bluuebunny/crossref_metadata_2025 huggingface dataset:
25-PUB: Exploratory Post Hoc Analysis of Effect of GlucoLo Plus on Renal Function in the GLEEN Randomized Trial—Efficacy and Safety of GlucoLo Plus in Type 2 Diabetes Management
Authors: ZARRUK ALEXANDRO R.
Published: June 2024

Introduction & Objective: GlucoLo Plus is a Complementary and Alternative Medicine (CAM) that has shown clinically significant HbA1c reduction of 0.843% in the GLEEN trial, a previously reported double-blind randomized placebo-controlled trial that evaluated the efficacy and safety of daily GlucoLo Plus. The renal data will now be presented.

Methods: The GLEEN Study was composed of 60 individuals with type 2 diabetes with a mean HbA1c 6.98% [52.8 mmol/mol], mean age 67.3 years [SD 9.5], 26 [43%] women, mean diabetes duration was 3.2 years, and mean body mass index 27.9 kg/m2. Participants were randomly assigned to GlucoLo Plus (n=32 [53%]), or placebo (n=28 [47%]). The renal safety was evaluated by measuring the serum Creatinine and urinary Albumine-to-Creatinine ratio (uACR) and by calculating the estimated Glomerular Filtration Rate (eGFR) with the Modification of Diet in Renal Disease equation (MDRD) at randomization and at the end of the trial.

Results: At the end of the 12-week long GLEEN trial, the GlucoLo Plus arm had a 0.77 % creatinine increase (85.47 to 86.13 µmol/L) and a 0.85% estimated eGFR decrease (76.38 to 75.73 ml/min/1.73m2) while the placebo group had a 1.77% creatinine increase (78.5 to 79.89 µmol/L) and a 0.65% eGFR decrease (81.4 to 80.8 ml/min/1.73m2). The trial participants randomized to receive GlucoLo Plus had a 38% uACR reduction (3.70 to 2.267 mg/mmol) while the placebo group had a 15.26% increase in uACR (2.01 to 2.32 mg/mmol).

Conclusion: The results of this post-hoc analysis of the GLEEN trial suggests that GlucoLo Plus is safe regarding renal function evaluated by serum creatinine and calculated eGFR. This analysis also revealed a potential benefit of GlucoLo Plus regarding albuminuria, but bigger and longer trial would be warranted to confirm these findings.

Disclosure

A.R. Zarruk: Consultant; Sanofi. Speaker's Bureau; Sanofi. Consultant; Bausch Health. Speaker's Bureau; Bausch Health. Consultant; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Consultant; Boehringer-Ingelheim. Speaker's Bureau; Boehringer-Ingelheim, Abbott. Consultant; Abbott.
261-OR: ADA Presidents' Select Abstract: Single-Dose GLP-1-Based Pancreatic Gene Therapy Durably Maintains Body Composition and Glycemia after Semaglutide Withdrawal in a Murine Model of Obesity
Authors: FITZPATRICK ALICE L. , WANG SUYA , REESE REBECCA , PICARD NICOLE , COZZI EMILY , KIEFFER TIMOTHY J. , CAPLAN JAY , RAJAGOPALAN HARITH
Published: June 2024

Background: Glucagon-like peptide 1 (GLP-1) therapies are effective for metabolic disease, but treatment cessation may lead to rapid weight and glucose rebound. We developed a novel pancreatic gene therapy (PGTx) platform enabling durable islet production of GLP-1-based peptides. Here, we assessed body composition and glycemic parameters of single-dose PGTx versus chronic semaglutide (Sema) in a murine diet-induced obesity model.

Methods: Mice fed 60% high-fat diet were randomized to: single-dose intraperitoneal PGTx (1e13 vector genomes [VG], n=10), daily subcutaneous Sema (10 nmol/kg/d x 4 weeks, n=10), PGTx vehicle control (VC) (n=8), or Sema VC (n=8). Sema was withdrawn at week (wk) 4, and mice were randomized to PGTx (5e12 VG, n=5) or VC (n=5). Mean body composition and fasting glucose (FG) were assessed. A 0-5-point histopathology score was used to evaluate islet inflammation and integrity. Statistical comparisons were made to cohort baselines.

Results: At wk 4, PGTx reduced fat mass by 21% and lean mass by 5% versus 16% fat mass and 5% lean mass with Sema (all, p<0.0001). Sema withdrawal led to a fat and lean mass regain to 1% and 2% below baseline, while Sema-withdrawn mice treated with PGTx maintained reductions of 17% (p<0.01) and 5% (p<0.001) at wk 8. In PGTx and Sema groups, FG reduced by 18% at wk 4 (both, p<0.0001). Sema-withdrawal resulted in FG rebound to baseline, while PGTx and PGTx-treated Sema-withdrawn mice maintained 21% (p<0.0001) and 22% (p<0.001) FG reductions at wk 8. No significant evidence of pancreas inflammation was observed with mean islet histopathology scores of <0.5 in all groups.

Conclusions: Single-dose PGTx can durably improve fat mass and glycemia and maintain these metabolic parameters upon Sema withdrawal without causing pancreatic inflammation. The data indicate that PGTx has the potential to advance GLP-1 therapies by offering durable efficacy in type 2 diabetes and obesity.

Disclosure

A.L. Fitzpatrick: Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. S. Wang: Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. R. Reese: Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. N. Picard: Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. E. Cozzi: Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. T.J. Kieffer: Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. J. Caplan: Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc. H. Rajagopalan: Board Member; Fractyl Health, Inc. Employee; Fractyl Health, Inc. Stock/Shareholder; Fractyl Health, Inc.
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<2e-16) and lifestyle classification (P<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) < 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<0.0001). High Lp(a) levels, defined as >30 mg/dl (n=227, 35%), were more frequent in women and people from sub-Saharan Africa, and associated with higher HDL (p<0.001) and LDL cholesterol (p<0.01), lower triglycerides (p<0.001) and lower EAT volume (91±36 vs. 97±42 cm3, p<0.001)). EAT volume decreased with increasing quartiles of Lp(a) (p<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<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<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<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<0.0001 vs STZ+RS) and then reduced in STZ+RH+MET (24±0.1 mg/kg/min, p<0.05 vs STZ+RH). The glucagon response to hypoglycemia in control STZ+RS (p<0.05 vs basal) was abrogated in STZ+RH (p=NS vs basal) and restored in STZ+RH+MET (p<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>0.05), but decreased during cycling on land (p<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<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<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
36-OR: Modulation of Cardiorenal Benefits for GLP-1RAs Treatment by GLP1R Genetic Variants
Authors: XUE QIAOCHU , LI PIAOPIAO , PASQUEL FRANCISCO J. , PHILLIPS LAWRENCE S. , LIANG DONGHAI , VENKAT NARAYAN K M , UMPIERREZ GUILLERMO , ALI MOHAMMED K. , SHAO HUI
Published: June 2024

Introduction: While previous research has investigated the influence of patients’ clinical characteristics on GLP-1RAs’ treatment benefits, the potential influence of genetic variants, remains insufficiently explored.

Methods: We included 3951 GLP-1 RAs new users from the All of Us program (2005-2022), and propensity-matched to a comparison group who started other second-line anti-diabetes medications. We examined 15 genetic loci significantly associated with GLP1R gene expression. Intention-to-treat analysis was performed to examine the effect of GLP-1RAs treatment with acute myocardial infarction (AMI) and acute kidney injury (AKI) using Cox proportional hazards models. Genetic variants were included as an interaction.

Results: Significant larger reductions in AMI risk were observed for eight variants (rs9296276, rs6923761, rs9296280, rs13216992, rs35887128, rs7753618, rs10305491) with GLP-1RAs treatment; and four unique variants (rs2268650, rs880347, rs5875653, rs10305439) were linked to decreased AKI risk with GLP-1RAs treatment. Polygenic scores utilizing these variants showed that higher scores were associated with higher GLP-1RA benefits in reducing AMI (high score: -59.1% vs Low: -14.4%) and AKI (high: -26.3% vs low: +36.3%) risk.

Conclusion: Our results and polygenic scores offer a pathway towards more personalization for decisions regarding GLP-1 RAs use in clinical practice.

Disclosure

Q. Xue: None. P. Li: None. F.J. Pasquel: Research Support; Tandem Diabetes Care, Inc., Insulet Corporation, Dexcom, Inc., Ideal Medical Technologies, Novo Nordisk. Consultant; Dexcom, Inc., Medscape. L.S. Phillips: Other Relationship; Diasyst, Inc. Research Support; Kowa Pharmaceuticals America, Inc., Janssen Pharmaceuticals, Inc., AbbVie Inc., Novo Nordisk, GlaxoSmithKline plc, Abbott, Sanofi-Aventis U.S., Pfizer Inc. D. Liang: None. K. Narayan: None. G. Umpierrez: Research Support; Abbott, Bayer Inc., Dexcom, Inc., AstraZeneca. Advisory Panel; Dexcom, Inc. M.K. Ali: Advisory Panel; Eli Lilly and Company. H. Shao: Consultant; Eli Lilly and Company.
364-OR: Beta-Cell SF1 as a Thermogenic Regulator against Diet-Induced Obesity in Mice—Elucidating Its Role in Islet—Adipose Cross Talk
Authors: GUO YAN , CHENG YANGLEI , LI YANBING
Published: June 2024

Context/Objectives: Our previous studies have established the crucial role of steroidogenic factor-1 (SF1) in beta-cell adaptation in obese mice by promoting insulin secretion. Given that deletion of SF1 in beta cells exacerbates diet-induced obesity (DIO), we aims to explore the involvement and mechanisms of SF1 in islet-adipose crosstalk and obesity related disturbance of glycometabolism.

Methods: We developed an inducible, beta-cell-specific SF1-knockout mouse model, both heterozygous and homozygous, along with control littermates of both genders. Adeno-associated virus was employed to mediate SF1 overexpression. Glucose tolerance test and insulin tolerance test were performed to evaluate glycometabolism parameters in vivo. Metabolic cages recorded food intake, physical activity and energy expenditure. Immunohistochemistry determined UCP1 and VDAC1 expression in adipocytes in brown adipose tissues (BAT), with metabonomics used to explore underlying mechanisms.

Results: The genetic deletion of SF1 in beta cells prediposed mice to obesity, glucose intolerance and insulin resistance upon high-fat diet, while ectopic SF1 expression facilitated weight loss and enhanced glucose tolerance. Notably, energy expenditure was significantly disrupted by SF1 knockout in beta cells, whereas forced expression stimulated thermogenesis. Neither food intake nor physical activity was influenced by beta-cell SF1. UCP1 and VDAC1 expression in BAT was down-regulated with beta-cell SF1 deletion but up-regulated with ectopic SF1 expression. Mechanistic investigations suggest roles for glutathione metabolism, thyroid hormone synthesis, and choline metabolism.

Conclusions: Beta-cell SF1 serves as a thermogenic enhancer in islet-adipose crosstalk thereby improving metabolic health in obese mice.

Disclosure

Y. Guo: None. Y. Cheng: None. Y. Li: Consultant; Sanofi, Novo Nordisk, AstraZeneca.

Funding

National Natural Science Foundation of China (82200876)
368-P: Identifying Causes and Improving Hypoglycemia in Hospitalized Patients—An Update
Authors: ZONFA IAN C. , LEWIS CLAUDIA , GALLOWAY NICHOLAS R. , HATIPOGLU BETUL , TSUSHIMA YUMIKO
Published: June 2024

Introduction & Objective: Hypoglycemia is known to increase morbidity, mortality, and lengthen hospital stay leading to increased health care costs. The purpose of our study is to investigate the prevalence and identify causes and risk factors contributing to inpatient hypoglycemia. We report findings from two of our largest community hospitals in combination with our previously reported data from a tertiary referral center to better represent the general population.

Methods: We performed a retrospective cross sectional analysis of adult patients 18 years and older who were admitted to two of our community hospitals and had a hypoglycemic event, defined as glucose ≤55 mg/dL. A chart review, during a six month period in 2022 and 2023, was conducted to identify causes and associated comorbidities. We incorporated data from our previously reported tertiary care center findings.

Results: We evaluated 1,928 episodes of hypoglycemia occurring in 1,044 adult patients hospitalized across 3 hospitals. 57% of the patients had diabetes mellitus. Hypoglycemia occurred most frequently due to decreased caloric intake related to critical illness (53%) followed by insulin-induced hypoglycemia (39%). In patients without diabetes, 75% of hypoglycemic events were due to decreased caloric intake and critical illness. Kidney failure (32%), coronary artery disease (20%) and malignancy (15%) were the comorbidities most frequently associated with hypoglycemia.

Conclusion: Hypoglycemic events were most frequently caused by decreased caloric intake and insulin administration. Within the 40% of patients who did not have diabetes, 75% had hypoglycemia due to decreased caloric intake. This sheds light onto a population which has traditionally not been associated with hypoglycemia. Identifying patients at risk for hypoglycemia, improving nutritional status in critically ill patients and optimizing glycemic monitoring/insulin management are areas where intervention can improve inpatient hypoglycemia rates.

Disclosure

I.C. Zonfa: None. C. Lewis: None. N.R. Galloway: Consultant; Tidepool. Board Member; Association Diabetes Care and Education Specialists. B. Hatipoglu: Research Support; Tandem Diabetes Care, Inc. Y. Tsushima: None.
369-P: How Common Is Fear of Hypoglycemia in Type 1 Diabetes Mellitus and Type 2 Diabetes Mellitus? (iNPHORM, USA)
Authors: RATZKI-LEEWING ALEXANDRIA , BLACK JASON E. , ZOU GUANGYONG , RYAN BRIDGET L. , HARRIS STEWART B.
Published: June 2024

Introduction & Objective: Fear of hypoglycemia (FoH) is linked to diminished diabetes clinical and psychosocial outcomes; yet its real-world burden in the United States remains poorly quantified. We analyzed iNPHORM data to address this gap.

Methods: Adults (≥18 years old) with T1DM or T2DM on insulin and/or secretagogues were recruited from a US-wide, probability-based internet panel. Online screening, baseline, and 12-month follow-up questionnaires (FQ) captured data prospectively. We measured FoH at FQ Month 6 using the Hypoglycemia Fear Survey II, which comprises Worry and Behaviour subscales. Per assessment guidelines, we calculated absolute total and subscale-specific FoH scores, and prevalences of elevated versus non-elevated scores, overall and by diabetes type. Wilcoxon rank-sum tests and Z-tests assessed differences in T1DM and T2DM responses (α=0.05).

Results: N=781 were analyzed (T1DM: 18.4%; age: 51.2 [SD: 14.6] years; male: 50.7%; retention rate: 64.8%). All T1DM respondents used insulin; among those with T2DM, 40.2% used insulin without secretagogues, 36.7% used secretagogues without insulin, and 23.1% used both. Median absolute FoH Worry and Behaviour subscale scores were 30 [IQR: 21] and 29 [IQR: 18], respectively. For both subscales, absolute scores were higher in T1DM than T2DM (Worry subscale: 35 [T1DM] vs. 29 [T2DM], p=0.003; Behaviour subscale: 32.5 [T1DM] vs. 28 [T2DM], p<0.001). The overall prevalence of elevated FoH was 16.3% (T1DM: 19.4%; T2DM: 15.5%, p-value=0.25). For Worry and Behaviour subscales, 15.0% (T1DM: 14.6%; T2DM: 15.1, p-value=0.88) and 16.3% (T1DM: 17.4%; T2DM: 16.0%, p-value=0.69) reported elevated scores, respectively.

Conclusion: Despite greater absolute FoH scores in T1DM, we observed no significant differences in elevated FoH prevalences by diabetes type. Our results underscore the high and ubiquitous burden of FoH in diabetes. Clinical interventions should target not only people with T1DM but also T2DM, including those on secretagogues without insulin.

Disclosure

A. Ratzki-Leewing: Research Support; Sanofi. Advisory Panel; Dexcom, Inc. Consultant; Abbott. Advisory Panel; Sanofi-Aventis U.S. Other Relationship; American Diabetes Association. Consultant; Novo Nordisk, Eli Lilly and Company. J.E. Black: None. G. Zou: None. B.L. Ryan: None. S.B. Harris: Consultant; Abbott. Research Support; Boehringer-Ingelheim. Consultant; Dexcom, Inc. Advisory Panel; Eli Lilly and Company. Consultant; Eli Lilly and Company, Novo Nordisk, Sanofi. Research Support; Novartis AG. Consultant; Bayer Inc.

Funding

The iNPHORM study was funded through an investigator-initiated grant from Sanofi Global.
373-P: Gastric Pouch Emptying Rate in Post-bariatric Hypoglycemia
Authors: TURK NICOLE , MORADI FARSHAD , AYHAN EKREM M. , MCLAUGHLIN TRACEY
Published: June 2024

Roux-en-Y gastric bypass surgery (RYGB) promotes long term remission of T2D in up to 90% of patients. Approximately 38%, however, develop post bariatric hypoglycemia (PBH), with 11.8%. Why some and not others develop this complication is unknown. We have previously shown that altered nutrient transit, with overstimulation of hind gut causes postprandial hypoglycemia via hypersecretion of GLP1 and insulin, which is reversible by restoring normal route of nutrient transit or by blocking GLP1. We hypothesized that following surgery, individuals with faster pouch emptying would comprise a group at higher risk for developing PBH. We tested this hypothesis by quantifying pouch emptying rates in post-RYGB patients with and without PBH.15 RYGB patients with PBH, 10 postsurgical controls (without PBH), and 12 nonsurgical BMI-matched controls underwent a solid meal scintigraphy with dynamic imaging for 60 minutes followed by additional imaging at 2, 3, and 4 hours to quantify pouch emptying rate. Both PBH and postsurgical controls had markedly accelerated pouch emptying as compared to nonsurgical controls (p=9.8E-7, and 0.0059, respectively). The PBH group had significantly faster emptying at 1-hour in comparison to the post-surgical controls (5.9% vs 17.8% residual, respectively; p=0.024).

Conclusion: PBH individuals have more rapid pouch emptying versus post-surgical controls, pointing to a potential route for treatment or prevention of PBH.

Disclosure

N. Turk: None. F. Moradi: Research Support; GE health care, Ashvattha Therapeutics. E.M. Ayhan: None. T. McLaughlin: Stock/Shareholder; Eiger BioPharmaceuticals. Board Member; January, Inc. Research Support; Eli Lilly and Company, Weight Watchers International, Merck & Co., Inc., Vogenyx.

Funding

American Diabetes Association (1-19-ICTS-073)
38-OR: Implementation of an EHR-Integrated Hospital-Wide CGM Protocol for Insulin Dosing
Authors: SEAV SUSAN M. , YEH LEE MING , ONGWELA LOICE , AUBYRN RACHEL , CAO FANG , LEE JULIE J.H. , KALINSKY ANNA F. , APARICIO RAMOS OLIVIA M. , GU YUNZI M. , IVANOVIC MAJA M. , BUCKINGHAM BRUCE A. , DESAI DIMPI , LAL RAYHAN , TAN MARILYN , BASINA MARINA , HUGHES MICHAEL S.
Published: June 2024

Objective: The study aimed to develop and assess a standardized electronic health record (EHR)-integrated hospital-wide protocol for personal continuous glucose monitor (CGM) use and CGM-based insulin dosing. The focus was on feasibility and acceptability from nurses and patients.

Methods: At Stanford Health Care, a hospital-wide protocol was implemented to support inpatient use of home CGM devices in lieu of frequent fingerstick blood glucose (FSBG) monitoring for insulin dosing. It includes requirements specific to each CGM device and protocols for ongoing accuracy monitoring through intermittent CGM-to-FSBG comparisons (“validations”) integrated directly into the EHR. User experience surveys were conducted among a subset of patients and nurses who used the protocol.

Results: From Nov 2022-Aug 2023, 135 patients used a personal CGM under the protocol in 185 inpatient encounters. This included 26% non-English speakers and 27% with type 1 diabetes. Most used CGMs were Dexcom G6 (44%), Libre 2 (42%), and Libre 3 (5%). Automated insulin delivery was used in 23% of encounters. Of 1506 CGM validations, 87.7% met the requisite accuracy criteria (“%20/20”) for CGM-based insulin dosing, and 99.3% fell within Clarke zones A or B. Surveys were completed by 27 nurses and 46 patients. A majority of nurses found glucose management under the protocol effective (74%), easy to use (67%), and efficient (63%); 80% of nurses preferred inpatient CGM to FSBG. A majority of patients liked glucose management under the CGM protocol (63%), reported positive interaction with nursing staff about CGM use (63%), and felt the number of interruptions related to diabetes management was reasonable (63%).

Conclusion: The inpatient CGM protocol, fully EHR-integrated and with real-time device accuracy monitoring, allowed for insulin dosing based on personal CGM data. It received favorable feedback from both nurses and patients, and is the first to offer guidance for multiple CGM types, tailored individually according to CGM type.

Disclosure

S.M. Seav: None. M. Lee: None. L. Ongwela: None. R. Aubyrn: None. F. Cao: None. J.J.H. Lee: None. A.F. Kalinsky: None. O.M. Aparicio Ramos: None. Y.M. Gu: None. M.M. Ivanovic: None. B.A. Buckingham: Advisory Panel; Medtronic. Research Support; Medtronic. Advisory Panel; Arecor. D. Desai: None. R. Lal: Consultant; Abbott, Adaptyx Biosciences, Biolinq, Capillary Biomedical, Inc., Deep Valley Labs, Gluroo, PhysioLogic Devices, Portal Insulin, Tidepool. Advisory Panel; Lilly Diabetes. M. Tan: None. M. Basina: None. M.S. Hughes: Consultant; Dexcom, Inc.

Funding

National Institutes of Health (5K12DK122550, 1K23DK122017, T32DK007217, P30DK116074)
381-P: Hypoglycemia and Hyperglycemia among Elderly Patients in Long-Term Care Facilities
Authors: SCHMIDT VANESSA , LANE KYRSTIN , LEE ROGER M. , FREEBY MATTHEW
Published: June 2024

Background: Hypoglycemia and hyperglycemia episodes are common in older adults living in long-term care (LTC) facilities, but often go undetected due to clinical complications and comorbidities in the elderly. There is limited data evaluating the frequency of hypoglycemia and hyperglycemia in the elderly who live in LTC facilities. We aimed to investigate and define hypoglycemia frequency (blood glucose <70 mg/dL) and hyperglycemia frequency (blood glucose >250 mg/dL) in the elderly at LTC facilities.

Methods: Patients with diabetes at the LTC facility were included if they were ≥65 years and their diabetes regimen included insulin or sulfonylurea therapy. Frequency of hypoglycemia and hyperglycemia was evaluated through the use of Freestyle Libre Pro CGM and events detected were compared to available finger-stick measurements over a 10-14 day period.

Results: Seventy-one percent of patients had at least one episode of hypoglycemia. 100 percent (106/106) of hypoglycemic episodes were captured by CGM but unrecognized by fingerstick. Forty-eight percent of patients had at least one episode of hyperglycemia.

Conclusion: There is high frequency of hypoglycemic and hyperglycemic episodes in older adults. Our study shows that the use of professional CGM in elders in LTC facilities can provide an in-depth assessment of hypoglycemia events and hyperglycemia events when combined with finger-stick glucose monitoring.

Disclosure

V. Schmidt: Research Support; Abbott. K. Lane: None. R.M. Lee: None. M. Freeby: Research Support; Abbott, Fractyl Health, Inc., Novo Nordisk.

Funding

Abbott Diabetes Care Inc (ADC-SRR-IIS-18-22)
390-P: Construction of a PANoptosis-Related Gene Signature for Diabetic Nephropathy
Authors: CHEN YAN
Published: June 2024

Background: In this study, we aimed to develop a diagnostic model for DN based on PANoptosis-related genes.

Methods: DEGs associated with DN were identified in the GSE96804 and GSE142025 datasets. Functional analyses included GO and KEGG. PANoptosis-related DEGs were also identified by intersecting PANoptosis-related genes with DEGs. Pairwise correlations among these genes were assessed via Pearson correlation analysis. Immune cell abundance in DN patients versus controls was compared in GSE96804. Feature genes for DN prediction were selected with machine learning, and a diagnostic model was constructed using LASSO regression. High-risk and low-risk groups were established based on risk scores, with GSEA used to explore enriched biological processes and pathways. The association between risk scores and immune cell infiltration was examined using CIBERSORT. Potential therapeutic drugs were investigated via the DGIdb database.

Results: We identified 573 DEGs_com in DN. Six PANoptosis-related DEGs were found, showing co-regulation and potential functional interactions. NMF classified patients into two clusters. Immune cell analysis revealed significant differences in abundance between DN patients and controls, with variations in dendritic cells, macrophages, mast cells, and neutrophils. Three feature genes (PDK4, YWHAH, PRKX) were selected for a diagnostic model, yielding high diagnostic accuracy for DN across multiple datasets (AUC = 0.8-1.0) and a reliable nomogram for DN prediction. Stratification based on the risk score revealed significant associations between risk levels and immune cell infiltration patterns. PPI network and correlation analyses indicated potential therapeutic targets (PRKX, PDK4) and drugs were identified.

Conclusions: The integration of PANoptosis-related genes PDK4, YWHAH, and PRKX offers a promising diagnostic model for DN, providing a novel diagnostic tool and potential targeted therapeutic strategies for DN management.

Disclosure

Y. Chen: None.

Funding

Youth of National Natural Science Foundation of China ( 82001480)