bluuebunny/crossref_metadata_2025_split huggingface dataset:
1569-P: Quantification of Postprandial Hepatic Glucose Disposal in Roux-en-Y Gastric Bypass and Non-operated Controls Using Stable Isotope Labelling and Liver Metabolic Imaging
Authors: BRUNASSO ALESSANDRO , DALLA MAN CHIARA , POLI SIMONE , HERZIG DAVID , KREIS ROLAND , BALLY LIA , SCHIAVON MICHELE 
Published: June 2024

Roux-en-Y gastric bypass surgery (RYGB) alters postprandial glucose metabolism due to changes in gastrointestinal tract anatomy and large weight loss. Here, we propose a model quantifying postprandial hepatic and peripheral glucose fluxes in post-RYGB patients at steady weight loss and healthy controls (HC). Ten RYGB (2M, age=39.2±3.1 y, BMI=28±1 kg/m2 - mean±SE) and 10 HC (5M, age=36.4±3.2 y, BMI=26±1 kg/m2) underwent Deuterium Metabolic Imaging (DMI) at a 7 Tesla MR scanner before and after ingesting 60g of [6,6-2H2]-glucose (D-Glc). Venous blood was sampled to measure plasma insulin (I) and D-Glc (GP). Hepatic DMI was used to track liver D-Glc levels (GL) over 150min. Data was used to develop a model describing postprandial hepatic and peripheral glucose appearance (RaL and RaP) and disposal (RdL and RdP) as well as first-pass hepatic glucose extraction (ISE). Incremental Area Under the Curve (iAUC) of GL was greater in RYGB compared to HC (iAUC(GL)0-150min = 620±39 vs 467±41 mM·min, p=0.010), as was iAUC(I)0-150min (49.8±4.9 vs 29.2±3.4 nM·min, p=0.003), while iAUC(GP)0-150min was not significantly different (628±69 vs 520±26 mM·min). iAUCs of RaL and RaP normalized to 60g were higher in the first 60min in RYGB vs HC (63.0±3.0 vs 27.8±2.7 %; 60.5±3.1 vs 26.0±2.6 %, p&lt;0.001), as were iAUCs of RdL and RdP after 150 min (24.6±1.1 vs 18.0±1.7 %, p=0.005; 53.6±2.9 vs 32.1±4.1 %, p&lt;0.001). Conversely, model-derived ISE was similar (8.6±0.3 vs 8.8±0.7 %) in the two groups.&lt;u&gt;&lt;/u&gt; A model using stable isotope and liver DMI data was developed to quantify peripheral and organ-level glucose turnover without portal vein catheterization. Results showed that the difference in glucose time course in RYGB vs HC is explained by the faster rate of appearance in RYGB, while disposal, at both liver and periphery, appears to be intact. The model also suggests that no saturation arises in the first-pass extraction, despite the high glucose levels.

Disclosure
A. Brunasso: None. C. Dalla Man: None. S. Poli: None. D. Herzig: Speaker's Bureau; Ypsomed AG. R. Kreis: None. L. Bally: None. M. Schiavon: None.

Funding
PNRR Next Generation EU (ex DM 118/23)-Swiss National Science Foundation (PCEGP3_186978)
1574-P: Catecholamine-Induced Adipose Lipolysis Drives Hepatic Steatosis in Pnpla3I148M Knockin Mice
Authors: PRAKASH GOLLA JAYA , SUH REBECCA , PAOLELLA LAUREN M. , STROBER JORDAN W. , ZHANG FENGRUI , PHILBRICK WILLIAM M. , VATNER DANIEL F. 
Published: June 2024

PNPLA3 (Patatin like phospholipid domain containing protein 3) I148M is the most common human genetic mutation associated with hepatic steatosis. Alterations in white adipose tissue (WAT) function are often linked to hepatic lipid accumulation, but current understanding of the effect of PNPLA3I148M on WAT function is limited to the finding that this mutation does not appear to impact WAT insulin responsiveness. We evaluated WAT catecholamine responsiveness using the β3-adrenergic agonist CL 316243 (CL) in Pnpla3I148M mice. In vivo, the plasma NEFA response to CL was increased in mutant mice (Basal NEFA: WT 0.65 ± 0.07 mM, MUT 0.66 ± 0.07 mM, P = 0.5; CL stimulated NEFA: WT 1.3 ± 0.1 mM, MUT 1.6 ± 0.1 mM, P = 0.03). Ex vivo, CL-induced fatty acid release from gonadal WAT was increased in mutant mice (1.22-fold increased NEFA release, P = 0.03). High sucrose diet fed Pnpla3I148M mice are a known model of increased hepatic steatosis; beta adrenergic blockade with propranolol did not alter hepatic triglyceride content in WT mice as compared with vehicle, but markedly decreased hepatic triglyceride in Pnpla3I148M mice (WT: VEH 37 ± 5 mg/g; PRO 36 ± 6 mg/g. MUT: VEH 55 ± 6 mg/g; PRO 19 ± 4mg/g, P = 0.0002). Acipimox, an inhibitor of WAT lipolysis, similarly had no effect on WT hepatic steatosis and markedly decreased hepatic triglyceride in Pnpla3I148M mice (WT: VEH 46 ± 5 mg/g; ACI 49 ± 10 mg/g. MUT: VEH 78 ± 11 mg/g; ACI 40 ± 5mg/g, P = 0.006).
Conclusions: WAT catecholamine responsiveness is increased in Pnpla3I148M mice contributing to hepatic steatosis in these mice. As human hepatic triglyceride biosynthesis is strongly weighted towards esterification of preformed fatty acids from extrahepatic sources, this biology may contribute to the increased susceptibility to fatty liver seen in patients with the PNPLA3I148M mutation.

Disclosure
J. Golla: None. R. Suh: None. L.M. Paolella: None. J.W. Strober: None. F. Zhang: None. W.M. Philbrick: None. D.F. Vatner: None.

Funding
National Institutes of Health (RO1DK124272;T32DK007058; P30DK045735)
1575-P: Differential Effects of Rising Glucagon Concentrations on Hepatic Amino Acid Extraction
Authors: CHRISTIE HANNAH E. , MOHAN SNEHA , EGAN AOIFE M. , VELLA ADRIAN 
Published: June 2024

To understand the actions of glucagon on hepatic amino acid (AA) metabolism, we studied nondiabetic individuals on one occasion after an overnight fast. On the morning of the study, femoral artery (FA), femoral vein (FV) and hepatic vein (HV) catheters were placed under fluoroscopic guidance in the interventional radiology suite. Infusion of indocyanine green (0.25mg/min), allowed measurement of splanchnic blood flow (SBF) throughout the experiment. At the start of the experiment (0 min), somatostatin was infused (60 ng/kg/min) to block endogenous hormone secretion. Insulin was infused at 0.8 mU/Kg/min together with glucagon at 1.5 ng/kg/min. To mimic ingestion of a protein load, Clinisol (15%, 0.003ml/kg/min; 51% essential AA, 18% branched-chain AA, 9% aromatic AA; Baxter, Healthcare, Deerfield, IL) was infused. Glucose was infused to maintain peripheral arterial concentrations at 160mg/dL. At 120 min glucagon infusion was increased to 3 ng/kg/min. AAs and their metabolites were measured using derivatized standards. Samples were analyzed on a triple quadrupole mass spectrometer coupled with an Ultra Pressure Liquid Chromatography system. Distinct patterns of % hepatic AA extraction (calculated using HV-FA difference as a function of SBF) were noted. The majority of AAs’ extraction increased in response to AA and glucagon infusion (e.g. Leucine [8 ± 5 vs. 14 ± 6 %], Serine, Glycine, Tyrosine and Methionine [27 ± 5 vs. 39 ± 5 %]). Notable exceptions included α-aminoadipic acid which is released by the liver in the fasting state (-9.0 ± 12%) and in response to AA and glucagon infusion (-13 ± 7%). Aspartate changed from net release (-40 ± 34%) to uptake (29 ± 14%) in response to glucagon. In other cases, hepatic extraction was unchanged (e.g. Threonine, Alanine [56 ± 10 vs. 55 ± 6%], Valine, Lysine and Cysteine). It remains to be ascertained if such patterns of hepatic extraction of AAs in response to glucagon differ in metabolic disease states thereby identifying novel therapeutic targets.

Disclosure
H.E. Christie: None. S. Mohan: None. A.M. Egan: None. A. Vella: Research Support; Novo Nordisk. Consultant; Hanmi Pharm. Co., Ltd., Crinetics Pharmaceuticals, Inc. Advisory Panel; Rezolute, Inc.

Funding
DK116723
1577-P: CIDEB Knockdown Promotes Increased Hepatic Mitochondrial Fat Oxidation and Reverses Hepatic Steatosis and Hepatic Insulin Resistance by the PKCε-Insulin Receptor Kinase Pathway
Authors: ZHENG JIE , NASIRI ALI , GASPAR RAFAEL C. , HUBBARD BRANDON T. , SAKUMA IKKI , MA XIAOXIAN , MURRAY SUE , PERELIS MARK , BARNES WILLIAM , SAMUEL VARMAN , PETERSEN KITT , SHULMAN GERALD I. 
Published: June 2024

Metabolic-dysfunction associated hepatic steatotic liver disease (MASLD) plays a major role in the pathogenesis of type 2 diabetes and can lead to end stage liver disease but there are currently no FDA approved treatments. CIDEB deficiency has been shown to be associated with reduced incidence of MASLD in humans however the mechanism by which it does so remains unknown. We found that knocking down hepatic expression of CIDEB using an antisense oligonucleotide decreased hepatic triglyceride accumulation by ~150% (p = 0.0001) in high fat fed (HFD) mice. This reduction in hepatic fat content could be mostly attributed to a ∼30% increase rates of hepatic mitochondrial fat oxidation as assessed by a novel [13C5]glutamine tracer infusion technique (Q-Flux). In order to assess the impact of reduced hepatic steatosis on hepatic and whole-body insulin sensitivity we performed hyperinsulinemic-euglycemic clamp studies. CIDEB knockdown ameliorated HFD-induced insulin resistance in mice, reflected by ∼2-fold (p = 0.001) increase in the glucose infusion rate required to maintain euglycemia. These improvements in hepatic insulin sensitivity were associated with decreased plasma membrane (PM)/cytosol PKCε translocation and increased insulin-stimulated phosphorylation of IRKY1158, IRKY1162, AktS473 and AktT308 (all p &lt; 0.05).
Conclusion: These results demonstrate that CIDEB knockdown increases mitochondrial fat oxidation and ameliorates HFD-induced hepatic steatosis and hepatic insulin resistance through the PKCε-insulin receptor kinase pathway and suggest that CIDEB knockdown may represent a novel therapeutic approach to treat MASLD.

Disclosure
J. Zheng: None. A. Nasiri: None. R.C. Gaspar: None. B.T. Hubbard: None. I. Sakuma: None. X. Ma: None. S. Murray: Employee; Ionis Pharmaceuticals. M. Perelis: Employee; Ionis Pharmaceuticals. W. Barnes: Employee; Ionis Pharmaceuticals. V. Samuel: None. K. Petersen: None. G.I. Shulman: None.
1583-P: Measuring Mitochondrial Metabolism In Vivo with [1,2-13C2]-L-Glutamine Mass Isotopomers
Authors: SIEBEL STEPHAN , CARDONE REBECCA L. , MASON GRAEME F. , KIBBEY RICHARD 
Published: June 2024

Background:Accuracy of tracer-based measurements of in vivo metabolic rates rely on assumptions, i.e., tracer non-interference with metabolism
Aim: [1,2-13C2]-L-glutamine was evaluated to trace hepatic (H) & renal (K) metabolism in rats fed control vs. highfat-highsucrose diets (HFHSD) with validation by independent models and compared to lactate, propionate, and acetate tracing
Methods: Sprague-Dawley rats underwent primed, continuous infusions of [1,2-13C2]-L-glutamine vis-à-vis lactate, propionate, acetate infusions.Plasma/freeze-clamped tissues were obtained at 7 timepoints. Isotopomers were interpreted by steady-state and kinetic Mass Isotopomer Multi-Ordinate Spectral Analysis (MIMOSA)
Results:[1,2-13C2]-L-glutamine equilibrated without significant impact on intermediary/glucose metabolism. Transaminase exchange (v x) was &gt;&gt; citrate synthase (v CS). v PEPCK/v CS was 1.5 in (H) and 1.9 in (K). Pyruvate contributed 76% of anaplerosis in (H) and 90% in (K) with the remainder from propionate (v PCC) (H) and glutamate (vGDH) (H, K)). Citrate lyase (v ACLY/v CS) was significant only in (H) (18%) increasing on HFHSD. Plasma insulin ([i]), glucose ([g]), and/or glucose turnover (Ra) were increased by acetate ([i]=1.5x, p=0.015; [g]=129mg/dl, p=0.021), lactate ([i]=2.03x, p=0.0001; [g]=156mg/dl, p=0.0001, Ra=7.2mg/kg/min, p=0.006), and propionate ([i]=1.7x, p=0.0013; [g]=165mg/dl, p=0.0001, Ra=7.8mg/kg/min, p=0.0017). Lactate, acetate, and propionate increased cataplerosis &gt; HFHSD
Conclusion: [1,2-13C2]-L-glutamine MIMOSA provided unaltered, direct measurements of mitochondrial metabolism validated by independent kinetic and steady-state models and demonstrated comparable v PEPCK and v CS, fast transaminase, substantial v ACLY, v PCC, and minimal v GDH. Metabolic changes induced by HFHSD were less than those caused by lactate, propionate, acetate.

Disclosure
S. Siebel: None. R.L. Cardone: None. G.F. Mason: Consultant; Merck & Co., Inc. R. Kibbey: None.

Funding
National Institutes of Health (5R01DK108283-04)
1589-P: Serum Triglyceride Better Indicator Compared with FiB4 Score for Diagnosis of Liver Fibrosis Assessed via Liver Fibroscan in Indian Patients with Type 2 Diabetes Mellitus Receiving SGLT2i Therapy
Authors: GUPTA VISHAL 
Published: June 2024

Aim: Identify biomarker that predicts risk of liver fibrosis (LF). Analyse role of FiB4 score in detecting LF.
Methods: Between Oct’ 22 & Mar’ 23, 66 T2DM patients (waist cmf &gt; 80 cms (F) &gt; 90 cms (M) receiving dapagliflozin irrespective of A1c & who underwent liver fibroscan (Lfib) were retrospectively analysed & studied. LF was performed by Lfib using ARFI. Metavir LF staging classified pt’s: F0 (N); F1 (N - mild); F2 (Mild - mod); F3 (mod - severe); F4 (cirrhosis). Wt-Kg, systolic/diastolic BP (mmHg), Lipid profile mg/dl (TC, LDL-C, TG, HDL), Hs-crp mg/L, LFT, NT-ProBNP pg/ml, eGFR (Cyst-C) & UACR mg/gm were recorded 2-3 mthly & data presented over 1 yr. Exclusion: Preg, &lt;3 mths illness/hospitalisation, alcoholism, hep B, C & autoimmune hepatitis (if LFT was raised). Statistics: ANOVA - compared parameters within stages of LF. One-Way ANOVA, followed by post-hoc Tukey test compared mean TG levels within LF stages. Pearson Chi-square test (comparison of two non-parametric variables) & Spearman rho’s (correlation between Fib4 & LF stages) was used with P-value &lt;0.05 considered statistically significant (S).
Results: Baseline (B) characters: Males 86.4%, avg (age 56.88&lt;u&gt;+&lt;/u&gt;8.82, Wt 83.72&lt;u&gt;+&lt;/u&gt;11.96, A1c 7.77&lt;u&gt;+&lt;/u&gt;1.54, TG 164.16&lt;u&gt;+&lt;/u&gt;90.82, hs-CRP 2.57&lt;u&gt;+&lt;/u&gt;2.83, GGT 49&lt;u&gt;+&lt;/u&gt;51.96 SGPT 40.44&lt;u&gt;+&lt;/u&gt;25.89, NT-ProBNP 46.65&lt;u&gt;+&lt;/u&gt;45.71, UACR 33.43&lt;u&gt;+&lt;/u&gt;99.55 & eGFRCys-C 84.98&lt;u&gt;+&lt;/u&gt;20.55. (B) - 1 yr: S reduction in Wt, DBP, A1c, TC, LDL, TG, hs-CRP, SGPT. (B) TG was S different between stages of LF {140.88&lt;u&gt;+&lt;/u&gt;71.98 (F0), 143.92&lt;u&gt;+&lt;/u&gt;54.32 (F1), 344.33&lt;u&gt;+&lt;/u&gt;76.22(F2), 178&lt;u&gt;+&lt;/u&gt;51.34 (F3), 259.83&lt;u&gt;+&lt;/u&gt;153.64 (F4) p-0.001}. TG &gt;128 (p-0.041) was found S for detecting LF (F2-F4, sensitivity 73.53% & specificity 53.13%). SGPT & GGT (&gt;50) was associated with LF severity (F2-F4), likelihood ratio -4.477 (p-0.031). No correlation was found between FiB4 & stages of LF.
Conclusion: Serum TG is a better predictor compared to FiB4 score in detecting LF in Indian patients with T2DM.

Disclosure
V. Gupta: None.
1591-P: Circulating Levels of ELABELA Is Inversely Associated with Hepatic Fibrosis of Nonalcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus
Authors: SHI MIN , CAO HUIMIN , LIU YUTING , GU WENSHA , ZHANG HONG 
Published: June 2024

Background: Non-alcoholic steatohepatitis is closely associated with the progression of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM). We aimed to investigate whether plasma ELABELA, recently identified as a latent biomarker for DKD, is related to the severity of NAFLD.
Methods: A total of 362 patients with T2DM were enrolled in this study. Noninvasive clinical markers of hepatic fibrosis including fibrosis-4 (FIB-4) index, NAFLD fibrosis score (NFS) and aspartate aminotransferase-to-platelet ratio index (APRI) were determined. The levels of plasma ELABELA, UACR, creatinine and glucometabolic parameters were measured. The relationships between plasma ELABELA and the clinical markers were statistically evaluated.
Results: Based on the median value of the plasma ELABELA, subjects were divided into low and high ELABELA groups. The low ELABELA group showed a significantly longer duration of diabetes, worsened nephropathic indices, and a more enhanced hepatic fibrosis index. A lower ELABELA was associated with a greater odds ratio for the risk of higher hepatic fibrosis stage (OR, 0.98; 95% CI, 0.966 to 0.994). Multiple regression analysis including confounding factors showed that ELABELA independently contributed to decreases in FIB-4 index (P=0.044), NFS (P=0.012). In addition, logistic regression analysis for the prevalence of advanced hepatic fibrosis defined by the cutoff points of the clinical scores showed that ELABELA was the sole and common negative factor for prevalence of advanced hepatic fibrosis (FIB-4 index: P=0.016, NFS: P=0.005).
Conclusion: The decline of plasma ELABELA was independently associated with a higher degree of hepatic fibrosis in patients with T2DM. Considering the common metabolic milieu of renal and hepatic fibrosis in T2DM, the potential use of plasma ELABELA as an effective biomarker reflecting hepatic fibrosis in T2DM needs to be validated in the future.

Disclosure
M. Shi: None. H. Cao: None. Y. Liu: None. W. Gu: None. H. Zhang: None.

Funding
Jiangsu Province Science and Technology Plan Special Funds (BE2023745); Jiangsu Health Commission Medical Scientific Research Project (H2023137)
1618-P: Progression to Glucose Intolerance Is Characterized by Glucagon Secretion Inappropriate for Circulating Glucose
Authors: MOHAN SNEHA , CHRISTIE HANNAH E. , LAURENTI MARCELLO C. , EGAN AOIFE M. , VELLA ADRIAN , DALLA MAN CHIARA 
Published: June 2024

As part of a series of studies to understand the pathogenesis of prediabetes, we studied 96 nondiabetic individuals (54 ± 1.2 years; BMI 28.4 ± 0.4 Kg/M2) on 2 occasions, 3 years apart using an oral 75g glucose challenge. Weight and body composition were measured prior to each study. Fasting and 120-minute glucose were used to classify subjects’ glucose tolerance at baseline, and at the 3-year visit. Indices for insulin secretion and action were estimated using the oral minimal model. Glucagon secretion rate (GSR) was estimated by deconvolution from peripheral glucagon concentrations. Overall, 32 subjects progressed from normal to Impaired Glucose Tolerance (IGT) or from IGT to type 2 diabetes. Anthropometric variables were similar between progressors and those with stable glucose tolerance at baseline (BMI 28.1 ± 0.7 vs. 28.7 ± 0.6 Kg/M2, p = 0.50), and at 3 years (29.1 ± 0.8 vs. 29.3 ± 0.6 Kg/M2, p = 0.81). No significant differences in baseline fasting and nadir GSR or in Disposition Index (DI - 659 ± 98 vs. 885 ± 86 10-4 dl/kg/min per μU/ml, p = 0.11) were noted. Although, peak glucose concentrations differed significantly at baseline (11.4 ± 0.3 vs. 10.3 ± 0.2 mmol/l, p &lt; 0.01), integrated concentrations did not (462 ± 47 vs. 402 ± 26 mmol/l per 6hr, p = 0.23). At 3-year follow-up, DI declined in the progressors (659 ± 98 vs. 451 ± 65 10-4 dl/kg/min per μU/ml, baseline vs. 3-years p = 0.04). This did not occur in the stable group (885 ± 86 vs. 893 ± 142 10-4 dl/kg/min per μU/ml, p = 0.94). α-cell suppression by glucose (fall in GSR (pmol/min)/glucose rise (mmol/l)) did not differ at baseline (1.3 ± 0.2 vs. 1.5 ± 0.1 nmol/min/L, p = 0.37) but was impaired at 3 years (1.0 ± 0.2 vs. 1.4 ± 0.1 nmol/min/L, p &lt; 0.01) in those who progressed. Analysis of the entire cohort showed that our index of glucagon suppression was inversely correlated to increase in glycemic excursion (R2=0.14, p &lt; 0.01). These data show that α-cell dysfunction accompanies a decline in β-cell function as IGT or overt type 2 diabetes develops.

Disclosure
S. Mohan: None. H.E. Christie: None. M.C. Laurenti: Employee; Angelini Pharma. A.M. Egan: None. A. Vella: Research Support; Novo Nordisk. Consultant; Hanmi Pharm. Co., Ltd., Crinetics Pharmaceuticals, Inc. Advisory Panel; Rezolute, Inc. C. Dalla Man: None.

Funding
National Institutes of Health (DK116723)
1624-P: Is the Contribution of Postoperative Adult Growth Hormone Deficiency to Fatty Liver Greater Than the Contribution of Type 2 Diabetes?
Authors: TSUJIMOTO YUKI , YAMASHIRO KENJI , NISHIMURA RIMEI 
Published: June 2024

Background: In recent years, adult growth hormone deficiency (AGHD) has been recognized as one of the risk factors for fatty liver. AGHD is often induced by surgery for pituitary tumors. However, there is no report comparing the contribution of AGHD and type 2 diabetes(T2D) to fatty liver in patients with both conditions following pituitary tumor surgery, so far. Therefore, this study examined the associations of AGHD and T2D with a surrogate marker of fatty liver, "ALT at 3 months post-surgery" in patients undergoing pituitary tumor surgery, using two-way analysis of variance.
Methods: The study included 69 patients who underwent surgery for pituitary tumors and underwent AGHD examination through growth hormone stimulation tests. The dependent variable was ALT at 3 months post-surgery, and independent variables were the presence of T2D (T2D group n=8, non-T2D group n=61) and the presence of AGHD (AGHD group n=23, non-AGHD group n=46).
Results and Conclusion: Both the presence of T2D and AGHD showed significant main effects (p&lt;0.001, p=0.015, respectively), and their interaction demonstrated a significant synergistic effect (p=0.048) as well. It was demonstrated that having T2D and having AGHD both contribute to elevated ALT. However, the contribution rates to ALT were 22.0% for T2D, 5.4% for AGHD, and 3.1% for interaction. Having T2D was identified as the main contributed factor for elevated ALT. Although AGHD is recognized as a risk factor for fatty liver after pituitary tumor surgery, this study revealed that it becomes an extremely strong risk when combined with T2D.

Disclosure
Y. Tsujimoto: None. K. Yamashiro: Other Relationship; Teijin Pharma Limited, Ono Pharmaceutical Co., Ltd. R. Nishimura: Speaker's Bureau; Abbott. Advisory Panel; Abbott Japan Co., Ltd. Speaker's Bureau; Boehringer-Ingelheim, Mitsubishi Tanabe Pharma Corporation, Kowa Company, Ltd., Medtronic, Sanofi, Taiho Pharmaceutical Co. Ltd., Sumitomo Dainippon Pharma Co., Ltd., Teijin Pharma Limited, Eli Lilly and Company, Novo Nordisk A/S. Consultant; Terumo Corporation.
1635-P: Survodutide Weight Loss Is Associated with Changes in Food Preference and Improvement of Dyslipidemia in the Free Choice Diet–Induced Obese Hamster Model
Authors: BRIAND FRANCOIS , AUGUSTIN ROBERT , WESCHE FRANK , DELIC DENIS , KLEIN THOMAS 
Published: June 2024

Introduction & Objective: Survodutide, a glucagon/GLP-1 receptor dual agonist, has recently shown significant weight loss in a Phase II trial. To test whether this weight loss is associated with changes in food preference and improvement in dyslipidemia, we evaluated survodutide in the free choice diet-induced obese and dyslipidemic hamster model, with human-like lipoprotein metabolism.
Methods: Obesity and dyslipidemia were induced with a 20-week free choice diet, with a choice between control chow or high fat/cholesterol diet, and normal or 10% fructose water. Obese hamsters were kept on this free choice diet and treated subcutaneously, once daily for 2 weeks with vehicle or survodutide 20 nmol/kg.
Results: Survodutide treatment for 2 weeks led to a 19% body weight reduction (p&lt;0.0001 vs vehicle). Compared to vehicle, both normal water and chow diet intake were significantly lower during week 1 of survodutide treatment, then returned to baseline values. In contrast, both 10% fructose water and high fat/cholesterol diet intake were rapidly reduced during the whole treatment period (p&lt;0.0001). Survodutide significantly reduced fasting glycemia and hyperinsulinemia, leading to a 75% reduction in HOMA-IR index (p&lt;0.0001). Survodutide reduced plasma free fatty acids (-49%) and triglycerides (-75%; both p&lt;0.001 vs vehicle). Survodutide reduced plasma total cholesterol levels (-41%, p&lt;0.001), resulting in cholesterol lowering in all lipoprotein fractions, including LDL-cholesterol (-31%, p&lt;0.0001 vs vehicle). These effects were further confirmed with fast protein liquid chromatography lipoprotein profiles.
Conclusion: Survodutide induces weight loss in the free choice diet-induced obese hamster model through beneficial changes in food preference, leading to improvement in HOMA-IR and dyslipidemia. These data highlight the potential benefits of survodutide for the treatment of obesity and related comorbidities.

Disclosure
F. Briand: Employee; PHYSIOGENEX. Stock/Shareholder; PHYSIOGENEX. R. Augustin: Employee; Boehringer-Ingelheim. F. Wesche: Employee; Boehringer-Ingelheim. D. Delic: None. T. Klein: Employee; Boehringer-Ingelheim.

Funding
Boehringer Ingelheim