bluuebunny/crossref_metadata_2025_split huggingface dataset:
275-OR: Associations of Combined Genetic and Lifestyle Risks with Incident Type 2 Diabetes in the UK Biobank
Authors: SPRACKLEN CASSANDRA N. , ZHAO CHI , BERTONE-JOHNSON ELIZABETH , CAI NA , HUANG LIANYUN , JANICZEK MARGARET , HYUN LEE CHI , MA CHAORAN , PALUCH AMANDA , STURGEON SUSAN , VANKIM NICOLE 
Published: June 2024

To determine whether unhealthy lifestyle behaviors were associated with similar increases in the risk of incident T2D among individuals with low, intermediate, and high genetic risk, we performed a genetic risk score (GRS) by lifestyle interaction analysis within 460,133 individuals from the UK Biobank. Multi-ancestry GRS were calculated by summing the effects of 1,286 T2D-associated variants (number of risk alleles multiplied by the reported effect size); low, intermediate, and high GRS were defined by tertiles of GRS. We used baseline self-reported data on smoking, BMI, physical activity, and diet to categorize participants as having an ideal, intermediate, or poor level of lifestyle factors. Cox proportional hazards regression models were used to generate adjusted hazards ratios (HR) and associated 95% confidence intervals (95% CI). During follow-up (median 8.9 years), 21,569 (4.7%) participants developed T2D. GRS (P&lt;2e-16) and lifestyle classification (P&lt;2e-16) were independently associated with increased risk for T2D. Compared with “ideal” lifestyle, “poor” lifestyle was associated with substantially increased risk in all genetic risk strata, with HR ranging from 7.5 to 29.5 (Figure 1). Overall, high genetic risk and poor lifestyle were the strongest risk factors for incident T2D. Individuals at all levels of genetic risk greatly mitigate their risk through their behavioral lifestyle.

Disclosure
C.N. Spracklen: None. C. Zhao: None. E. Bertone-Johnson: None. N. Cai: None. L. Huang: None. M. Janiczek: None. C. Lee: None. C. Ma: None. A. Paluch: None. S. sturgeon: None. N. VanKim: None.

Funding
American Diabetes Association (11-22-JDFPM-06)
285-OR: m6A carRNA Methylation Regulates Chromatin State and Transcription in Islets from Humans with Type 2 Diabetes
Authors: SHUKLA NAMRATA , JU CHENG-WEI , HE CHUAN , KULKARNI ROHIT 
Published: June 2024

RNA N6-methyladenosine (m6A) is among the most abundant mRNA modifications in mammals. Seminal work from our lab has reported that the “writers” of m6A (e.g. methyltransferase-like [METTL3] and METTL14) are significantly downregulated in islets of humans with type 2 diabetes (T2D). Consequently, the global m6A landscape in the islets segregates the T2D from the control group significantly better than the transcriptome (n=7 for Control and n=8 for T2D islets). Hypomethylation of key transcripts in the insulin/IGF-1-AKT-PDX1 pathway impaired insulin secretion and decreased β-cell proliferation. We now show this decreased m6A on RNA is not limited to the mRNA but also affects chromatin-associated regulatory RNAs (carRNA). carRNAs, which include promoter- and enhancer-associated RNAs as well as several non-coding repeat elements have been previously shown to regulate gene expression in an m6A-dependent manner. Intriguingly, downregulation of METTL3 and METTL14 in human β-cell line EndoC-βH1 differentially regulates these regulatory versus protein-coding transcripts. We observe that while METTL14 KD causes global downregulation of transcripts belonging to pathways important for β-cell identity and function (including calcium signaling, PI3K-AKT/MAPK signaling pathway, pancreatic secretion etc.), it leads to an upregulation of pathways involved in RNA processing and global gene transcription (Transcription by RNA Pol II, metabolism and splicing of mRNA, chromatin organization and modification etc.) {false discovery rate (FDR) &lt; 0.05}. Considering carRNAs have been previously reported to regulate global chromatin accessibility and transcription, our observations on their ability to get differentially regulated m6A writer proteins provide novel insights into the epigenetic regulation of human islet cells. These findings provide opportunities to develop therapeutic approaches to regulate β-cell identity and/or insulin secretion in T2D.

Disclosure
N. Shukla: None. C. Ju: None. C. He: None. R. Kulkarni: Advisory Panel; Novo Nordisk, Biomea Fusion, Inc. Consultant; Inversago Pharma. Advisory Panel; REDD Pharmaceutical.

Funding
R01 DK067536
294-OR: The Role of Inositol Polyphosphate Multikinase in Progression of Nonalcoholic Steatohepatitis
Authors: JUNG IKRAK , ANOKYE-DANSO FREDERICK , AHIMA REXFORD , KIM SANGWON F. 
Published: June 2024

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease globally, ranging from simple steatosis to the advanced stage of nonalcoholic steatohepatitis (NASH). Despite ongoing clinical trials exploring NAFLD treatments, there are currently no approved therapies. We have reported that inositol polyphosphate multikinase (IPMK), a crucial enzyme in inositol polyphosphate biosynthesis, is involved in regulating hepatic insulin signaling both in vitro and in vivo. Given the central role of Insulin resistance in the progression of NAFLD, and implicated in disease progression from steatosis to NASH, we examined how IPMK contributes to the progression of NAFLD/NASH. To investigate the role of IPMK in NAFLD/NASH, we explored the impact of IPMK on lipid metabolism by studying primary mouse hepatocytes (PMH) from wild-type (WT) and liver-specific IPMK knockout (LKO) mice after treating free fatty acids (FFA). Moreover, we subjected both WT and liver-specific IPMK knockout LKO mice to a high-fat diet (HFD) or a methionine-choline deficient diet (MCDD). Here, we demonstrate that an excess of FFA reduces IPMK protein levels and enhances lipid accumulation in PMH. In addition, loss of IPMK leads to a significant increase in lipid accumulation compared to WT. Consistent with PMH, IPMK protein levels decreased in the liver from WT mice fed both HFD and MCDD compared to a normal chow diet (ND). In both HFD and MCDD conditions, LKO mice showed a significant increase in triglycerides (TG) and elevated expression of pro-inflammatory genes compared to their WT mice. Notably, LKO mice exhibited worsened MCDD-induced NAFLD/NASH, as evidenced by elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), along with hepatic TG accumulation, fibrosis, and increased pro-inflammatory gene expression. Our results demonstrate that loss of IPMK mediates the progression of NAFLD/NASH and may be potentially targeted for the treatment of NAFLD/NASH.

Disclosure
I. Jung: None. F. Anokye-Danso: None. R. Ahima: None. S.F. Kim: None.
297-OR: A Novel GLP-1/FGF21 Dual Agonist ZT003 Has Therapeutic Potential for Obesity, Diabetes, and Nonalcoholic Steatohepatitis
Authors: ZHANG YUANYUAN , ZHANG YUYING , ZHAO CHUNLAI , LIN SIMEI , GUO WEI , WU BO 
Published: June 2024

Introduction: Combining two mechanisms (GLP-1 and FGF21) can deliver synergistic and complementary functions. ZT003 is a novel long-acting GLP-1/FGF21 dual agonist, and in this study, its therapeutic potential has been explored in animal models.
Methods: In vitro GLP-1 and FGF21 activities of the fusion protein were measured using a BHK cell line overexpressing human GLP-1 receptor and a HEK293 cell line overexpressing human beta-Klotho. In vivo tests were carried out in DIO mice, db/db mice and NASH mice to demonstrate the pharmacological efficacy of ZT003 on body weight, food intake, plasma glucose, circulating lipids, liver fat content, NAS score and other metabolic parameters as compared to the benchmark molecules. The pharmacokinetic parameters were measured in non-human primates.
Results: ZT003 is an engineered dual agonist fusion protein comprising GLP-1, anti-HSA nanobody (for half-life extension) and FGF21 conjugated with a small molecule to prevent C-terminal degradation. In cell-based assays, ZT003 showed an optimal GLP-1/FGF21 activity ratio. When tested in DIO obese mice and db/db diabetic mice, ZT003 demonstrated synergistic, sustained, and superior body weight reduction and glucose-lowering effect versus semaglutide, tirzepatide and YH25724. When tested in DIO NASH mice, ZT003 significantly improved lipid metabolism, hepatic steatosis, and liver histology, all of these effects being greater than semaglutide. The pharmacokinetic study in cynomolgus monkeys demonstrated the half-life of ZT003 is comparable to that of semaglutide, indicative that ZT003 is likely to be amenable for once-weekly dosing in humans.
Conclusion: In conclusion, this novel GLP-1/FGF21 fusion protein in animals reveals therapeutically efficacious to treat obesity, diabetes, NASH and related co-morbidities, thus demonstrating the promise of the poly-pharmaceutical approach in metabolic drug discovery and development.

Disclosure
Y. Zhang: Employee; QL Biopharmaceutical Co. Ltd. Y. Zhang: None. C. Zhao: Employee; Beijing QL Biopharmaceutical Co., Ltd. S. Lin: None. W. Guo: Employee; Beijing QL Biopharmaceutical Co., Ltd. B. Wu: Employee; Beijing QL Biopharmaceutical Co. Ltd.
3-OR: Lipoprotein(a) Levels and Epicardial Adipose Tissue in Diabetes—Unraveling Novel Connections
Authors: COSSON EMMANUEL , TATULASHVILI SOPIO , BIHAN HELENE , BOUBAYA MAROUANE , GALLO ANTONIO 
Published: June 2024

Introduction & Objectives: While extremely high levels of lipoprotein (a) [Lp(a)] are associated with an increased risk of cardiovascular disease, very low levels of Lp(a) have been associated with an increased risk of diabetes. The underlying mechanisms explaining this association are still unknown. Epicardial adipose tissue (EAT) is increased in diabetes and predicts the development of coronary artery disease and heart failure. This study aimed at evaluating the correlation between Lp(a) and EAT in subjects living with diabetes.
Methods: We collected clinical data from 1,093 subjects living with diabetes in a monocentric retrospective observational study. Patients were included if they were in primary prevention, had had a measurement of Lp(a) and computed tomography (CT) for coronary artery calcium score quantification. Volumetric quantification of EAT was performed on CT images.
Results: We included 649 people living with diabetes (76.3% T2DM, 16.5% T1DM, 7.2% others) for 13.5±9.6 years, body mass index (BMI) 29.3±6.0 kg/m², HbA1c 8.9±2.3%, EAT volume 91±41 cm3. EAT volume and Lp(a) levels were correlated (r=-0.2, p&lt;0.0001). High Lp(a) levels, defined as &gt;30 mg/dl (n=227, 35%), were more frequent in women and people from sub-Saharan Africa, and associated with higher HDL (p&lt;0.001) and LDL cholesterol (p&lt;0.01), lower triglycerides (p&lt;0.001) and lower EAT volume (91±36 vs. 97±42 cm3, p&lt;0.001)). EAT volume decreased with increasing quartiles of Lp(a) (p&lt;0.001). After adjustment for age, sex, ethnic origin, type of diabetes, triglycerides, LDL and HDL cholesterol, EAT volume remained negatively associated with higher Lp(a) levels (per 10 cm3: odds ratio 0.93 [95% confidence interval 0.88-0.99], p&lt;0.05).
Conclusions: Low Lp(a) is associated with higher EAT volume in asymptomatic subjects living with diabetes. These exploratory results provide pivotal insights into the unexplored dynamics between Lp(a) levels and diabetes that deserve further exploration.

Disclosure
E. Cosson: Advisory Panel; Abbott, AstraZeneca, Lilly Diabetes, Novo Nordisk, Sanofi, Roche Diagnostics, Novartis AG, Amgen Inc. S. Tatulashvili: None. H. Bihan: None. M. Boubaya: None. A. Gallo: Consultant; Akcea Thearpeutics, Inc. Speaker's Bureau; Amarin Corporation. Consultant; Amgen Inc. Advisory Panel; Amryt Pharma Plc. Research Support; Eli Lilly and Company, Ionis Pharmaceuticals. Consultant; Novartis Pharmaceuticals Corporation, Sanofi. Speaker's Bureau; Servier Laboratories. Board Member; Ultragenyx.
302-OR: The Antimyostatin Antibody SRK-439 Promotes Healthy Body Composition in Combination with GLP-1RAs in a Mouse Model of Obesity
Authors: FULHAM MELISSA A. , CHAPRON CHRISTOPHER , DANEHY FRANCIS T. , STREICH FREDERICK C. , LIANG BRIAN , BOSTON CHRISTOPHER J. , JACKSON JUSTIN W. , HUANG YAN , NICHOLLS SAMANTHA E.B. , CORTES LESLIE , QATANANI MO 
Published: June 2024

One of the challenges with obesity treatments is maintaining a healthy body composition during weight loss; lean mass is reduced during weight loss (15%-40% of total weight lost) which may impact long-term durability and health benefits. Identifying an agent that safely maintains lean mass during obesity treatments could be key to sustainable, healthier weight management and improve cardiometabolic outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective treatments for obesity but cause considerable lean mass loss and are often discontinued due to adverse effects. Upon withdrawal, weight is regained and cardiometabolic benefits are reversed. We hypothesized that inhibiting myostatin, a negative regulator of muscle mass, during GLP-1RA-induced weight loss would maintain lean mass and result in a favorable body composition after GLP-1RA withdrawal. SRK-439 is a selective anti-pro and latent myostatin antibody that increases lean mass in mice. We tested SRK-439 in combination with the GLP-1RA semaglutide (sema) in a mouse model of diet-induced obesity (DIO). DIO mice were treated concurrently with either SRK-439 or an IgG control and sema for four weeks, sema was withdrawn, and antibody treatment was maintained for an additional four weeks. Body weight and body composition were assessed. As expected, sema treatment reduced body weight and lean mass. Animals regained their body weight two weeks after withdrawal. However, mice that received SRK-439 were protected against lean mass loss during sema treatment. Importantly, SRK-439 treatment attenuated the fat mass rebound after sema withdrawal. Mice that received sema + SRK-439 had 18.0% body fat, compared to 28.7% in the sema + IgG group (p&lt;0.05) and circulating leptin was lower in the sema + SRK-439 group when compared to the sema + IgG group (21.7 vs 37.9 ng/mL, p&lt;0.01). These results demonstrate that SRK-439 maintains a healthy body composition during GLP-1RA-induced weight loss.

Disclosure
M.A. Fulham: Employee; Scholar Rock, Inc. Stock/Shareholder; Scholar Rock, Inc. C. Chapron: Employee; Scholar Rock, Inc. F.T. Danehy: Other Relationship; Scholar Rock, Inc. F.C. Streich Jr.: Employee; Scholar Rock. Stock/Shareholder; Centessa, Cybin, Gritstone, Seres. B. Liang: Employee; Scholar Rock. Stock/Shareholder; Scholar Rock. C.J. Boston: Employee; Scholar Rock, Inc. Stock/Shareholder; Scholar Rock, Inc. J.W. Jackson: Employee; Scholar Rock, Inc. Stock/Shareholder; Scholar Rock, Inc. Y. Huang: Employee; Scholar Rock, Inc. Stock/Shareholder; Scholar Rock, Inc. S.E.B. Nicholls: Employee; Scholar Rock, Inc. Stock/Shareholder; Scholar Rock, Inc. L. Cortes: Employee; Scholar Rock. Stock/Shareholder; Scholar Rock. M. Qatanani: Employee; Scholar Rock.
313-OR: Metoclopramide Improves Hypoglycemic Counterregulation in Diabetic Rats
Authors: DEVORE MICAH H. , ILES ASHLEY , SCHOEDER LILY A. , MUSIC MEGAN B. , PATEL BANSI , MARKSBURY ASHLEE R. , WOOTEN MASON , THOMPSON ANDREA , BECKNER ZACH , MACON ERICA L. , FISHER SIMON J. 
Published: June 2024

Introduction & Objective: To investigate the potential of metoclopramide, a dopamine antagonist, in mitigating impaired hypoglycemic counterregulation in a diabetic animal model.
Methods: Diabetes was induced in 10-week-old Sprague-Dawley rats with streptozotocin (STZ, 65 mg/kg IP). Rats were randomized into three groups: 1) diabetic controls treated with recurrent saline (STZ+RS, n=6), 2) diabetic rats preconditioned with recurrent hypoglycemia (STZ+RH, n=7), and 3) diabetic rats preconditioned with recurrent hypoglycemia and metoclopramide (STZ+RH+MET: 3mg/kg IP, n=7). Following 3 days of preconditioning, all animals underwent a hyperinsulinemic (50mU/kg/min) hypoglycemic (~45 mg/dl) clamp.
Results: Glucose infusion rates to maintain hypoglycemia for STZ+RS (19±0.8 mg/kg/min) were higher in STZ+RH (27±0.9 mg/kg/min, p&lt;0.0001 vs STZ+RS) and then reduced in STZ+RH+MET (24±0.1 mg/kg/min, p&lt;0.05 vs STZ+RH). The glucagon response to hypoglycemia in control STZ+RS (p&lt;0.05 vs basal) was abrogated in STZ+RH (p=NS vs basal) and restored in STZ+RH+MET (p&lt;0.05 vs basal).
Conclusions: In this model of insulin deficient diabetes, the detrimental effect of recurrent hypoglycemia on glucoregulatory and counterregulatory hormonal response to hypoglycemia was reversed with metoclopramide treatment. It is concluded that the impaired response to hypoglycemia may be regulated via dopaminergic signaling.

Disclosure
M.H. Devore: None. A. Iles: None. L.A. Schoeder: None. M.B. Music: None. B. Patel: None. A.R. Marksbury: None. M. Wooten: None. A. Thompson: None. Z. Beckner: None. E.L. Macon: None. S.J. Fisher: None.

Funding
R01DK1180825T32DK0913171R25DK1098941T32DK110966
318-OR: Podocyte-Specific Expression of REDD1 Promotes Altered Glomerular Pathology and Renal Function Deficits in a Rodent Model of Diabetic Nephropathy
Authors: SUNILKUMAR SIDDHARTH , TORO ALLYSON , YERLIKAYA ESMA I. , DENNIS MICHAEL D. 
Published: June 2024

Introduction & Objective: The pathogenesis of diabetic nephropathy (DN) is complex and multi-factorial; however, it is well accepted that podocyte injury and death are crucial factors in the development of renal complications. We previously observed that the stress response protein REDD1 (Regulated in Development and DNA Damage 1) is required for podocyte apoptosis and renal function deficits in DN. Herein, we investigated the hypothesis that diabetes-induced REDD1 expression specifically in podocytes contributes to podocyte foot process effacement and subsequently compromises glomerular filtration function in DN.
Methods: REDD1fl/fl and podocyte specific NPHS2-cre REDD1 knockout (REDD1podKO) mice were administered low dose streptozotocin to induce diabetes. Spot urine albumin and creatinine levels were assayed. Kidneys were removed after 16 weeks of diabetes, weighed, and analyzed for protein and mRNA expression. Similar analyses were performed on isolated glomeruli. Kidneys were also processed for immunofluorescence (IF) and electron microscopy.
Results: Diabetic REDD1fl/fl mice exhibited increased REDD1 mRNA and protein expression in renal homogenates and in isolated glomeruli. IF microscopy showed reduced expression of the podocyte slit diaphragm protein podocin in diabetic REDD1fl/fl but not in REDD1 podKO mice. Podocyte-specific REDD1 deletion prevented altered glomerular ultrastructure changes including increased glomerular basement membrane thickness and podocyte foot process width that was observed in diabetic REDD1fl/fl mice. Importantly, deletion of REDD1 in podocytes attenuated diabetes-induced albuminuria.
Conclusion: Overall, the findings provide new insight into the role of podocyte REDD1 expression in regulating renal pathology and function and support the possibility that therapeutics targeting podocyte REDD1 could be beneficial in the context of DN.

Disclosure
S. Sunilkumar: None. A. Toro: None. E.I. Yerlikaya: None. M.D. Dennis: None.

Funding
American Diabetes Association (11-23-PDF-84); National Institutes of Health (R01 EY029702 and R01 EY032879)
327-OR: Does Exercise in Cool Water Result in a Greater Decrease in Blood Glucose Concentration than Exercise in Thermoneutral Water or on Land in People with Type 1 Diabetes?
Authors: ABRAMOFF KRISTINA , MALONEY SHANE K. , JONES TIM , DAVIS ELIZABETH A. , FOURNIER PAUL A. 
Published: June 2024

Introduction: It is unclear whether exercise in cool water, typical of many popular beaches, increases the risk of hypoglycaemia in individuals with type one diabetes mellitus (T1DM).
Objective: To test the hypothesis that exercise in cool water results in a greater decrease in blood glucose concentration than does exercise in thermoneutral water or on land in individuals with T1DM.
Methods: Eight overnight-fasted individuals (aged 18 to 40 years) with T1DM completed 3 x 60-min cycling sessions on an ergometer at 40% of their on-land V̇O2peak under the following conditions; while immersed in cool water (22°C), in thermoneutral water (32°C) or on land at thermoneutrality (22°C). At regular time intervals, the following variables were measured: concentration of blood glucose and plasma insulin, skin blood flow and skin temperature, and rate of carbohydrate and fat oxidation.
Results: Blood glucose concentration did not change during cycling in cool or thermoneutral water (p&gt;0.05), but decreased during cycling on land (p&lt;0.05). During 60 minutes of on-land recovery at 24°C after cycling in cool water, blood glucose concentration increased significantly (~2 mmol/L, p&lt;0.05), but not after cycling in thermoneutral water or on-land. The concentration of plasma insulin decreased during and early after cycling in cool water (p&lt;0.05).
Conclusion: Exercise in cool water in people with type 1 diabetes mellitus does not cause a greater decrease in blood glucose concentration than does exercise in thermoneutral water or on land, but increases blood glucose early during on-land recovery probably as a result of a transient decrease in plasma insulin concentration.

Disclosure
K. Abramoff: None. S.K. Maloney: None. T. Jones: None. E.A. Davis: None. P.A. Fournier: None.
351-OR: Role of Mef2a in Beta-Cell Differentiation and Function during ER Stress
Authors: SHARMA ROHIT B. , DARKO CHRISTINE O. , WANG YING 
Published: June 2024

Introduction and Objective: Short-term ER stress engages adaptative unfolded protein response (UPR) associated with higher β-cell function and proliferation. Chronic ER stress or decompensated UPR leads to loss of b-cell identity and function and causes death, ultimately leading to diabetes. The objective of this study was to identify genes and pathways responsible for this UPR switch from adaptive to decompensated.
Methods: To define UPR states, we performed bulk RNA seq using three different models: 1) Mild UPR (High glucose-increased β-cell proliferation, maturity, and function), 2) Medium UPR (Atf6 activation-increased β-cell proliferation and loss of maturity but no death), 3) Decompensated UPR (Grp78 knockdown- no change in β-cell proliferation, increased de-differentiation, and death).
Results: We performed bulk RNA sequencing on mouse primary islet cells. Our RNA seq data identified myocyte enhancer factor 2a (Mef2a) as a novel transcription factor dysregulated during decompensated ER stress. Mef2a is a Ca2+-regulated gene which senses Ca2+ changes in the cells. Our data shows that overexpression of Mef2a causes β-cell de-differentiation, resulting in the loss of insulin secretion. ER stress caused by Thapsigargin (Tg) and Tunicamycin (Tm) increased Mef2a activity, β-cell de-differentiation, and loss of function. Knockdown of Mef2a partially and fully rescued β-cell de-differentiation and loss of function caused by Tg and Tm, respectively.
Conclusion: Mef2a could act as a molecular switch sensing Ca2+ changes during continuous β-cell ER stress, leading to its hyperactivity. This study shows that Mef2a knockdown rescued the loss of β-cell identity and function under decompensated ER stress.

Disclosure
R.B. Sharma: None. C.O. Darko: None. Y. Wang: None.

Funding
Institutional Startup Fund