bluuebunny/crossref_metadata_2025 huggingface dataset:
1995-LB: Prevalence, Risk Factors, and Clinical Characteristics of NAFLD in Individuals with Type 1 Diabetes Mellitus
Authors: JIANG WEIWEI , HUANG QINGYING , XU WEN , YAN JINHUA , WANG CHAOFAN , YANG DAIZHI
Published: June 2024

Objective: Nonalcoholic fatty liver disease (NAFLD) prevalence data in age- and BMI-matched reference groups are scarce. We aimed to investigate the prevalence, risk factors, and clinical characteristics of NAFLD in individuals with type 1 diabetes mellitus (T1DM).

Methods: A retrospective study was conducted on 1,132 people with T1DM who attended the Endocrinology Department from January 2014 to December 2022. After screening, a cohort of 832 T1DM patients was included for prevalence investigation. NAFLD diagnosis was based on ultrasound findings. A 1: 2 propensity score matching based on age, sex, and duration of diabetes was performed between the NAFLD and non-NAFLD groups. Additionally, 156 age-, sex-, and BMI-matched controls with normal glucose tolerance were enrolled, with laboratory measurements recorded. The t-test, χ2 test, and nonparametric test were used for comparison between the two groups when appropriate. Multivariate logistic regression models were used to assess risk factors for NAFLD.

Results: 61 individuals of NAFLD were identified among 832 individuals with T1DM, with a lower prevalence compared to the matched controls (7.3% vs 23%, P <0.05). The NAFLD group exhibited higher BMI, glucose, triglycerides (TG), ALT, GGT, and hsCRP levels but lower HDL-C compared to the non-NAFLD group (P < 0.05). Logistic regression analysis showed that BMI (OR= 1.27, 95% CI= 1.16 - 1.51), modified HOMA-IR (OR= 1.04 [1.01,1.08]), GGT (OR= 1.03 [1.01 - 1.05]), and TG (OR= 1.55 [1.19 - 2.13]) were associated with increased risk for NAFLD after adjusting for age, sex, metabolic syndrome, and its components (P<0.001). The predictive model combining BMI, modified HOMA-IR, GGT, and triglycerides demonstrated an area under the curve of 0.823 (95% CI= 0.76 - 0.89).

Conclusion: NAFLD is less prevalent in individuals with T1DM than in matched controls. A model integrating BMI, modified HOMA-IR, GGT, and triglycerides effectively predicts NAFLD risk in this population.

Disclosure

W. Jiang: None. Q. Huang: None. W. Xu: None. J. Yan: None. C. Wang: None. D. Yang: None.
2006-LB: Polygenic Scores for Metabolic Diseases Are Associated with Gene Expression Networks across Tissues
Authors: BRYAN CHRISTOPHER , SMITH KIRK , DASHTI HESAM , CLAUSSNITZER MELINA , MANNING ALISA , MERCADER JOSEP M. , UDLER MIRIAM , HUANG YI
Published: June 2024

Genetic risk for type 2 diabetes (T2D), coronary artery disease (CAD), and obesity can be estimated with global extended polygenic scores (gePS), which capture risk across thousands of genetic variants. Nevertheless, knowledge of underlying disease pathways remains limited. Expression Quantitative Trait Scores (eQTS) connecting gePS to gene expression could help prioritize disease-causing genes and pathways in specific tissues. We generated gePS for T2D, CAD, and body mass index (BMI) in the Genotype-Tissue Expression (GTEx) database of 838 individuals and 49 tissues. eQTS were calculated using a linear model of association between gePS and tissue transcript expression level, adjusting for age, sex, 5 genetic PCs, and 20 gene expression PCs. Gene set enrichment was performed using Enrichr with Gene Ontology pathway sets and Fisher’s Exact Test (Q < 0.05). T2D, CAD, and BMI gePS were each associated with > 500 transcript expression levels (eQTS) across multiple tissues at p < 0.05. In multiple tissues, both T2D and BMI eQTS were significantly enriched for pathways related to mitochondrial function (Q<10-7), with the most significant T2D signal found in the heart atrial appendage and BMI signals in subcutaneous (SC) and visceral adipose. For T2D, pancreas eQTS were enriched for pancreatic beta cell development and mature onset diabetes of the young (MODY) (Q<10-3). For CAD, cholesterol metabolism pathways were enriched in the coronary artery (Q<10-7). In summary, T2D and BMI eQTS share mitochondrial and metabolic transcription mechanisms across several tissues, including SC adipose. Cholesterol metabolism was enriched in the coronary artery in CAD eQTS. This study provides novel insight into the shared genetic and transcriptomic architecture of T2D, CAD, and obesity.

Disclosure

C. Bryan: None. K. Smith: None. H. Dashti: None. M. Claussnitzer: None. A. Manning: None. J.M. Mercader: None. M. Udler: Other Relationship; Up-To-Date. Y. Huang: None.

Funding

Doris Duke Foundation
2012-LB: Type 2 Diabetes GWAS Signal C2CD4A/B Insulin Resistance Mechanisms in Skeletal Muscle
Authors: EPELLE IBIERE L. , VARSHNEY ARUSHI , ORCHARD PETER , ZHANG ZHENHAO , FENG FAN , LAAKSO MARKKU , TUOMILEHTO JAAKKO , LAKKA TIMO A. , MOHLKE KAREN L. , BOEHNKE MICHAEL , SCOTT LAURA , KOISTINEN HEIKKI A. , COLLINS FRANCIS S. , LIU JIE , PARKER STEPHEN C.
Published: June 2024

Mechanisms of insulin action differ between fasting and postprandial states across tissues, with postprandial disturbance in insulin action being crucial in the development of type 2 diabetes (T2D). We generated single nucleus (sn-) chromatin accessibility and transcriptome profiles of 287 skeletal muscle biopsies from the FUSION Tissue Biopsy Study. These data found chromatin accessibility quantitative trait loci (caQTL) in muscle fibers colocalized with a T2D GWAS signal and a recently identified C2CD4A/B GWAS signal for insulin fold change (IFC) (coloc PP H4 = 0.969). This chromatin accessibility peak had previously been identified in an islet stretch enhancer and implicated C2CD4A/B in islet dysfunction. However, there has been no formal colocalization with any current islet QTL signals. In our skeletal muscle data, chromatin looping models nominated VPS13C as a candidate target gene. VPS13C encodes a lipid transfer protein. A previous study showed that VPS13C knockdown in an adipocyte cell model decreased insulin-induced translocation and cell-surface abundance of the glucose transporter, GLUT4, thereby implicating this candidate target gene in insulin resistance (IR) mechanisms. We hypothesize that VPS13C modulates IR and T2D risk in skeletal muscle in a cell-type and cell-state-specific manner. We are evaluating the allele-specific activity of the caQTL regulatory element with luciferase reporter assays in the LHCN-M2 human skeletal myoblast cell line. The chromatin looping models predict low contact with the VPS13C transcription start site for the risk allele. Reporter assay results that support this model would suggest a role for VPS13C in glucose uptake mechanisms in skeletal muscle fibers. Moreover, we are generating gene co-expression networks of the sn-transcriptome profiles to identify the network relationships of VPS13C. Collectively, these results will help illuminate the context-specific risk mechanisms at the C2CD4A/B T2D and IR GWAS locus.

Disclosure

I.L. Epelle: None. A. Varshney: None. P. Orchard: None. Z. Zhang: None. F. Feng: None. M. Laakso: None. J. Tuomilehto: Stock/Shareholder; Orion Pharma, Aktivolabs, Digostics. T.A. Lakka: None. K.L. Mohlke: None. M. Boehnke: None. L. Scott: None. H.A. Koistinen: Other Relationship; AstraZeneca, Novo Nordisk. F.S. Collins: None. J. Liu: None. S.C. Parker: Research Support; Pfizer Inc.
2028-LB: Investigate Sex- and Fat Depot–Specific Glucose Metabolism after Consuming Carbohydrate-Enriched Diets with (Un)interrupted Prolonged Sitting
Authors: KUO FENG-CHIH , CHEN YUNG-CHIH
Published: June 2024

Introduction & Objective: Carbohydrate-enriched diets and sedentary behavior are risk factors for diabetes. However, their impacts on glucose metabolism in abdominal and gluteal subcutaneous adipose tissues, especially considering sex differences, remain unexplored.

Methods: Twenty healthy subjects (10 females) [age 30.5±7.5 years, BMI 22.9±2.2 kg/m2 (mean±SD)] participated in mixed-feeding trials lasting 320 minutes, with breakfast and lunch containing 77% carbohydrates and either prolonged sitting (SIT) or interrupted prolonged sitting (2 min walking at 6.4 km/h every 20 min) (ACTIVE) in a randomized crossover design. Continuous glucose monitoring (CGM) was inserted simultaneously at abdominal (ABD) and gluteal (GLUT) fat-depots. Body composition was precisely quantified by dual-energy x-ray absorptiometry. Oral glucose tolerance test was performed for measuring insulin sensitivity and resistance. In vitro experiments using paired human abdominal and gluteal preadipocyte cell lines were conducted to investigate molecular mechanisms.

Results: In the SIT trial, GLUT CGM showed a slower increase in interstitial blood glucose (BG) during lunch compared to ABD CGM, particularly in females. Interrupted prolonged siting (ACTIVE trial) led to numerically lower BG levels in both ABD and GLUT CGM, with the most significant impact observed in female ABD CGM. While males with higher insulin resistance and android fat displayed a notable correlation with decreased BG levels in the ACTIVE trial. Our in vitro experiments further revealed steady glucose uptake (GLUT1 expression) and de novo lipogenesis (ChREBP protein) were significantly enhanced in gluteal adipocytes during post-feeding 3 to 6 hours.

Conclusion: Breaking prolonged sitting improves glucose control and gluteal fat depot may play roles to stabilize carbohydrate-enriched diets related hyperglycemia.

Disclosure

F. Kuo: None. Y. Chen: None.

Funding

TSGH-E-112257
2042-LB: The Gut–Fat Cross Talk in Metabolic Regulation through Microbiome
Authors: ZHANG ERYUN , CEBALLOS HANNAH M. , HUANG WENDONG
Published: June 2024

Current treatments are still limited in their ability to mitigate obesity and its complications. Obesity develops due to an imbalance between nutrient intake and energy expenditure; therefore, there is an urgent need to better understand the mechanisms governing nutrition and energy balance, with the long-term goal of developing novel strategies to treat obesity and associated metabolic diseases. Our previous study uncovered a novel link between intestinal AMPK activation and brown adipose tissue (BAT) thermogenic regulation through modulating the anti-microbial peptides (AMPs)-controlled gut microbiota and their metabolites. We also identified the new AMPK-mediated mechanism of intestine-BAT communication that may partially underlie the effects of metformin in metabolic diseases. Our current study discovered that another nutrient sensor mTOR crosstalk with white adipose tissue (WAT) browning regulates glucose homeostasis and energy metabolism. We observed significantly enhanced WAT browning and glucose homeostasis in intestinal epithelium-specific mTOR knockout (mTOR-IKO) mice compared to mTORfl/fl mice. Moreover, the gut microbiota profile of mTOR-IKO mice was markedly shifted compared to that of mTORfl/fl mice. Similarly, we identified significant differences in the serum and fecal levels of some bacterial metabolites in mTOR-IKO mice. Furthermore, we observed enhanced WAT browning and glucose homeostasis in WT mice after fecal microbiota transplantation from mTOR-IKO mice. Mechanistically, we found that the expression of various AMPs, including REG3 and RELMb were significantly lower in the intestines of mTOR-IKO mice compared to controls. These results indicate that intestinal mTOR remotely controls WAT browning through a mTOR-AMPs-microbiome-WAT axis. Determining the role of intestinal AMPK/mTOR-AMPs pathways in energy and metabolism will help fill the gap in our current understanding of how the intestine serves as an important site of AMPK/mTOR action in metabolic regulation.

Disclosure

E. Zhang: None. W. Huang: None.
2047-LB: METTL2 Knockout Mitigates Obesity and Metabolic Disorders Induced by High-Fat Diet
Authors: HE SUNYUE , NAN WU , ZHAO YUCHEN , LU LUSI , LIN XIHUA , ZHANG WENJING , ZHOU JIAQIANG
Published: June 2024

Objective: METTL2 is a tRNA methyltransferase primarily accountable for m3C modification of cytoplasmic tRNA. However, the existing comprehension of METTL2 is relatively limited, and the association between METTL2 and metabolic diseases remains undisclosed. This study aims to investigate the role of METTL2 in glucose-lipid metabolism and elucidate its underlying mechanism.

Methods: Studies were conducted in age-matched male METTL2 whole-body knockout (MeKO) and wild-type (WT) mice that fed normal chow (NC) or a high-fat diet (HFD) for 20 weeks. We performed comprehensive longitudinal assessment of body weight, energy balance, glucose homeostasis and global fat deposition. Additionally, we assessed steatohepatitis, adipose hypertrophy and adipose inflammation, and further explored potential mechanism.

Results: In the basal state, MeKO mice exhibited slower weight gain and body length compared to WT mice, although there was no significant difference in glucose homeostasis. In HFD-induced obesity model, MeKO mice showed reduced body weight and fat mass compared to WT mice. This reduction was accompanied by increased energy expenditure, while food intake remained unchanged. As a result, metabolic homeostasis was significantly improved in MeKO mice. METTL2 knockout alleviated the progression of steatohepatitis by inhibiting hepatic fatty acid uptake and synthesis. Furthermore, METTL2 knockout upregulated the expression of the lipolysis molecule ATGL in epididymal white adipose tissue and ameliorated adipose tissue inflammation.

Conclusion: Taken together, these findings suggested that METTL2 represents a novel molecule involved in HFD-induced obesity and associated metabolic disorders.

Disclosure

S. He: None. W. Nan: None. Y. Zhao: None. L. Lu: None. X. Lin: None. W. Zhang: None. J. Zhou: None.

Funding

National Natural Science Foundation of China (grant number: 82270857)
2049-LB: Robust Single Nucleus RNA Sequencing Reveals Depot-Specific Cell Population Dynamics in Adipose Tissue Remodeling during Obesity
Authors: SO JISUN , CHEOL ROH HYUN
Published: June 2024

Single nucleus RNA sequencing (snRNA-seq) has emerged as an alternative approach to address the inherent limitations of single cell RNA sequencing (scRNA-seq). However, snRNA-seq encounters technical challenges in obtaining high-quality nuclei and RNA, which persistently hinder its applications. Here, we present a robust technique for isolating nuclei that effectively overcomes these challenges across various tissue types. Our method demonstrates a marked enhancement in the quality of snRNA-seq data, surpassing that of previously reported datasets. Employing this approach, we comprehensively characterize the cellular dynamics underlying adipose tissue remodeling during obesity. Various cell types within adipose tissue display substantial responses to obesity, with significant variations observed depending on fat depots. Through the integration of nuclear RNA-seq data acquired from adipocyte nuclei of different sizes, we identify multiple adipocyte subpopulations that can be categorized by size and functionality. Specifically, we characterize dysfunctional hypertrophic adipocytes prevalent in visceral adipose tissues during obesity, exhibiting hallmark features such as cellular stress, inflammation, and impaired gene expression. The adipocyte subpopulations contribute differentially to a range of biological pathways involved in the pathophysiology of adipose tissue during obesity. Collectively, our study establishes a robust snRNA-seq method that offers novel insights into the mechanisms orchestrating adipose tissue remodeling during obesity, with broader applicability extending to diverse biological systems.

Disclosure

J. So: None. H. Roh: None.

Funding

American Diabetes Association (7-21-JDF-056); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK129289)
2050-LB: The Effect of Pharmacological Activation of Liver X Receptor (LXR) in the Heart of Obese Mice
Authors: ALFARQANI YOUSUF , OLICHWIER ADAM J. , YOUNG JAMEY , BEDNARSKI TOMASZ
Published: June 2024

Even though fatty acids (FAs) are the main source of energy for cardiomyocytes, in pathological conditions heart shifts its metabolism toward increased glucose reliance, which leads to excess accumulation of FAs in the form of triglycerides (TGs) and cardiac dysfunction. Therefore, we have investigated the role of liver X receptor (LXR), a nuclear receptor that regulates lipid and glucose homeostasis, in cardiac muscle during progressive obesity. As a model we used 8-week-old, male, hyperphagic MC4R knockout mice (MC4RKO), and wildtype C57BL/6J mice (WT) as a control, placed on either standard laboratory diet (Chow) or high-fat, high-fructose, high-cholesterol western diet (WD) for additional 8 weeks. Some of the WD-fed mice had their food supplemented with LXR activator, GW3965. LXR activation significantly decreased whole body and fat mass in both WT and MC4RKO mice which was accompanied by improved glucose tolerance and insulin sensitivity as indicated by glucose tolerance test and HOMA-IR score. LXR activation significantly upregulated plasma free FAs content in WT animals, decreased plasma TGs level in MC4RKO mice, and did not affect plasma cholesterol. We therefore investigated if plasma lipids changes affected cardiac metabolism. Interestingly, LXR activation significantly decreased expression of lipogenic factors, such as sterol regulatory element-binding transcription factor 1 (Srebpf1), lysophosphatidylcholine acyltransferase 1 (Lpcat1), fatty acid synthase (Fasn), when compared to WD-fed WT and MC4RKO mice. Interestingly, those changes were correlated with downregulated expression of endoplasmic reticulum stress marker, activating transcription factor 6 (Atf6) and fibrotic marker, expression of collagen 1 (Col1). Summarizing, normalization of lipid metabolism by LXR activation may have protective effect on during obesity by mitigating lipogenesis.

Disclosure

Y. Alfarqani: None. J. Young: Research Support; Merck Sharp & Dohme Corp. Consultant; Metalytics. Stock/Shareholder; Eli Lilly and Company. T. Bednarski: None.
2051-LB: Rhein Targets Macrophage SIRT2 to Promote Adipose Tissue Thermogenesis in Obesity
Authors: ZHOU RUONAN , ZHU ZIWEI , XU PINGYUAN , SHEN LIXUAN , WANG ZIWEI , XUE YINGYING , XIANG YINGYING , CAO YUE , YU XIZHONG , YU JIN , ZHAO JUAN , YAN JING , YANG QIN , FANG PENGHUA , SHANG WENBIN
Published: June 2024

Introduction & Objective: Rhein, a component derived from rhubarb as well as the active metabolite of the anti-osteoarthritis drug diacerein, has been proven to possess strong anti-inflammatory properties. However, the exact mechanism underlying the anti-inflammatory effects of rhein, and the role of rhein in ameliorating obesity remains unclear.

Methods: Diet induced obese (DIO) mice were employed to observe the effects of rhein on metabolism. A macrophage-adipocyte co-culture system was constructed to elucidate the exact mechanism underlying the beneficial effect of rhein on metabolism. Acetylome analysis was performed to screen the acetylation-modifying enzymes regulated by rhein. Surface plasmon resonance assay was used to verify the interaction between rhein and SIRT2. Lyz2-iCre mice injected with rAAV-DIO-shSirt2 were used to verify the durg target of rhein in vivo. PBMCs from patients with obesity receiving diacerein or placebo treatment were collected for acetylation assay.

Results: Rhein mitigated obesity by promoting white adipose tissue thermogenesis in DIO mice, and rhein promoted adipocyte thermogenesis through inhibiting the activation of NLRP3 inflammasome in macrophages. Further study proved that rhein directly interacts with SIRT2 and inhibits NLRP3 inflammasome activation in a SIRT2-dependent way. Myeloid knockdown of Sirt2 abrogated the metabolic benefits induced by rhein in DIO mice. PBMCs from patients with obesity receiving diacerein treatment had significant lower level of acetylation than those from the placebo group.

Conclusion: Rhein promotes adipose tissue thermogenesis by targeting SIRT2 to regulate acetylation-mediated NLRP3 inflammasome activation in macrophages during obesity. Rhein and its derivatives may become potential drug for treating obesity.

Disclosure

R. Zhou: None. Z. Zhu: None. P. Xu: None. L. Shen: None. Z. Wang: None. Y. Xue: None. Y. Xiang: None. Y. Cao: None. X. Yu: None. J. Yu: None. J. Zhao: None. J. Yan: None. Q. Yang: None. P. Fang: None. W. Shang: None.

Funding

National Natural Science Foundation of China (81873060, 81473391 and 82374100); Priority Academic Program Development of Jiangsu Higher Education Institutions (ZYX03KF058); Graduate Research and Innovation Projects of Jiangsu Province (KYCX23_2133 and SJCX23_0728).
2069-LB: ANGPTL7 Promotes Oxidative Stress and Inflammatory Response in HepG2 Cells via Targeting the STAT3-iNOS, COX-2 Signaling Pathway
Authors: GAO QIAN , ZHOU YARU , LIU YAN , LI MIN , GAO MINGMING
Published: June 2024

Objective: Elevated hepatocyte oxidative stress and inflammation may trigger lipid accumulation and promote the formation of NAFLD. As a new member of the ANGPTL family, ANGPTL7 plays an important role in inflammatory responses, angiogenesis and oxidative stress. However, whether ANGPTL7 participates in the pathogenesis of NAFLD still remains unknown. Therefore, in this study, we investigated the role of ANGPTL7 in HepG2 cells.

Methods: HepG2 cells were divided into control group (pcDNA3.1(+)), ANGPTL7 overexpression group (Angptl 7 OE ) and ANGPTL7 overexpression group with STAT3 knockdown group (Angptl 7 OE + si-STAT3). Cell viability was assessed by CCK-8 assay. Cell lipid level was checked by oil red O staining. Cellar IL-6, TNF-α, ROS, MDA, SOD and GSH level were determined by kits. The expression of ANGPTL7, STAT3, iNOS and COX-2 were measured by RT-PCR and western blot.

Results: Compared with CON group, ANGPTL7 overexpression led to elevated cellular IL-6, TNF-α, ROS and MDA, and reduced GSH and SOD, and increased expression of STAT3, iNOS and COX-2, indicating promoted oxidative stress and inflammatory responses. All these alterations caused by ANGPTL7 can be partly reversed by STAT3 knockdown.

Conclusion: Angptl7 could cause oxidative stress and inflammatory response partly via activating STAT3 in HepG2 cells.

Disclosure

Q. Gao: None. Y. Zhou: None. Y. Liu: None. M. Li: None. M. Gao: None.
207-OR: Food Insecurity Patterns and Mental Health among Youth and Young Adults with Diabetes
Authors: ALFALKI ALI M. , JULCEUS EMMANUEL F. , FLORY KATE , MENDOZA JASON A. , MALIK FAISAL , FRONGILLO EDWARD A. , REBOUSSIN BETH A. , BELLATORRE ANNA , DABELEA DANA , PIHOKER CATHERINE , LIESE ANGELA D.
Published: June 2024

Introduction & Objective: We explored the associations of food insecurity (FI) patterns with symptoms of depression, anxiety, stress, and changes therein in youth and young adults (YYA) with type 1 (T1D) and type 2 diabetes (T2D).

Methods: Longitudinal data (2016-2022) from 747 YYA with T1D and 97 with T2D were analyzed using multivariable linear regression. Food security was ascertained with the Household Food Security Survey Module at 3 times (t1, t2, and t3) and patterned as persistently food secure (PFS), persistently food insecure (PFI), and intermittently food insecure (IFI). Mental health at t3 and changes from t2 to t3 were characterized with the Center for Epidemiologic Studies Depression Scale, the Generalized Anxiety Disorder Scale, and Cohen’s Perceived Stress Scale; higher scores indicated greater severity.

Result: Among YYA with T1D, 6.6% experienced PFI and 20.3% IFI; among YYA with T2D, 16.5% were PFI and 42.3% IFI. In T1D, PFI and IFI were associated with greater depressive, anxiety, and stress symptoms at t3 but not with changes. In T2D, PFI was associated with greater depressive symptoms at t3 but not with symptom changes.

Conclusion: Both persistent and intermittent patterns of FI were associated with mental health symptoms, more so for those with PFI, underscoring the critical interplay between FI and mental health symptoms in YYA with diabetes.

Disclosure

A.M. Alfalki: None. E.F. Julceus: None. K. Flory: None. J.A. Mendoza: None. F. Malik: None. E.A. Frongillo: None. B.A. Reboussin: None. A. Bellatorre: None. D. Dabelea: None. C. Pihoker: None. A.D. Liese: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (R01DK117461)
2073-LB: Unveiling the Hidden—Insulin Resistance and Cardiometabolic Risks in Overweight Adolescents
Authors: CHHABRA SAHIL , CHHABRA SARAH , PATIL RANJIT , ARORA SAHIBA , CHHABRA NAMRATA
Published: June 2024

Introduction and Objectives: Adolescent obesity escalates cardiometabolic complications and insulin resistance (IR). While adult IR criteria are clear, their adaptation for adolescents is inconsistent due to standardization challenges. The study aimed to determine the prevalence of insulin resistance and its association with anthropometric measurements, cutaneous indicators, and specific biochemical parameters in overweight and obese adolescents.

Methods: A cross-sectional study was conducted encompassing 182 adolescents aged 10-19. Participants underwent comprehensive assessments, including physical examinations, questionnaires, and biochemical tests.

Results: The study divided participants into normal-weight, overweight, and obese groups. It found high rates of central obesity, hypertension, and hyperglycemia, especially among obese participants. The mean HOMA-IR value stood at 3.5, with 62.6% of participants displaying insulin resistance, more common in males (66.6%) than females (58.6%). Pubertal individuals showed a higher incidence (82.2%). Signs suggesting non-alcoholic fatty liver disease were prominent in overweight and obese groups. In total, 13.18% had metabolic syndrome, with varying degrees of its components present in others.IR was also linked with sleep disturbances, low physical activity, and excessive screen time.

Conclusion: Our study unveiled critical surrogate markers for IR in overweight and obese adolescents. Comprehensive clinical assessments, prompt lifestyle changes, and therapeutic measures are essential in addressing IR and related conditions. Recognizing and responding to these markers early could be fundamental for mitigating associated health risks and optimizing clinical management strategies for overweight and obese adolescents.

Keywords Obesity; Insulin resistance; Adolescence; Dyslipidemia, and Metabolic syndrome

Disclosure

S. Chhabra: None. S. Chhabra: None. R. Patil: None. S. Arora: None. N. Chhabra: None.
2079-LB: Sociodemographic Profile and Obesity—An Indian Perspective
Authors: DESHPANDE NEETA , SINGH NAGENDRA K. , PARIKH RAKESH M. , SAHAY RAKESH K. , AGARWAL SANJAY , KAPOOR NITIN , MAKKAR BRIJ , SREENIVASA MURTHY L.
Published: June 2024

Introduction & Objective: Diverse sociodemographic profiles play a pivotal role in shaping health behaviours. This survey presents the lifestyle habits and health profiles among different socio-economic populations in India.

Methods: A pan-Indian survey using social media and awareness camps, collected demographics, BMI, and health history. responses on BMI perception, lifestyle practices, and obesity awareness. Participants were categorized by residence, education, and occupation.

Results: In a survey of 60,327 individuals with a male-to-female ratio of 1.9, 65% in the age group of 30-60 years (M:F), ~79% from urban/semi-urban areas, 63% were employed (78.4% M). Majority of the students (76.6%) and employed (56.8%) had at least a bachelor’s degree. No schooling was the highest among unemployed (22%) and homemakers (16%). Obesity was higher among home makers (70%) and lowest among students (42%); diabetes, hypertension, high cholesterol was highest among the retired (70.1%, 59.9%, 32.5%), followed by homemakers (67.7%, 45.5%, 25.8%). BMI distribution (overweight, obese) was (44.7%, 3.1%) in rural; (42.2%, 2.8%) in semi-urban and (45.2%, 2.1%) in urban. Longer screen times were in urban [weekdays (3.3% > 10h, 15.1 6-10h) and weekends (3.0% >10h, 16.5% 6-10h)] and students [weekdays (5.9% >10h; 17.6% 6-10h) and weekends (5.6% >10h; 26.5% 6-10h)]. Similarly, for order-in frequency, urban dwellers had at least one meal per week (76.1%) and students (82%) had at least one meal per week and 25% had more than two meals per week. Urban dwellers (57.3%), Students (60%) and employed (58%) individuals liked to exercise for at least 30 min a day. Obesity prevalence remained comparable across education levels (~64-68%), with weight loss efforts and willingness to receive weight loss information increasing with higher education (master’s degree ~35%).

Conclusion: Lifestyle, wellness, and management varies across diverse sociodemographic groups in India.

Disclosure

N. Deshpande: None. R.M. Parikh: None. R.K. Sahay: Speaker's Bureau; Novo Nordisk, Sun Pharmaceutical Industries Ltd., USV Private Limited, Eris Lifesciences Ltd. S. Agarwal: None. N. Kapoor: None. B. Makkar: None. L. Murthy: None.
2096-LB: Mitochondrial DNA Integrity Is Required for ß-Cell Health In Vivo
Authors: DAVIDSON REBECCA K. , ZHU JIE , RECK EMMA C. , SOLEIMANPOUR SCOTT
Published: June 2024

Type 2 diabetes (T2D) is a metainflammatory disease characterized by impairments in mitochondrial function and ultrastructure that contribute to the overall disruption of β-cell function. Mitochondria rely on both the nuclear genome as well as their own 16.6 kilobase-pair circular genome to generate the machinery required for oxidative phosphorylation (OXPHOS). Recently, our group identified a reduction in mitochondrial DNA (mtDNA) copy number in islets from donors with T2D, indicating a disruption in mitochondrial genome stability. While mtDNA genome instability is implicated in several diseases, its impact on β-cell dysfunction in diabetes has yet to be explored. Here, we generated a mouse model prone to increased β-cell mtDNA deletions by selective expression of a dominant negative Twinkle (TwnkK320E) helicase mutant, which is essential for mtDNA maintenance. Beginning at 5 weeks, β-TwnkK320E mice exhibited impaired glucose tolerance, which progressively worsened with age. Circulating insulin concentrations following glucose stimulation were also reduced in β-TwnkK320E mice by 5 weeks of age, yet there was no difference in β-cell mass, suggestive of a β cell functional defect. Further, we observed a complete loss of MafA, a key regulator of β-cell maturity, from a subset of β cells in β-TwnkK320E mice. While mitochondrial mass was unchanged between groups, β‑TwnkK320E islets have altered expression of subunits of all OXPHOS complexes, as well as reduced glucose-stimulated oxygen consumption, indicative of impaired mitochondrial function. Together, these data suggest that the accumulation of mtDNA deletions diminishes β-cell function and support the importance of mitochondrial genome integrity to β-cell health.

Disclosure

R.K. Davidson: Employee; Eli Lilly and Company. J. Zhu: None. E.C. Reck: None. S. Soleimanpour: Advisory Panel; Novo Nordisk. Research Support; Ono Pharmaceutical Co., Ltd.

Funding

National Institutes of Health (T32DK101357)
2098-LB: Identification and Structural Elucidation of a Novel KATP Channel Modulator Demonstrating Dual Pharmacochaperone and Inhibitory Actions
Authors: ELSHEIKH ASSMAA M. , DRIGGERS CAMDEN M. , SHYNG SHOW-LING
Published: June 2024

Introduction & Objectives: Pancreatic KATP channel trafficking defects underlie congenital hyperinsulinism (CHI) cases unresponsive to the KATP opener diazoxide, the mainstay medical therapy for CHI. Current clinically used KATP channel inhibitors have been shown to act as pharmacochaperones (PCs) and restore surface expression of trafficking mutants; however, their therapeutic utility for CHI is hindered by irreversible binding, which limits the functional recovery of rescued channels. Cryo-electron microscopy (Cryo-EM) structures of KATP channels bound to inhibitors offer prospects of structure-guided drug discovery for CHI treatment. The study aims to identify KATP channel PCs with reversible inhibitory effects to enable functional recovery of rescued channels and to elucidate the reversible PC mechanism using cryo-EM.

Methods: Functional and biochemical studies were used to identify a novel compound with PC effects and pancreatic KATP isoform specificity. Single-particle cryo-EM and mutagenesis studies were used to elucidate the mechanisms of the PC and inhibitory actions of this compound.

Results: We identified a novel compound exhibiting robust chaperoning effects on KATP channel trafficking mutations and reversible inhibition of KATP channel function. This PC displayed pancreatic KATP channel specificity and distinct binding features compared to inhibitors with persistent effects.

Conclusion: Our findings unveil a novel KATP PC enabling functional recovery of rescued channels, holding promise for novel therapeutics in CHI caused by KATP trafficking defects.

Disclosure

A.M. ElSheikh: None. C.M. Driggers: None. S. Shyng: None.

Funding

(R01DK066485) to Show-Ling Shyng; (U24GM129547) to PNCC
214-OR: Human Genetic Study of Triglyceride to HDL-C Ratio Adjusted for BMI Identifies New Insulin Resistance-Associated Loci, Genes, Pathways, and Disease Subtypes
Authors: OLIVERI ANTONINO , REBERNICK RYAN , SPELIOTES ELIZABETH K.
Published: June 2024

Introduction & Objective: Insulin Resistance (IR) is heritable and predisposes to cardiometabolic disease, but few causes are known due to limited samples with direct measures of IR.

Methods: To increase power to identify IR-associated loci we carried out a genome wide association study (GWAS) of an indirect marker of IR, the triglyceride to high-density lipoprotein cholesterol ratio (TG:HDL-C) adjusted for BMI (TG:HDL-C adj BMI) in UK Biobank (N=401,090). We used a mixed linear model controlling for age, sex and principal components in SAIGE. Genome wide significant SNPs with effects (FDR < 0.05) on MAGIC Consortium fasting insulin, HOMA-IR and insulin sensitivity were deemed ‘high-confidence IR-associated’ loci (HCIRL). HCIRL tissue, pathway, and gene enrichment analyses were done using DEPICT. A HCIRC polygenic risk score (PRS) was tested for association with ICD-defined Phecodes from the Michigan Genetics Initiative (N=51,527) and results were Bonferroni-adjusted for multiple comparison. PheWAS/FUMA analysis of HCIRL across cardiometabolic traits with hierarchical clustering identified disease subtypes and their biology.

Results: 343 independent SNPs were genome-wide significantly associated with TG:HDL-C adj BMI (p<5e-08); 119 were HCIRL. HCIRL associated genes exhibited enrichment in adipose tissue and adipocytes (all p<3.79e-06) and metabolic syndrome (MetS) affected systems. A HCIRL PRS showed association with MetS-related phenotypes including hyperglyceridemia, hyperlipidemia, hypertension, T2D, coronary atherosclerosis, chronic liver disease and cirrhosis (all padj<5.29e-03). We identify 5 subtypes, highlighting familial hyperlipidemia type 4 and PI3KAKT signaling genes.

Conclusion: HCIRL identify new loci, genes, pathways and disease subtypes. This increases our understanding of the disease and opens up new avenues for identifying and treating subtypes and their complications.

Disclosure

A. Oliveri: None. R. Rebernick: None. E.K. Speliotes: Other Relationship; University of Michigan.

Funding

National Institutes of Health (R01DK106621, R01DK107904, R01DK128871, R01DK131787), The University of Michigan Department of Internal Medicine, MBIOFar
231-OR: Differences in Weight Reduction Efficacy of Tirzepatide in Adults Without vs. With Type 2 Diabetes with Overweight or Obesity in SURMOUNT 1 and 2
Authors: GALINDO RODOLFO J. , TIMOTHY GARVEY W. , NEFF LISA M. , STEFANSKI ADAM , CAO DACHUANG , LEE CLARE
Published: June 2024

Tirzepatide (TZP), a once-weekly GIP and GLP-1 receptor agonist approved in the US for treatment of type 2 diabetes and obesity, led to significant weight reduction (WR) in participants with overweight or obesity without type 2 diabetes (T2D, SURMOUNT (SM)-1) or with T2D (SM-2). Reasons behind higher WR efficacy with obesity treatment observed in people without T2D compared to people with T2D are unknown. We estimated the WR efficacy with TZP in SM-1 vs SM-2 after matching key baseline characteristics. Propensity score matching was used to create a balanced cohort of participants from SM-1 (excluding TZP 5 mg) and SM-2 (excluding those on sulfonylurea or pioglitazone), matched by age, gender, weight, BMI, antidepressant use or depression, and obesity-related comorbidities (ORCs). MMRM was performed to compare the percent of WR at Week 72 between the groups. At baseline, SM-2 cohort was on average older with more males, lower weight, higher HbA1c and higher comorbidity burden, compared to SM-1. The differences in WR remained after balancing baseline characteristics in the propensity matched sample (mean age 51.6 vs 53.9 yrs, females 55% vs 55%, weight 103.3 vs 99.5 kg and ≥2 ORCs 85% vs 85%) (FIG). The differences in WR efficacy with TZP between the SM-1 and SM-2 studies persisted after matching key baseline characteristics suggesting additional contributing factors.

Disclosure

R.J. Galindo: Consultant; Abbott. Other Relationship; Dexcom, Inc. Consultant; Bayer Inc. Other Relationship; Novo Nordisk, Eli Lilly and Company. Consultant; Boehringer-Ingelheim, AstraZeneca. W. Garvey: Advisory Panel; Novo Nordisk, Eli Lilly and Company, Boehringer-Ingelheim, Inogen, Zealand Pharma A/S, Alnylam Pharmaceuticals, Inc., Pfizer Inc., Merck & Co., Inc., Fractyl Health, Inc., Allurion. Research Support; Novo Nordisk, Eli Lilly and Company, Epitomee, Neurovalens, Pfizer Inc. Consultant; Boehringer-Ingelheim, Eli Lilly and Company. L.M. Neff: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. A. Stefanski: Employee; Eli Lilly and Company. D. Cao: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. C. Lee: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
238-OR: Effect of Baseline Antihyperglycemic Medications on Weight Reduction with Tirzepatide—SURMOUNT-2 Subgroup Analysis
Authors: MACHINENI SRIRAM , JAOUIMAA FATIMA-ZAHRA , GRIFFIN RYAN , ZHANG MICHELLE X. , FRASEUR BRUMM JULIA
Published: June 2024

Background: Antihyperglycemic medication (AHM) may influence body weight causing weight gain or weight reduction. In SURMOUNT-2, tirzepatide, a once weekly GIP/GLP-1 receptor agonist, resulted in significantly greater weight reduction compared to placebo in participants with BMI ≥27 kg/m2 and type 2 diabetes. We conducted a subgroup analysis to explore the association between the weight-reduction efficacy of tirzepatide and concomitant AHMs at randomization categorized as promoting weight loss (WL), weight gain (WG), or weight neutral (WN).

Methods: A mixed model for repeated measures assessed the change in body weight from randomization to endpoint (week 72). Logistic regression was conducted to analyze the proportion of participants achieving ≥5%, ≥10%, and ≥15% weight reduction targets at endpoint.

Results: At baseline, mean weight was 95.7, 100.6, and 101.8 kg and BMI was 34.5, 36.0, and 36.4 kg/m2 in the WL, WG, and WN subgroups, respectively. Tirzepatide resulted in significantly greater weight reduction than placebo in all AHM subgroups (all p<0.001). No differences were observed among tirzepatide-treated AHM subgroups in the percent change in body weight and the proportion of participants achieving weight reduction targets.

Conclusion: Tirzepatide was superior to placebo for weight reduction and showed similar weight reduction efficacy across AHM subgroups.

Disclosure

S. Machineni: Research Support; Eli Lilly and Company. Advisory Panel; Eli Lilly and Company. Consultant; Novo Nordisk. Research Support; Rhythm Pharmaceuticals, Inc. Consultant; Rhythm Pharmaceuticals, Inc. F. Jaouimaa: Employee; Eli Lilly and Company. R. Griffin: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M.X. Zhang: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. J. Fraseur Brumm: None.

Funding

Eli Lilly and Company
239-OR: CGM Has a Specific Effect on the Reduction of Nocturnal Hypoglycemia in People with Type 1 Diabetes on an MDI Treatment Regimen
Authors: HERMANNS NORBERT , EHRMANN DOMINIC , KULZER BERNHARD , FRECKMANN GUIDO , HEINEMANN LUTZ
Published: June 2024

MDI users with type 1 diabetes may be less able to respond to circadian changes in insulin demand than CSII or AID users, which may increase the risk of nocturnal hypoglycemia. Therefore, we re-analyzed data from the HYPO.DE RCT to evaluate the effect of CGM on the percentage of low glucose levels < 70 mg/dl (% < 70 mg/dl) and < 54 mg/dl (% < 54 mg/dl) during 12 two-hour periods throughout the day. We compared 4-week baseline data from 141 participants using spot glucose monitoring (SMBG) with 4-week outcome data after a 6-month follow-up period in which the control group (n=66) remained on SMBG and the intervention group (n=75) used CGM (Dexcom G5). At baseline without CGM, there were significantly higher proportions of %<70 mg/dl or %54 mg/dl during the night (00:00 am - 06:00 am) than during the day (8.5 ±1.0% vs. 6.5 ±0.6%, p<0.001 respectively 4.0 ±0.6% vs. 2.4 ±0.3%, p<0.001). CGM had a greater effect on nocturnal hypoglycemia than on daytime hypoglycemia (see Figure 1). The greatest reduction in favor of the CGM users was between 04:00 a.m. and 06:00 a.m., with a between-group difference of -8.5% (95% CI -10.4% to -6.7%, p<.001) for %<70 mg/dl and -5.5% (95% CI 4.4 - 6.6%, p<.001) for %<54 mg/dl. The data suggest that CGM provides benefits to MDI users with type 1 diabetes in preventing nocturnal hypoglycemia, potentially compensating for lack of responsiveness to a circadian changing insulin demand.

Disclosure

N. Hermanns: Speaker's Bureau; Berlin-Chemie AG, Sanofi-Aventis Deutschland GmbH. Research Support; Sanofi-Aventis Deutschland GmbH. Speaker's Bureau; Roche Diabetes Care. Research Support; Roche Diabetes Care. Speaker's Bureau; Dexcom, Inc. Advisory Panel; Abbott Diagnostics, Ypsomed AG. D. Ehrmann: Advisory Panel; Dexcom, Inc. Speaker's Bureau; Dexcom, Inc., Sanofi-Aventis Deutschland GmbH. Advisory Panel; Roche Diabetes Care. Speaker's Bureau; Roche Diabetes Care, Berlin-Chemie AG. B. Kulzer: Advisory Panel; Abbott Diagnostics, Berlin-Chemie AG, Dexcom, Inc., Sanofi, embecta, Novo Nordisk, Roche Diabetes Care. Speaker's Bureau; Bayer Inc., Insulet Corporation, Lilly Diabetes. G. Freckmann: Advisory Panel; Abbott. Research Support; Ascensia Diabetes Care. Advisory Panel; Boydsense, Dexcom, Inc., Lilly Diabetes. Speaker's Bureau; Novo Nordisk. Advisory Panel; Perfood, PharmaSens. Consultant; Roche Diabetes Care. Research Support; Roche Diabetes Care. Consultant; Sinocare. Speaker's Bureau; Terumo Corporation. Consultant; Ypsomed AG. L. Heinemann: Stock/Shareholder; Science Consulting in Diabetes GmbH, Profil Institut für Stoffwechselforschung GmbH. Advisory Panel; embecta. Board Member; Lifecare A/S. Stock/Shareholder; diateam GmbH.

Funding

The HYPO.DE study was funded by Dexcom, San Diego
24-OR: Inaccurate and Unaware—Perceived and Objective Diabetes Knowledge among Adults with Type 2 Diabetes
Authors: CLAYTON COLTER K. , LEE AARON A.
Published: June 2024

Introduction & Objective: A substantial body of research among healthcare professionals has demonstrated modest correlations between perceived and objective diabetes knowledge and the potential impact on diabetes management. However, no research has compared perceived and objective knowledge among patients with diabetes. The objective of this study was to examine the strength of the linear and quadratic relationships between perceived and objective diabetes knowledge among adults with type 2 diabetes.

Methods: Two separate and independent samples of adults with type 2 diabetes were collected from a web-based panel. This cross-sectional study examined objective knowledge with the Diabetes Knowledge Test-2 (DKT-2) and patient self-reported knowledge using the novel Perceived Diabetes Knowledge Scale (PDKS). For both samples, linear regression analysis was performed to examine the linear and quadratic relationships between perceived diabetes knowledge and objective diabetes knowledge. Control variables (education level, diabetes duration, and prior diabetes education) were entered in step 1. The linear and quadratic terms for perceived diabetes knowledge variables were entered in steps 2 and 3, respectively.

Results: Study sample 1 (N = 321) and 2 (N = 255) were older (M = 64 and 69 years) and primarily White (85.7%, 89.0%). The PDKS demonstrated strong internal consistency reliability in samples 1 and 2 (α = .86, α = .87). The linear regression terms in samples 1 and 2 accounted for 5.6% and 5.2% of the variance in objective diabetes knowledge (ps < .05) after controlling for covariates entered in step 1. The quadratic terms were not significant in sample 1 or 2.

Conclusion: Patient perceived knowledge is weakly related to their objective diabetes knowledge. Healthcare professionals should not rely on patients’ self-report of their diabetes self-management knowledge and instead, use objective assessment (e.g., DKT-2) to determine patients' diabetes knowledge.

Disclosure

C.K. Clayton: None. A.A. Lee: None.
245-OR: Proteomic Analysis of Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA)—Results and Integrated Predictors of Response
Authors: VERGARA-MARTEL ARMANDO , DAZARD JEAN-EUDES , DOBRE MIRELA , CONNELLY KIM A. , EDWARDS-GLENN JONNELLE , TENSOL GABRIEL , CAMERON CHERYL , CAMERON MARK , AL-KINDI SADEER G. , BROOK ROBERT D. , WEIR MATTHEW R. , RAJAGOPALAN SANJAY
Published: June 2024

Background: Mineralocorticoid receptor (MR) antagonists (MRA) benefit patients with diabetic chronic kidney disease (CKD) and heart failure, and may act upstream on multiple cardioprotective pathways. The NHLBI-sponsored MAGMA trial, a 12-month, randomized, double-blind, placebo-controlled trial compared Spironolactone vs. placebo in Type 2 diabetics with CKD stages 3-4 on maximal renin-angiotensin system blockade and a prior atherosclerotic event and/or left ventricular (LV) hypertrophy.

Methods: Seventy-nine patients were randomized to Spironolactone 25 mg (n = 37) or placebo (n = 42) for 12 months. The primary outcome was % change in total aortic wall volume (TWV) at 12 months by magnetic resonance imaging (MRI). Baseline, 3-month, and 12-month plasma samples were measured for 7,596 protein biomarkers. We used the general linear hypothesis framework and Linear mixed-effect models to generate lists of differentially expressed proteins by effect. A multi-visit matching approach was used to model the association of proteomic expression changes with TWV changes. We fit a Mixed Multivariate Random Forest model to take the experimental design into account and build predictive proteomic predictors associated with primary outcome changes of TWV.

Results: Patients had a mean age of 64±8 years with 50% African Americans and 46% women. Spironolactone reduced PWV versus placebo. Plasma proteome revealed downregulation of MR targets including fibrosis, immune activation/inflammation, leukocyte activation, proliferation and pathways involved in cytokine stimulation. Predictors of plaque progression involved cytokine-receptor, complement-coagulation, cell adhesion and axonal guidance targets.

Conclusions: The changes in plasma proteomic profile with Spironolactone were consistent with downregulation in multiple inflammatory, immune response and profibrotic pathways.

Disclosure

A. Vergara-Martel: None. J. Dazard: None. M. Dobre: None. K.A. Connelly: Research Support; AstraZeneca. J. Edwards-Glenn: None. G. Tensol: None. C. Cameron: None. M. Cameron: None. S.G. Al-Kindi: None. R.D. Brook: Advisory Panel; Alnylam Pharmaceuticals, Inc. M.R. Weir: Advisory Panel; AstraZeneca, Bayer Inc., Novo Nordisk, Vifor Pharma Management Ltd., Boehringer-Ingelheim. S. Rajagopalan: Consultant; Novo Nordisk, Bayer Inc.

Funding

NHLBI