bluuebunny/crossref_metadata_2025_split huggingface dataset:
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 &lt; 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&lt;5e-08); 119 were HCIRL. HCIRL associated genes exhibited enrichment in adipose tissue and adipocytes (all p&lt;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&lt;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&lt;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 &lt; 70 mg/dl (% &lt; 70 mg/dl) and &lt; 54 mg/dl (% &lt; 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 %&lt;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&lt;0.001 respectively 4.0 ±0.6% vs. 2.4 ±0.3%, p&lt;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&lt;.001) for %&lt;70 mg/dl and -5.5% (95% CI 4.4 - 6.6%, p&lt;.001) for %&lt;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 &lt; .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
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&lt;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&lt;0.01) and 5% (p&lt;0.001) at wk 8. In PGTx and Sema groups, FG reduced by 18% at wk 4 (both, p&lt;0.0001). Sema-withdrawal resulted in FG rebound to baseline, while PGTx and PGTx-treated Sema-withdrawn mice maintained 21% (p&lt;0.0001) and 22% (p&lt;0.001) FG reductions at wk 8. No significant evidence of pancreas inflammation was observed with mean islet histopathology scores of &lt;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.