bluuebunny/crossref_metadata_2025 huggingface dataset:
1854-LB: Predicting Insulin Timecourse in Prediabetes Individuals Using a Human Digital Twin Model
Authors: HOR CHENG KOH , CHAN JAMES C.
Published: June 2024

Individuals with early prediabetes often present with slight elevations or even normal glucose level. However, their insulin profiles are often dysregulated with either hyper- or hypoinsulinemia, suggesting insulin as a more sensitive biomarker for prediabetes detection. We developed a human digital twin that can predict an individual’s insulin time course and glycaemic status from an oral glucose tolerance test (OGTT) time-course. The model incorporates homeostatic processes such as insulin secretion and glucose uptake in adipose and muscles. The model was fed with individualized data such as age, BMI and OGTT glucose time-course to predict insulin profiles. Overlay of clinical and simulated glucose and insulin profiles can be seen in Figure 1. Insulin time-course, area-under-the-curve (AUC) and Matsuda Index were accurately predicted for three Chinese males, one healthy (subject 1), one exhibiting insulin insufficiency (subject 2) and one insulin resistance (subject 3). Fold-change of predicted to actual insulin AUC and Matsuda Index were all within 1.5 times. We demonstrated high accuracy of our model in predicting difficult-to-obtain insulin data using easily obtained glucose data. We envision more validation and use of our model to predict insulin-related metrics in different ethnicities and glycaemic status.

Disclosure

K. Hor Cheng: None.
1855-LB: Metformin Mitigates Insulin Signaling Variations Induced by COVID-19 Vaccine Boosters in Type 2 Diabetes
Authors: ZHUANG MIN , ZHAI LIXIANG , BIAN ZHAOXIANG , LIN CHENGYUAN , WONG HOI KI
Published: June 2024

Objective: Diabetes is associated with an increased risk of coronavirus disease 2019 (COVID-19) morbidity and mortality. COVID-19 vaccines substantially reduce the risks of serious COVID-19 outcomes, but the impact of COVID-19 vaccines, including their effectiveness and adverse effects in patients with diabetes, is not well known.

Methods: Firstly, we used the mRNA COVID-19 vaccine to validate the effects of glucose control in mice after 4 dorse. Then, between 1 June 2023 and 31 October 2023, we recruited 176 adults who had received two doses of the mRNA COVID-19 vaccine (BNT162b2). The participants ranged in age from 18 to 65 years (median=53.5 years, interquartile range (IQR) 12.0), and (104/176)59.09% were male. Human volunteers were recruited to determine their immune responses and glucose control before and 2 weeks after the booster shot of the COVID-19 mRNA vaccine.

Results: We showed that four doses of the COVID-19 vaccine weekly could impair insulin sensitivity in healthy mice, and this effect can still be maintained after four weeks. Following that, we showed that 65/176 patients with type 2 diabetes exhibited aggravated insulin resistance toward booster shots of the COVID-19 vaccine after 2 weeks. We found that the aggravation of insulin resistance in patients with type 2 diabetes taking metformin was significantly lower than in patients not taking metformin after the booster shots of the COVID-19 vaccine.

Conclusion: This study suggests the clinical importance of close monitoring of glycemic control in diabetes after receiving COVID-19 vaccines and indicates the beneficial action of metformin, a common antidiabetic medication, in counteracting insulin signaling variations induced by COVID-19 vaccination in diabetes.

Disclosure

M. Zhuang: None. L. Zhai: None. Z. Bian: None. C. Lin: None. K. Hoi: None.

Funding

Health@InnoHK Initiative Fund from the Hong Kong SAR Government (ITC RC/IHK/4/7 ); Key-Area Research and Development Program of Guangdong Province (2020B1111110003 ); NSFC Excellent Young Scientist Scheme (32322091); Innovation and Technology Support Programme from the Hong Kong SAR Government (ITS/058/22MS); General Research Grants from the Hong Kong SAR Government (22104123).
1876-LB: Blood Glucose Target Ranges for IV Insulin Infusions Impact Inpatient Glucose Metrics
Authors: ALOI JOSEPH , PRICE CATHERINE E.
Published: June 2024

Inpatient hyperglycemia is associated with prolonged hospital length of stay (LOS) and morbidity. Minimizing both hypo and hyperglycemic events are an overall strategy to avoid hospital complications related to dysglycemia. Diabetic ketoacidosis (DKA) and stress related hyperglycemia are frequently managed in the critical care setting with IV insulin where guidelines recommend a blood glucose (BG) target of 140 - 180 mg/dL. Best practices regarding optimal BG targets in critical care settings are evolving. The EndoTool IV (ETIV) de-identified data base was studied for glycemic events as a function of BG ranges. ETIV is an insulin dosing algorithm that utilizes patient factors to adjust insulin dosing and allows selection of target BG values. For the calendar year 2023 73,458 patient runs with IV insulin were studied. Target BG ranges fell into 4 major groups as shown in Table 1. No significant differences in number of BG checks, use of steroids or renal function was noted among the groups. There are statistically significant differences in hypoglycemia between target ranges compared to BG 140-180.These data suggest that for a heterogeneous patient population treated with IV insulin 120-160 mg/dL offers minimal hypoglycemic and hyperglycemic events with acceptable time in goal range.

Table 1: BG target ranges mg/dL with event rates for hyper and hypoglycemia and relative risk (RR) for hypoglycemia compared to 140-180 BG

Disclosure

J. Aloi: Research Support; Abbott, Medtronic. C.E. Price: Other Relationship; American Diabetes Association.
1877-LB: Use of Faster Aspart in Pregnancy
Authors: GHOHSH MANIKANTAN NAIR SAKUNTHALA ANEESH
Published: June 2024

Aims: The present study aimed to study the pregnancy outcomes, efficacy, and safety of faster aspart among Indian women with gestational diabetes.

Background: In several countries, fast-acting insulin aspart (faster aspart) has been approved for use in pregnancy. There is a lack of data related to maternal glycemic control and fetal and perinatal outcomes with faster aspart in gestational diabetes among the Indian population.

Objective: To compare and evaluate the efficacy and safety of faster aspart in the management of gestational diabetes.

Methods: This retrospective study evaluated the medical records of 60 pregnant women diagnosed with gestational diabetes and managed with faster aspart or insulin aspart at a tertiary care center, between March 2019 and September 2020. Self-monitored blood glucose levels recorded at 4 timepoints (fasting, and 1 hour post breakfast, lunch, and dinner) during 6 consecutive days any time before delivery but after

achieving steady state were analyzed. Pregnancy and neonatal outcomes studied in the cohort.

Results: The mean postprandial glucose value following dinner was significantly lesser in the faster aspart group compared to the insulin aspart group (123.61 +/- 2.52 mg/dL vs. 125.87 +/- 2.98 mg/dL, respectively; p=0.0024). Women in the faster aspart group had significantly lower glycemic variability (fluctuations). Lesser number of hypoglycemic events were noted in the faster aspart group (10 vs. 20; p=0.0595).Conclusion: Faster aspart was associated with better glycemic control compared to insulin aspart among women with gestational diabetes. The MAGE analysis revealed that women in the faster aspart group had significantly lower glycemic variability (fluctuations) at all three mealtimes compared to those in the insulin aspart group. The birth weight, respiratory rate, and pulse rate of the neonates born to mothers on insulin aspart were significantly higher compared to those born to mothers on faster aspart

Disclosure

A. Manikantan Nair Sakunthala: None.
1878-LB: Medication Use in Adults with Type 1 Diabetes in U.S. Clinical Practice
Authors: STOKES MICHAEL E. , LI QIAN , DEX TERRY A. , WILSON LAURA
Published: June 2024

Introduction & Objective: Type 1 diabetes (T1D) remains associated with substantial clinical burden and long-term medication use. We assessed medication use in adults with T1D in US clinical practice.

Methods: We identified data (Merative MarketScan® Jan 1, 2014-Jun 30, 2019) for adults (≥18 years) with prevalent T1D (≥2 T1D claims ≥30 days apart, and either a T1D:T2D diagnosis code ratio >0.5 with prescribed glucagon/no oral hypoglycemic agents [excluding metformin] or a prescribed urine acetone test, prior to Jan 1, 2017 [index]). Clinical characteristics and medication use during the 12-month pre-index period were recorded.

Results: Compared with patients on Commercial plans, those on Medicare and Medicaid generally had higher comorbidity burden (Table). Insulin was the most frequently used medication across health plans. Patients on Commercial plans often received atorvastatin, lisinopril and metformin, but less frequently than with other health plans. Patients on Medicare plans patients frequently received atorvastatin, furosemide, lisinopril, and amlodipine. Patients on Medicaid plans frequently received acetaminophen/hydrocodone, lisinopril, and gabapentin.

Conclusions: Compared with patients on Commercial plans, those on Medicare and Medicaid plans more frequently received non-insulin drugs relating to cardiovascular and neuropathic conditions, likely reflecting higher comorbidity in these patients.

Disclosure

Q. Li: None. T.A. Dex: Stock/Shareholder; Pfizer Inc. Employee; Sanofi. Stock/Shareholder; Viatris Inc., Teva Pharmaceutical Industries Ltd. L. Wilson: Employee; Sanofi. Stock/Shareholder; Sanofi.

Funding

Sanofi
1880-LB: Efficacy and Safety of iGlarLixi vs. IDegAsp in Non-Asian People with Type 2 Diabetes Inadequately Controlled with Basal Insulin—A Systemic Literature Review and Network Meta-analysis
Authors: HOME PHILIP , LAUAND FELIPE , DJABALLAH KHIER , BOURHIS FRANCOIS , LI XUAN , HAFIDH KHADIJA , MEHTA ROOPA , FARAOUN KHADRA , ANAFOROGLU INAN , POURRAHMAT MIR-MASOUD
Published: June 2024

Introduction and Objective: The objective of this systematic review and network meta-analysis (NMA) was to estimate the relative treatment effect of iGlarLixi (insulin glargine 100 U/mL + lixisenatide) versus premixed insulin IDegAsp (insulin degludec + insulin aspart) in people with T2D inadequately controlled with basal insulin (BI).

Methods: A systematic review identified recently published randomized controlled trials (RCTs) by searching Embase (including congress abstracts from 2021-2023), MEDLINE, and CENTRAL in October 2023. Outcomes from RCTs for non-Asian people with T2D previously treated with BI who switched to iGlarLixi or IDegAsp were compared using an NMA. Differences in the definitions of hypoglycemia used in the included RCTs preclude secure comparisons. Data analysis was performed using R, version 4.0.2.

Results: Four RCTs were included (N=2535). iGlarLixi (n=810) demonstrated a significant reduction in HbA1c vs IDegAsp (n=454) (−0.39; 95% credible interval [CrI] −0.58, −0.21 %-points). The chance of achieving HbA1c <7.0% was 42% greater with iGlarLixi (risk ratio: 1.42; 95% CrI 1.18, 1.71). iGlarLixi resulted in a significant reduction in post-prandial glucose (PPG). Weight gain and insulin dose were significantly lower with iGlarLixi vs IDegAsp with mean differences of −1.5 (95% CrI −2.3, −0.8) kg and −5.1 (95% CrI: −8.5, −1.7) U/day. The reported event rate of documented hypoglycemia (<54-56 mg/dL) was 35% lower for iGlarLixi vs IDegAsp (event rate ratio 0.65; 95% CrI 0.46, 0.89).

Conclusion: Treatment with iGlarLixi versus premix IDegAsp was associated with a greater reduction in HbA1c, PPG, and morning and afternoon SMPG, with less weight gain and lower insulin dose.

Disclosure

P. Home: Consultant; Eli Lilly and Company. Research Support; Sanofi. Other Relationship; Gan & Lee. F. Lauand: Employee; Sanofi. Stock/Shareholder; Sanofi. K. Djaballah: None. F. Bourhis: Employee; Sanofi. X. Li: Employee; Sanofi. K. Hafidh: None. R. Mehta: Advisory Panel; Boehringer-Ingelheim, Eli Lilly and Company, Novo Nordisk. Speaker's Bureau; Abbott, Amgen Inc., AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Novo Nordisk, Sanofi, Silanes. K. Faraoun: None. I. Anaforoglu: None. M. Pourrahmat: Employee; Evidinno Outcomes Research Inc.

Funding

Funded by Sanofi
1893-LB: Effects of High Fibers and Probiotics Supplements Diet and Lifestyle Intervention in Type 2 Diabetes or Prediabetes—A Randomized, Double-Blind, Placebo-Controlled Pilot Trial
Authors: WANG XIANGHONG , WEN JINGHUI , PANG LICHUN , LI PENG , GENG XIAOJING , ZOU LINGLING , YANG ZHE , LI XIAOBING , LU HONGYUN
Published: June 2024

High-fiber diets and lifestyle interventions have been shown to be the most effective ways to treat metabolic diseases such as obesity and diabetes, but which treatment is more effective and how effective the combination of these two interventions remain unclear. This study evaluated the clinical efficacy of a high-fiber and probiotic supplement diet (HFPD) combined with a lifestyle intervention (LSII) in overweight or obese patients with type 2 diabetes mellitus (T2DM) or prediabetes, and analyzed their impact on patients' gut microbiota and metabolomics. A randomized, double-blind, placebo-controlled trial was conducted in obese or overweight patients with T2DM or prediabetes (ChiCTR1800016411). 110 eligible participants were enrolled, randomly assigned to 4 groups (1:1:1:1) as following, HFPD add LSII group (HL), HFPD add non-LSII group (HNL), placebo add LSII group (PL), and placebo add non-LSII group (PNL) to complete the this 12-weeks treatment. Our results showed that HbA1c in the HL group decreased significantly compared with that in the PL group (-0.7±0.7% vs -0.4±0.9%, P=0.0166). The Hip circumference in PL group decreased more significantly than that in PNL group (-2.2±3.1 cm vs -0.2±3.6 cm, P=0.0244). In addition, compared with PNL group, HL group was significantly better in reducing body weight (-4.2±3.7kg vs -1.7±3.6 kg, p=0.0203), body mass index (-1.6±1.5kg/m2 vs -0.7±1.3kg/m2, p=0.0249), hip circumference (-3.3cm±4.1cm vs -0.2±3.6cm, p=0.0070), HbA1c (-0.7±0.7% vs -0.2±0.7%, p=0.0147) and HOMA-IS (0.18±0.36 vs -0.01±0.20, p=0.0263). Combining further 16S rRNA sequencing and untargeted metabolomics studies suggests that HFPD and LSII both contribute to reducing weight and BMI in obese or overweight T2DM patients, and their combined use is particularly significant in improving metabolic parameters. This may be related to the improvement of the patients' gut environment.

Disclosure

X. Wang: None. J. Wen: None. L. Pang: None. P. Li: None. X. Geng: None. L. Zou: None. Z. Yang: None. X. Li: None. H. Lu: None.
1906-LB: Identification of Missed Mealtime Insulin in Type 1 Diabetes Using Connected Insulin Pens
Authors: WOLPERT HOWARD , XUE JIE , CHEN CHAO , DAVIDSON MICHAEL B. , BOSS ANDERS , JOHNSON JENNAL , DASSAU EYAL
Published: June 2024

Introduction & Objective: Omission of only three mealtime insulin doses a week is associated with a 1% increase in HbA1c. Retrospective Identification of missed mealtime insulin doses is challenging, but the integration of connected insulin pen (CIP) and CGM data will enable the identification of missed mealtime insulin by healthcare professionals. This study was undertaken to evaluate different approaches to characterize insulin dosing practices.

Method: CIP and CGM data from the Type 1 Diabetes Exercise Initiative study participants (with minimum of 3 recorded insulin injections and 2 meals per day for 190-day period) was analyzed to evaluate methodologies to identify missed mealtime insulin. Three algorithms to identify glucose excursions (MAGE, Delta G, Mo-Delta G) and several insulin dosing windows (before and after onset of the glucose excursion) were examined to evaluate the accuracy and opportunity for intervention.

Results: Analysis of data from 22 subjects (age 34±13; A1c 6.9±0.9% [mean±SD]) meeting inclusion criteria indicated that 12-13% of the 398, 397 and 304 glucose excursions identified with the different algorithms had no insulin recording in a ±2h window from excursion onset.

Conclusions: The integrated analysis of CIP and CGM data provides actionable insights about insulin dosing behavior that could drive improvements in glycemic control in people with T1D.

Disclosure

H. Wolpert: Research Support; Abbott. Consultant; Eli Lilly and Company. J. Xue: Employee; Eli Lilly and Company. C. Chen: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M.B. Davidson: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. A. Boss: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. J. Johnson: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. E. Dassau: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.
1919-LB: GlucoseReady—Technical Validation of a Novel GxP Platform for Real-Time CGM Capture
Authors: ANDERSON DAVID , MERICKEL MICHAEL , BEST ALLEN , SEVERSON BRIAN T. , DJURHUUS CHRISTIAN B. , GOLDMAN JONATHAN
Published: June 2024

Introduction: FDA guidance recommends continuous glucose monitoring (CGM) for diabetes clinical trials. Real-time monitoring in such trials demands high-speed data frameworks. Here, we sought to develop a fully GxP-compliant platform that integrates with CGM devices and rapidly transmits regulatory submission quality data to study servers.

Methods: Software acquired glucose readings directly from Dexcom G6 CGM transmitters and sensors via Bluetooth. Live transmitter samples were considered real-time readings; backfill samples were excluded from real-time classification. Software synchronized with study servers after each sample acquisition, pending network connectivity. Descriptive statistics were evaluated for this pilot study.

Results: CGM readings (n=5,996) were generated over a 24 day study period. Median inter-sample interval was 5.0 minutes, and 99.4% of all sample intervals were between 4.9 and 5.1 minutes. Sample validity was high (98.6%), where 1.3% of samples were lost to sensor warmup and 0.05% of samples were lost to sensor error. Real-time measurements made up 96.4% of readings. Median transmitter sync time was 0.50 seconds (IQR: 0.26 - 0.75 seconds). Server upload times were fastest at 12 seconds; median upload time was 10.3 minutes (IQR: 5.3 - 25.3 minutes). Participant showed normal glycemic variability (19.7%), time-in-range (97.3%), and glycemic risk index (3.6%), with few Level-1 (n=3) and Level-2 (n=1) hypoglycemic events.

Conclusions: We developed a fully GxP-compliant high-speed data platform directly integrated with CGM devices. There is potential for low latency data availability - on the order of seconds - and further investigation is required to understand sources of server upload lag, for example network connectivity. Future development of this platform will include integrated hypo forms triggered by CGM data streams. Further work is needed to understand network dynamics of this framework in a larger study cohort.

Disclosure

D. Anderson: Employee; Clinical ink. M. Merickel: None. A. Best: Employee; Clinical Ink. B.T. Severson: Employee; Clinical Ink. C.B. Djurhuus: Stock/Shareholder; Novo Nordisk A/S. J. Goldman: Employee; Clinical ink.
1969-LB: Insulin Deficiency in Women with Early Postpartum Glucose Intolerance
Authors: GITLIN EMILY S. , KULKARNI VANDANA , ALEXANDER MALLIKA , NAIK SHILPA , KOLE ADITI , TAMBE SANJAYKUMAR , DESHPANDE PRASAD , BROWN TODD , MATHAD JYOTI S. , CHEBROLU PUJA
Published: June 2024

Diabetes during pregnancy (GDM) increases type 2 diabetes (T2DM) risk after delivery. Insulin deficiency postpartum may play a greater role in T2DM development than insulin resistance in South Asian populations due to early life undernutrition and lack of excessive weight gain. We studied insulin pathophysiology after pregnancy in Indian women with GDM. Women were enrolled at delivery and followed until 6 months postpartum at an Indian public hospital serving lower socioeconomic strata. Fasting oral glucose tolerance testing (75 g) with insulin levels at 0, 30, and 120 min at 6 weeks (baseline) and 6 months postpartum were used to assess insulin resistance (by HOMA-IR) and insulin deficiency (by insulinogenic index (IGI) and fasting insulin oral disposition index (oDI)). Prediabetes and T2DM were defined per ADA criteria. Among 49 women at baseline, median age was 28 yrs (IQR 25-32). By 6 months postpartum, 9/49 women (18.4%) had T2DM and an additional 13/49 (26.5%) had prediabetes. IGI and oDI at 6 weeks postpartum were significantly lower in women who had prediabetes/T2DM by 6 months postpartum compared to women with normal glucose tolerance ([0.21 vs 0.48, p=0.03] and [0.03 vs 0.06, p<0.01], respectively), whereas there was no difference in HOMA-IR. Insulin deficiency postpartum may be more predictive of future T2DM than insulin resistance in South Asian women. Larger longitudinal studies are needed to further examine this association.

Disclosure

V. Kulkarni: None. M. Alexander: None. S. Naik: None. A. Kole: None. S. Tambe: None. P. Deshpande: None. T. Brown: Consultant; Merck & Co., Inc., Janssen Pharmaceuticals, Inc., ViiV. J.S. Mathad: None. P. Chebrolu: None.

Funding

Weill Cornell Fund for the Future Grant (R01A162235)
1980-LB: Post-recovery of Acute Hyperglycemia during Hospitalization and Incident Cardiovascular Health Outcomes
Authors: SANTOS MARIA P. , LEY SYLVIA H.
Published: June 2024

Introduction & Objective: While research links acute hyperglycemia to adverse hospitalization outcomes, post-discharge implications are unclear. We examined the association between acute hyperglycemia during hospitalization and incident cardiovascular health outcomes post-discharge using a large-scale EHR database.

Methods: Using data from the National COVID Cohort Collaborative, we analyzed 5174261 patients in the U.S. with hospital admission between March 1, 2020, and March 1, 2022. Acute hyperglycemia was defined as blood glucose levels exceeding 140 to 180 mg/dL in patients without a pre-existing diabetes diagnosis. Outcomes were defined as physician-diagnosed cerebrovascular disorders, dysrhythmias, inflammatory heart disease, ischemic heart disease, heart failure, and thrombotic disorders ascertained more than 30 d after discharge until end of follow-up on January 31, 2024. HRs were analyzed by Cox regression, adjusted for age, sex, race/ethnicity, hypertension, obesity, coronary artery disease, chronic kidney disease, chronic lung disease, and cardiovascular medication use.

Results & Conclusion: Individuals with acute hyperglycemia during hospitalization faced a higher risk of incident cardiovascular disease (Figure). Those experiencing acute hyperglycemia during hospitalization may benefit from longer-term follow-up focusing on cardiovascular health.

Disclosure

M.P. Santos: None. S.H. Ley: None.

Funding

National Heart, Lung, and Blood Institute of the National Institutes of Health (T32HL158290).
2008-LB: Identification of Genome-Wide Significant Loci for Childhood Glycemic Traits in HAPO Follow-up Study
Authors: DIEGUEZ ABIGAYIL , JOSEFSON JAMI L. , LOWE WILLIAM L. , KUANG ALAN , SCHOLTENS DENISE , GEOFFREY HAYES M.
Published: June 2024

Introduction & Objective: Type 2 Diabetes (T2D) among children is increasing. Compared to T1D and adult-onset T2D, it is more aggressive with more rapid disease progression. The genetic risk associated with youth-onset T2D has not been elucidated. We performed a GWAS of childhood dysglycemia and precursors to T2D in a diverse youth cohort.

Methods: The Hyperglycemia and Adverse Pregnancy Outcome Follow Up Study (HAPO FUS) cohort, a diverse cohort of children (N=4,160, ages =11-14 years) representing several ancestry groups (African=AFR, Mexican American=AMR, South Asian=SAS, European=EUR, and East Asian=EAS) was used to identify genetic variants associated with glucose dysregulation. The primary outcomes included the lowest quartile of Disposition Index (DI) and Matsuda index (MI), and highest quartile of sum of glucose Z-scores from a fasting 2-hr OGTT (2hGZ). Genome-wide SNP data were imputed to TOPMed. GWAS was performed using an additive model, adjusting for field center, 3 principal components of genetic ancestry, maternal confounders during pregnancy, and offspring confounders during childhood.

Results: We identified two genome-wide significant associations in AFR (intronic in SHOC1 and C8ORF37-AS1) and one in EAS (intergenic between GPIHBP1 and LY6H) with lowest quartile of DI. Four additional genome-wide significant associations were found in AFR (ADI1, MOK, intergenic between SLC37A3 and KDM7A-DT, and intergenic between LINC01541 and GTSCR1) for 2hGZ. One genome-wide significant locus in EAS (intronic in C2CD2) and one in EUR (intronic within INSC) were identified with MI. No associations were identified in our AMR or SAS populations.

Conclusion: Multiple loci were associated with markers of dysglycemia in ancestry-specific analyses of HAPO FUS children. While loci previously reported to be associated with glycemic measures were not identified, subsequent analyses with greater power using trans-ethnic meta-analyses will likely identify additional loci.

Disclosure

A. Dieguez: None. J.L. Josefson: None. W.L. Lowe: None. A. Kuang: None. D. Scholtens: None. M. Hayes: None.

Funding

AD: National Institutes of Health (5T32DK00716JLJ); NIH (R01DK118403MGH: R01DK117491, R01HD100630)
2017-LB: Comparison of Nuclear Preparation for Single-Nucleus RNA-seq of Adipose Tissue
Authors: ONOGI YASUHIRO , WADA TSUTOMU , FUJISAKA SHIHO , SASAOKA TOSHIYASU , IIDA KEITA , OKADA YUKINORI , KADOWAKI MAKOTO , SAITO SHIGERU , TOBE KAZUYUKI
Published: June 2024

Introduction & Objective: To appreciate the pathophysiological changes in the transcriptome and cell type landscape during obesity, single-nucleus (sn)RNA-seq overcomes the difficulty of maintaining intact transcripts. Sedimentation of dissociated live cells is used to concentrate adipocytes (Ads) and stromal cells. The current study compared the single cell level transcriptome in libraries with and without the fractionation.

Methods: C57BL/6J mice were fed an HFD for 12 weeks starting at 8 weeks of age. Dissected epididymal fat from the same donor was divided into three conditions: 1) nuclei from unfractionated frozen fat (UF), 2) nuclei from the Ad fraction (AF) after enzymatic digestion and centrifugation, and 3) cells from the stromal fraction corresponding to the AF. As a dietary control, nuclei were prepared from the UF of an age-matched normal chow-fed mouse. Single cell/nucleus transcriptome libraries were sequenced using short-read NGS.

Results: A total of 32,949 cells were recovered by snRNA-seq. Fractionation lost recovery of certain cell types, including epithelial, mesothelial, and B cells. Fractionation barely enriched Ads in the AF at 12.4%, comparable to the Ads (11.2%) in the UF. Macrophages (Mφs), rather than Ads, accounted for 54.6% of the AF. The Mφs were clustered into six subtypes by Seurat independent of dietary conditions or fractionation. However, certain cytokines were more highly expressed in Mφs from fractions than those from UF. In support of this, functional annotation-driven unsupervised clustering, ASURAT, mapped three Mφ subtypes in the libraries from fractions that differed from those from the UF, where there were four other subtypes.

Conclusion: The current study suggests that the conventional fractionation could bias the transcriptome and a nuclear library from unfractionated frozen fat would represent a naïve comprehensive transcriptome that better reflects the pathophysiology of obesity, which should be important for understanding cell function.

Disclosure

Y. Onogi: None. T. Wada: None. S. Fujisaka: None. T. Sasaoka: None. K. Iida: None. Y. Okada: None. M. Kadowaki: None. S. Saito: None. K. Tobe: None.

Funding

JST Moonshot R&D (JPMJMS2021)
2018-LB: ABHD17B Modulates Diet-Induced Abdominal Obesity and Chronic Inflammation
Authors: HADLEY JASON , RYU JIYOON , BAI JULI , PAN MEIXIA , BAO HANMEI , HAN XIANLIN , LEADBETTER ELIZABETH , LIU FENG , DONG LILY Q.
Published: June 2024

Overnutrition induces abdominal obesity and chronic inflammation in humans. Despite the central role of hyperactive pro-inflammatory macrophages, the mechanisms underlying macrophage dysregulation due to overnutrition remains poorly understood. Here, we present the first evidence of the physiological role of ABHD17B, a putative depalmitoylase, in rodents through the generation of whole-body knockout mice and macrophage-specifical knockout mice. Our findings identify macrophages as the primary cellular source of ABHD17B and reveal reduced ABHD17B expression in high fat diet-fed mice. ABHD17B deficiency exacerbates diet-induced abdominal obesity, gut dysfunction, insulin resistance, and inflammation in both knockout mouse models. Furthermore, the loss of ABHD17B amplifies macrophage pro-inflammatory responses and compromises phagocytic efficiency. Mechanistically, ABHD17B de-palmitoylates C5aR2, a pro-inflammatory complement C5a receptor, in macrophages. Deletion of the Abhd17b gene in macrophages enhances the receptor expression and plasma membrane location, stimulates ROS production, and potentiates TLR4-mediated pro-inflammatory signaling. Collectively, our study unveils ABHD17B as a novel anti-inflammatory depalmitoylase crucial for maintaining protein palmitoylation homeostasis in macrophages. Additionally, ABHD17B-C5aR2 signaling emerges as a critical player in safeguarding against over-nutrition induced excessive macrophage inflammation and abdominal obesity.

Disclosure

J. Hadley: None. J. Ryu: None. J. Bai: None. M. Pan: None. H. Bao: None. X. Han: None. E. Leadbetter: None. F. Liu: None. L.Q. Dong: None.

Funding

National Institutes of Health (1R01DK134637-01A1)
2019-LB: The Characteristic Activity of Regulatory B Cells during the Occurrence and Development of Insulin Resistance
Authors: WEI LINGLING , ZHANG LIJIE , MA YAN , ZHAO DONG , YANG LONGYAN
Published: June 2024

Introduction & Objective: To investigate the aberrant distribution and clinical relevance of regulatory B cells (Bregs) subsets in the peripheral blood of individuals with different levels of insulin resistance (IR).

Methods: A cohort of 124 subjects were divided into five groups according to their insulin resistance index (HOMA-IR) and diabetes diagnosis. The groups comprised HOMA-IR<3 (IR- without T2DM), HOMA-IR<3 (IR- with T2DM), 3≤HOMA-IR<6 (IR+ without T2DM), 3≤HOMA-IR < 6 (IR+ without T2DM) and HOMA-IR≥6 (IR++ with T2DM). Peripheral blood samples were collected from each group, the percentages of CD19+CD24+CD27+ and CD19+CD24+CD38+ Bregs and the levels of IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, IFN-γ were detected by flow cytometry and flow microsphere matrix method. Additionally, the cytokines levels were validated through ELISA. The activation of Bregs and the production of IL-10 among different groups were analyzed. Spearman correlation analysis was used to analyze the correlation between Bregs activation rate and IR degree.

Results: The results showed that the levels of CD19+CD24+CD27+ and CD19+CD24+CD38+ cells were increased whether in IR+ without or with T2DM groups compared to the IR- group, with the most significant increase observed in the IR++ with T2DM group. Moreover, the plasma levels of IL-6, IL-10, IL-17, TNF-α and IFN-γ in the IR+ group were higher than those in the IR- group. The expression and activation level of Bregs were positively correlated with the severity of IR in T2DM.

Conclusion: These results suggest that the increase level of Bregs is closely related to the severity of IR, highlighting the potential significance of Bregs in the clinical progression of Type 2 Diabetes Mellitus (T2DM) and its associated insulin resistance.

Disclosure

L. Wei: None. L. Zhang: None. Y. Ma: None. D. Zhao: None. L. Yang: None.

Funding

This research was funded by Beijing Tongzhou District Science and Technology Plan Project, (KJ2022CX023, KJ2023SS027); Beijing-Tianjin-Hebei Basic Research Joint Project, (22JCZXJC00110) and Cultivation project (PYZ22178) was funded by Capital Medical University.
2020-LB: Immunometabolomics Reveals Little Autoimmunity in Type 1 Diabetes (T1D)—Cross-Sectional Pathway Analysis across Multiple Autoimmune Diseases
Authors: MONEDEIRO FERNANDA , ZÜGNER ELMAR , PRIETL BARBARA , OBERHUBER MONIKA , STRADNER MARTIN , KHALIL MICHAEL , MAGNES CHRISTOPH , PIEBER THOMAS
Published: June 2024

Introduction & Objective: Metabolic reprogramming has a critical role in the differentiation and function of PBMCs in autoimmune diseases. Here, comparative cellular immune-metabolomics was applied to multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and T1D.

Methods: PBMCs were isolated from healthy individuals (CTRLs, n=10), patients with T1D (n=11), MS (n=8), RA (n=14) and SLE (n=10). Obtained PBMCs were either T cell-stimulated using anti-CD3/CD28 dynabeads or treated with placebo. LC-HRMS metabolomics data was controlled for extraneous variables, submitted to statistical examination and pathway enrichment analysis.

Results: T1D shows a distinct dissimilarity to all tested autoimmune diseases and a striking congruence with controls (Fig.). MS, RA and SLE displayed enhanced metabolism concerning cell growth and death, energetics, transport and catabolism, and signal transduction, while these pathways were only moderately downregulated or not significantly altered in T1D. Metabolome after T cell activation shows a similar but less pronounced pattern.

Conclusion: T1D immune cell metabolome is closely related to that of healthy controls, whereas in MS, RA and SLE several metabolic pathways are highly deregulated. Our findings challenge the concept of immune interventions as monotherapies in T1D.

Disclosure

F. Monedeiro: None. E. Zügner: None. B. Prietl: None. M. Oberhuber: None. M. Stradner: Research Support; Novartis AG. Consultant; Janssen Pharmaceuticals, Inc. Speaker's Bureau; Pfizer Inc., AstraZeneca, Sobi, Eli Lilly and Company, Otsuka America Pharmaceutical, Inc., Bristol-Myers Squibb Company, Takeda Pharmaceutical Company Limited. M. Khalil: None. C. Magnes: None. T. Pieber: Advisory Panel; Arecor. Research Support; AstraZeneca. Consultant; Novo Nordisk A/S. Research Support; Novo Nordisk Foundation. Consultant; Lilly Diabetes, Sanofi. Speaker's Bureau; Roche Diabetes Care, Novo Nordisk.

Funding

COMET ? Common Mechanism in Autoimmunity, funded by JDRF and LRA (2-SRA-2021-1043-S-B).
2029-LB: Myokine X, a New Therapeutic Approach for Type 2 Diabetes
Authors: BERNARD DAPHNÉ , VION-CHAMBRIAL JULIE , PINGET MICHEL , SULTAN ARIANE , BOUZAKRI KARIM
Published: June 2024

An energy imbalance, often involved in Type 2 diabetes (T2D), leads to adipose tissue dysfunction which will worsen the disease and lead to complication. Thus, the need to find new therapies targeting adipose tissue is necessary. We have already demonstrated the beneficial impact of Myokine X on pancreatic islets survival and functionality. This study aims to investigate the impact of Myokine X, which is secreted after a resistance effort, on adipose tissue of a rodent model of T2D.

Zucker Diabetic Sprague-Dawley (ZDSD) rat, naturally developing type 2 diabetes, received a daily peritoneal injection of either a saline solution (control group) or a Myokine X solution at 1 µg/mL for 20 weeks. Animals were sacrificed at the end of the 20 weeks and adipose tissue was analysed by western blotting or by qPCR for gene expression. Figures and statistical analyses were performed using GraphPad Prism software. The significance of the data was assessed using Student's t test to compare two conditions. When several factors were present, two-way ANOVAs were performed.

Myokine X treatment revealed (i) an impact on insulin pathway with an increase of 16.5% of Akt p-ser473 phosphorylation capacity, with simultaneously a significant increase of 78% for GLUT4 mRNA expression, (ii) a significant decrease of HSL phosphorylation on ser660 (-24%), (iii) an increase of adipokines mRNA expression with beneficial impact on insulin pathway.

This study shows that Myokine X treatment had a positive impact on adipose tissue in a rodent model of T2D, in terms of insulin sensitivity improvement, HSL activation decrease and improvement of adipose tissue secretion, adipokines. Thus, Myokine X could represent a therapeutic approach for T2D treatment.

Disclosure

D. Bernard: None. J. Vion-Chambrial: None. M. Pinget: Other Relationship; ASDIA, Novo Nordisk, VitalAir. A. Sultan: Speaker's Bureau; Abbott. Board Member; Lilly Diabetes, Amgen Inc., Novartis AG. Speaker's Bureau; Sanofi, Servier Laboratories, Boehringer-Ingelheim. Board Member; Pfizer Inc. Speaker's Bureau; AstraZeneca. K. Bouzakri: None.
2043-LB: hERG Potassium Channels as Novel Targets for GLP-1 and GIP Secretagogue Therapies in Diabetes and Obesity
Authors: YUAN YING-CHAO , WANG HAO , YANG JIN-KUI
Published: June 2024

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), derived from enteroendocrine cells (EECs), play critical roles in blood glucose regulation as incretin hormones. While medications targeting GLP-1 analogues and GLP-1 receptor activators are widely used for managing type 2 diabetes (T2D) and obesity, there remains a need for agents that stimulate endogenous incretin secretion. In this study, we uncover the pivotal role of hERG potassium channels in regulating incretin secretion. Co-localization of hERG channels with EECs in the intestinal epithelium of rodents underscores their significance. Intestine-specific knockout of hERG in mice enhances glucose tolerance and augments GLP-1 and GIP secretion triggered by oral glucose intake. Moreover, primary intestinal epithelial cells deficient in hERG exhibit heightened incretin secretion upon glucose stimulation. Mechanistically (see Figure 1), (1) hERG deficiency leads to reduced Kv currents and (2) prolonged repolarization in enteroendocrine cells, (3) resulting in increased Ca2+ influx and intracellular Ca2+ accumulation, (4) ultimately leading to augmented incretin secretion. Given the therapeutic benefits associated with GLP-1 and GIP, these findings underscore the potential of hERG as an auspicious novel target for addressing obesity and diabetes therapeutically.

Disclosure

Y. Yuan: None. H. Wang: None. J. Yang: None.
2052-LB: Semaglutide Depot, a Long-Acting Injection of Semaglutide Administered Once Every Four Weeks, Demonstrates Similar Efficacy and PK Profile to Daily Semaglutide Administration
Authors: RUBNOV SHAI , ZATS GALINA , BLEICH KIMELMAN NADAV , POPPER LAURA , DANON URI , MAROM EHUD
Published: June 2024

Introduction and Objectives: Semaglutide Depot consists of extended-release microspheres administered every 28 days, aiming to provide improved dosing regimen over the currently available once weekly dose Semaglutide Depot efficacy and PK profile were evaluated in mice and minipigs. The study aimed to assess the efficacy and the PK profile of Semaglutide Depot injected once compared to Semaglutide API daily in mice or every 72 hours in minipigs.

Methods: In the PK study, db/db mice received SC injection of 2mg/kg Semaglutide Depot on day 0 or daily injections of 0.02mg/kg Semaglutide API for 42 days. In a parallel PD study, db/db mice were injected IM with 2mg/Kg Semaglutide Depot on day 0 or daily injections of 0.02mg/kg Semaglutide API, for 28 days. The PK profile, fasting blood glucose, HbA1c levels and feed intake were measured. In the minipigs PK study, animals were injected with 0.5mg/kg Semglutide Depot IM on day 0 or with 0.008mg/Kg Semaglutide API SC once every 72 hours for 28 days.

Results: PK studies in both species demonstrate sustained release profile maintaining plasma concentrations within the therapeutic range for at least 30 days. The PK profile is correlated with PD in mice. Significant reductions in fasting glucose levels at days 14 and 28, as well as HbA1c levels at day 28 in Semaglutide Depot-treated mice were noted, compared with vehicle treated controls. Additionally, feed intake was significantly lower in Semaglutide Depot-treated mice. Notably, a single dose of Semaglutide Depot given on day 0 was comparable to 28 daily doses of Semaglutide API.

Conclusions: Semaglutide Depot given as a single dose on day 0 showed a one-month lasting PK profile and a comparable efficacy to that of Semaglutide API given daily or every 72 hours in mice and minipigs, respectively. Phase I/IIa clinical study is planned to explore Semaglutide Depot bioavailability and efficacy in diabetic patients.

Disclosure

S. Rubnov: Employee; MAPI pharma ltd. G. Zats: None. N. Bleich Kimelman: Employee; Mapi Pharma Ltd. L. Popper: Employee; Mapi Pharma. U. Danon: None. E. Marom: Stock/Shareholder; Mapi Pharma Ltd.
2060-LB: Erythropoietin Regulation of Fat Mass and Glucose Tolerance Mediated by Receptor Expression in Adipose Tissue
Authors: ROGERS HEATHER , NOGUCHI CONSTANCE T.
Published: June 2024

The cytokine erythropoietin (EPO) is known for the regulation of red blood production, but its receptor (EpoR) is expressed beyond hematopoietic tissues. Studies in animal models have suggested that EPO regulates glucose homeostasis and fat mass accumulation. To assess EPO metabolic activity, wild-type mice (WT, C57BL/6) and mice lacking EPOR in adipose tissue, ΔEpoRAdipo (using Adipo-Cre) and ΔEpoRaP2 (using aP2-Cre), were fed a high-fat diet (HFD, 60% kCal fat) and treated with EPO (3000U/kg 3X per week) or saline for 3 weeks at ages 3, 4, and 6 months. Endogenous EPO regulated fat mass in WT mice, and ΔEpoRAdipo and ΔEpoRaP2 mice had increasing trends in fat mass accumulation, becoming significant in older mice. EPO treatment increased hematocrit and decreased fat mass accumulation and body weight in WT male mice at 6 months, showing EPO protection against diet induced obesity (DIO) in male mice while estrogen in female mice protects against DIO. ΔEpoRAdipo and ΔEpoRaP2 mice had increased GTT indicating that endogenous EPO activity in adipose tissue improves glucose tolerance. EPO treatment decreased GTT in WT mice. EPO treatment in ΔEpoRAdipo and ΔEpoRaP2 mice decreased GTT at 3 months and only in female mice at 4 months that was diminished at 6 months. This demonstrates that with age, adipose tissue response to EPO treatment improves glucose tolerance in a sex dimorphic manner, beginning in male mice at 4 months of age and then in female mice to a lesser extent by 6 months of age. Overall, these findings highlight the potential role of EPO in metabolic regulation beyond erythropoiesis and the contribution of sex and EpoR in adipose tissue in mice to regulate fat mass accumulation and glucose tolerance. Further research into the molecular mechanisms by which EPO signaling influences glucose and lipid metabolism may lead to new therapeutic strategies for the treatment of metabolic disorders such as obesity and type 2 diabetes.

Disclosure

H. Rogers: None. C.T. Noguchi: None.
2063-LB: Transgenic Erythropoietin Overexpression Inhibits Dermal Fat Formation and HIF1a in the Skin and Causes Telogen Effluvium in Mouse Pups during the First Hair Cycle
Authors: YIN WEIQIN , ROGERS HEATHER , AN XIULI , GASSMANN MAX , NOGUCHI CONSTANCE T.
Published: June 2024

Erythropoietin (EPO) plays an important role in promoting red blood cell production. In non-erythroid tissue, the EPO:EPO receptor (EPOR) interaction might affect fat synthesis and catabolism. Mice with deletion of EPOR in non-erythroid tissue become obese while transgenic mice overexpressing human EPO (Tg6) exhibit reduced body weight and fat mass compared with wild-type controls. How EPO:EPOR affects the synthesis and breakdown of dermal fat in skin, thereby affecting hair growth, is unknown. We verified EPOR expression in the dermal fat by fluorescent staining of skin tissue of EPOR-TdTomato-cre mice. We observed that EPOR knockout in HF stem cells did not affect skin hair growth nor showed significant differences in body weight and fat mass. In contrast, HF development in Tg6 mice was disrupted during the first catagen phase, resulting in formation of epithelium-lined HF cysts, filled with disorganized cysts. Transgenic human EPO in skin tissue was significantly higher than murine EPO during the first degenerative phase of HF development in Tg6 mice. The concomitant decrease in BODIPY positive cells suggested that high expression of transgenic EPO may affect hair growth during the first catagen phase by modulating lipogenesis and lipolysis of dermal fat. We assessed expression of transcription factors associated with EPO expression, HIF1aby Q-PCR. Indeed, increased EPO was accompanied by an increase in HIF1a. We found that EPO overexpression affected lipogenesis and lipolysis of dermal fat and HIF1a expression, disrupted hair growth during the first catagen phase and led to the formation of epithelial-lined HF cysts filled with disorganized keratin that ultimately manifest as truncal alopecia. In summary, we show here for the first time that EPO-HIF1a is essential in hair growth for the normal development and homeostasis of HFs.

Disclosure

W. Yin: None. H. Rogers: None. X. An: None. M. Gassmann: None. C.T. Noguchi: None.
2064-LB: Novel Amylin and Calcitonin Receptor Coagonists Reduce Food Intake and Body Weight in Rodents
Authors: YAGIZ KADER
Published: June 2024

Amylin analogs have been shown to significantly reduced body weight and dosage of insulin. Dual amylin and calcitonin receptor agonists (DACRAs) are the most potent amylin receptor agonists. We developed a series of novel long-acting amylin agonists to assess the potency on both calcitonin (CTR) and amylin 3 (AMY3) receptor activation on body weight and other metabolic parameters. We report herein the results from an evaluation of these compounds in rodent models.In vitro screening consisted of measurement of ligand-induced β-arrestin recruitment and assessment of cAMP production on human CTR and AMY3 receptors as an indicator of receptor activity, followed by in vivo evaluation. Acute food intake and pharmacokinetic evaluations in lean rats were determined following single subcutaneous administration of selected analogs. Diet-induced obese (DIO) mice were treated with subcutaneous injections of vehicle or one of a series of amylin agonists for 24 days. Cagrilintide was used as positive control. Cohorts were assessed for changes in BW, food intake and other markers.A series of amylin agonists reduced food intake in rats in the range of 56-93%, compared to vehicle, in the period from 0-72 hr post-dose. In comparison, cagrilintide was able to reduce food intake mostly from 0-48 hr and up to 72 hr only at 30 nmol/kg. Durable appetite suppression was further confirmed in a pharmacokinetic study. Treatment with selected novel amylin agonists resulted in reductions to BW in rats up to 10% compared to vehicle. In DIO mice, BW loss effects were comparable to those observed in cagrilintide-treated animals. Improvements in other metabolic markers were also observed.

A novel series of amylin analogs produced significant reductions in BW in rodents, with effect sizes comparable to those observed in an active control group. Dual agonism of CTR and AMY3 receptors represents a promising therapeutic approach to metabolic disorders such as obesity and diabetes. Further evaluation of these compounds is ongoing.

Disclosure

K. Yagiz: None.