabetic humans have induced genes associated with glucocorticoid (GC) exposure, which is in line with literature demonstrating elevated GC levels in obese adipose tissue. Our preliminary data suggest that GC receptor signaling may contribute to mitochondrial impairment, as treatment of the white adipose stromal vascular fraction with synthetic GC reduces mitochondrial mass and membrane potential in ATT cells. Overall, we have observed ATT cells experience loss of mitochondria and metabolic activity with diet-induced obesity and GC treatment. These findings will help expand understanding of the role of ATT cells in metabolic health and immunity.

Disclosure

H. Guak: None. C.N. Lumeng: None.

Funding

American Diabetes Association (4-24-PDF-81); National Institutes of Health (R01DK090262); National Institutes of Health (T32DK101357)
1492-P: Quiescent Adipose-Derived Mesenchymal Stromal Cells (ADSCs) Rejuvenate Themselves and Provide Factors That Remotely Restore Cellular Functions of Aged ADSCs
Authors: FUNAKI MAKOTO , HATA AKIKO
Published: June 2024

Although a number of studies have shown therapeutic effects of mesenchymal stem cells (MSCs) on type 1 diabetes or diabetic complications, clinical applications of MSCs for these diseases are still limited. One of the reasons is aging of MSCs due to older donor age and ex vivo culture of MSCs before usage, which results in attenuation of their anti-inflammatory/immunomodulatory functions, as well as their proliferation/differentiation potencies. We previously reported that adipose tissue-derived stromal cells (ADSCs), one type of MSCs used in multiple clinical trials, exhibit anti-inflammatory/immunomodulatory functions when they become quiescent in gels with a stiffness mimicking that of adipose tissue. We also showed that transplants containing quiescent ADSCs enhanced diabetic wound healing more than did those containing non-quiescent ADSCs. Here, we investigated the effect of inducing quiescence in aged ADSCs on themselves and their neighboring ADCSs. ADSCs at high passage exhibited a flattened shape and impaired DNA damage repair response, accompanied by attenuated proliferation and increased secretion of monocyte chemoattractant protein-1 (MCP-1). However, introducing quiescence into these aged ADSCs by embedding them in soft gels eliminated these phenotypes associated with aging. Furthermore, administration of conditioned medium derived from ADSCs rendered quiescent at high passage significantly improved age-associated impaired proliferation and biased differentiation (impaired osteogenic differentiation) of ADSCs at high passage. These results suggest that quiescence rejuvenates ADSCs, which in turn provide factors that contribute to rejuvenation of other ADSCs. Thus, introducing quiescence in ADSCs may contribute to overcoming challenges in ADSC-based cell therapies due to their aging.

Disclosure

M. Funaki: Board Member; Mechanogenic, Inc. Stock/Shareholder; Mechanogenic, Inc. A. Hata: None.
150-OR: Gut Microbial Metabolism of Bile Acids, Mediterranean Diet and Cardiometabolic Risk in the DIRECT-PLUS Trial
Authors: GAO PEIPEI , MEI ZHENDONG , WANG FENGLEI , DONG DANYUE , STAMPFER MEIR , SHAI IRIS , WANG DONG
Published: June 2024

Objective: To examine the associations of fecal bile acid (BAs), interacting with the Mediterranean diet (MedDiet), with body adiposity and lipid biomarkers and explore the gut microbiome’s role in BA metabolism.

Method: In the 18-month DIRECT-PLUS Trial, 284 participants (mean 51 y, 88% men) were randomized to one of the three isocaloric interventions: healthy dietary guidelines, MedDiet, and MedDiet+polyphenols and measured for baseline fecal BA levels by LC-MS. Their gut microbiomes were profiled by shotgun metagenomics.

Results: Among 39 detected BAs, 4 were associated with body mass index (BMI) and 11 were associated with serum lipids (Fig. 1A). For example, per 1-SD increment in isoursodeoxycholic acid-sulfate level was associated with a 3.0 kg/m2 increase in BMI (95% confidence interval [CI]: 1.8-4.2) and 12.5 mg/dL increase in triglycerides (95% CI: 5.4-19.7). The MedDiet’s effects for reducing BMI varied by BA levels (Fig. 1B). For example, this effect was more pronounced in those with lower 12-dehydrocholic acid levels (qinter=0.004). We identified several Ruminococcus spp. as major BA metabolizers and their role in modifying fecal BAs’ association with body adiposity and lipid levels (Fig. 1C-D).

Conclusion: The gut microbial metabolism of BAs is associated with host adiposity and lipid profiles and potentially modifies the beneficial effects of MedDiet on cardiometabolic health.

Disclosure

P. Gao: None. Z. Mei: None. F. Wang: None. D. Dong: None. M. Stampfer: Advisory Panel; Elysium Health. I. Shai: None. D. Wang: None.

Funding

National Institutes of Health (R00DK119412, R01NR01999, and R01AG077489)
1502-P: Metabolic Dysfunction Associated Steatohepatitis–Derived HCC Model Mouse for Cancer Immunology
Authors: HASHIGUCHI TAISHI
Published: June 2024

Introduction: Metabolic dysfunction-associated steatohepatitis (MASH) is a is linked to type II-diabetes and marked by steatosis, steatohepatitis, fibrosis and eventually HCC. The number of patients with MASH-derived HCC is increasing worldwide. Currently, the first line of cancer treatment drugs are immune checkpoint inhibitors (ICIs). Although ICls have been approved by the FDA for various cancers, it has been reported that the response rate for HCC is low, and the development of new therapeutic drugs including ICIs for HCC is expected. Therefore, a mouse model for evaluating MASH-derived liver cancer is needed for drug discovery against HCC. In this study, in order to examine whether the STAM mouse, a MASH-HCC model mouse, can be used for the evaluation of ICIs, we conducted an analysis of immunohistochemistry and RNA-seq related to the immuno-oncology (IO) of HCC derived from STAM mice.

Methods: MASH was induced in male mice by a single subcutaneous injection of 200 µg streptozotocin solution 2 days after birth and feeding with high fat diet after 4 weeks of age. The mice were sacrificed and livers collected at 6, 8, 10, 12, 16, 20 and 24 weeks of age. For RNA-seq analysis, total RNA from the left lateral lobe was isolated using RNeasy mini kit. Liver specimens were stored at -80°C embedded in Optimal Cutting Temperature compound for immunohistochemistry (IHC). IHC for CD3, CD4, CD8, FOXP3, a-SMA and FAP was performed.

Results: Expression analysis of IO-related genes was performed. Increased expression was observed in CCl5, CD4, CD8a, CD274, CXCR4, CXCR10 and PDCD1. Additionally, mutations were observed in some genes. As a result of IHC, CD3, CD4, CD8, a-SMA and FAP-positive signals were detected in the peri-tumor region. Furthermore, CD8-positive signals were also detected in the intra-tumor region.

Conclusion: STAM mouse model, is the model that allows the evaluation of drugs that genetic mutations, immune cells, and tumor microenvironment in addition to molecular targeted drugs.

Disclosure

T. Hashiguchi: None.
158-OR: Relationship between Obesity, Sarcopenia, and Insulin Resistance in Older Adults
Authors: RIZVI ALI A. , AMIN VRAJ , AMOY FRASER MARSHA , PERIASAMY MUTHU
Published: June 2024

The prevalence of overweight/obesity is increasing in older adults worldwide. Ageing is generally associated with decline in muscle mass and strength (sarcopenia) and worsening insulin resistance (IR). We examined whether the coexistence of overweight/obesity and sarcopenia, termed sarcopenic obesity (SO), was associated with elevated IR, thus predisposing to increased cardiometabolic risk. After informed consent, we obtained the following anthropometric and laboratory data in 77 adults (43 females, 34 males, age range 65-80 years, mean age 71 years): body mass index (BMI, as a determinant of overweight/obesity); waist circumference (WC, abdominal obesity); thigh circumference and grip strength (measures of muscle mass and sarcopenia) ; fasting glucose and plasma insulin levels (for calculation of Homeostatic Model Assessment of Insulin Resistance, or HOMA-IR); and A1c.­­ 32 of the participants (42%) were normal weight, and 45 (58%) were overweight/obese. 15 individuals (19%) were classified as sarcopenic, and the prevalence was similar in normal weight vs. overweight/obese groups (19% vs. 20%). Selected mean parameters were: BMI 28.05, WC 113.8 cm, and HOMA-IR index 1.73 (normal <1). Analysis of the data showed a statistically significant positive association of HOMA-IR with BMI and WC (p<0.05), but not with sarcopenia. The WC correlated with glucose and insulin levels in both sexes (p<0.05), and with A1c in females only. Findings from our study thus far do not support a higher prevalence of sarcopenia in overweight/obese individuals than in those of normal weight. In both sexes, IR was significantly associated with overweight/obesity and central fat deposition, but not with sarcopenia. Interventions primarily targeting weight loss, with or without enhanced muscle conditioning, would be expected to be most effective in ameliorating IR and reducing cardiovascular and metabolic risk in older adults.

Disclosure

A.A. Rizvi: None. V. Amin: None. M. Fraser: None. M. Periasamy: None.

Funding

University of Central Florida College of Medicine Internal Grant Program 2022