bluuebunny/crossref_metadata_2025_split huggingface dataset:
1167-P: Nonalcoholic Fatty Liver Disease, Metabolic Dysfunction Associated Fatty Liver Disease, and Associations with All-Cause and Cause-Specific Mortality
Authors: HUANG QI , ZOU XIANTONG , ZHOU XIANGHAI , JI LINONG 
Published: June 2021

The change in terminology from nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) has raised heated discussion. Our study aims to investigate which has closer association with all-cause and cause-specific mortality in a population-based cohort. We investigated the association between fatty liver disease and mortality in 12,480 adults from National Health and Nutrition Examination Survey III with a medium follow-up time of 22.7 years. Characteristics were compared in participants without NAFLD or MAFLD, with only NAFLD, only MAFLD, or both; survival analysis and subgroup analysis were applied. Participants with NAFLD or MAFLD were highly overlapped (Weighted Cohen’s kappa coefficient 0.78). MAFLD increased the risk for total mortality in a greater magnitude than NAFLD (HR: 2.07 [95% CI 1.86, 2.29] vs. 1.48 [1.35, 1.65]) in crude, but the risks were neglectable when metabolic parameters were adjusted. The risk for cardiovascular, neoplasm and diabetes-related mortality was similar between MAFLD and NAFLD. In reference to participants without NAFLD or MAFLD, patients with only NAFLD showed a reduced risk for total (0.48 [0.34, 0.68]) and neoplasm mortality (0.46 [0.24, 0.89]), while participants with only MAFLD was independently associated with enhanced risk for total (1.74 [1.40, 2.15]), neoplasm (1.94 [1.30, 2.90]) and diabetes-related mortality (3.24 [1.05, 9.97]) after adjustment. The risk of MAFLD for overall mortality was consistence between subgroups except for race-ethnicity.
In conclusion, participants with MAFLD or NAFLD were highly concordant. Compared with NAFLD, MAFLD was certified with greater risk in all-cause mortality and similar risk in cause-specific mortality. The new terminology excluded participants with lower mortality risk and included participants with higher risk. Drug development for MAFLD should consider ethnicity difference.

Disclosure
Q. Huang: None. X. Zou: None. X. Zhou: None. L. Ji: None.

Funding
National Key Research and Development Program of China (2016YFC1304901, 2016YFC1305603); National Natural Science Foundation of China (81800515); Beijing Nova Program of Science and Technology (Z191100001119026)
1174-P: Application of NIS4 Technology for Stand-Alone and Sequential Identification of At-Risk NASH or Advanced Fibrosis in Nondiabetic, Prediabetic, and Type 2 Diabetic Patients
Authors: ROSENQUIST CHRISTIAN , HAJJI YACINE , MAGNANENSI JÉRÉMY , STANKOVIC-VALENTIN NICOLAS , HOSMANE SUNEIL , SANYAL ARUN J. 
Published: June 2021

Background: Type 2 diabetes (T2D) is an independent risk factor for the development of nonalcoholic steatohepatitis (NASH. However, there is a need for non-invasive tests (NIT) to identify at-risk NASH patients requiring intense lifestyle or clinical intervention.
Aim: The aim of this study was to access clinical performance metrics of NIS4™ either alone or in combination with other NITs in patients characterized as nondiabetic, pre-diabetic and T2D and with either at-risk of NASH (NAS≥4 and F≥2) or advanced fibrosis (F≥3).
Methods: Patients in the RESOLVE-IT DIAG cohort presented with one or more risk factors for NAFLD and had corresponding NIT data: NIS4™ (miR-34a-5p, α2M, YKL-40, HbA1c), Fibrosis-4 (FIB-4), NAFLD activity score (NFS), and FibroScan™ (FS). NIT data were used to simulate different testing strategies to identify patients with at-risk NASH or advanced fibrosis.
Results: The 467 patients were divided into 3 subgroups with 200 (43%) non-T2D, 67 (14%) pre-diabetic and 200 (43%) T2D with a prevalence for at-risk NASH ranging 42-71%, 58-78% and 66-84%, respectively. The corresponding prevalence for advanced fibrosis in the same groups was 18-27%, 34-40%, 42-49%, respectively. Generally, the performance was impacted by variability in sample size and prevalence which mainly affected PPV and NPV. Under these circumstance NIS4™ together with FS or FIB-4 provided a strong overall balanced performance (Acc: 66-82%, Sen: 50-80%, Spe: 58-94%).
Conclusion: In this cohort, the sequential use of NIS4™ together with another blood-based test FIB-4 or an imaging-based FibroScan™ test provided an overall more balanced performance for identification of at-risk NASH or advanced fibrosis for nondiabetic and T2D patients. Therefore, NIS4™ has the potential to be a valuable clinical tool for also identifying diabetic patients at higher risk of negative outcomes.

Disclosure
C. Rosenquist: Employee; Self; GENFIT. Y. Hajji: None. J. Magnanensi: Employee; Self; GENFIT. N. Stankovic-valentin: Employee; Self; GENFIT, Stock/Shareholder; Self; GENFIT. S. Hosmane: Stock/Shareholder; Self; GENFIT, Stock/Shareholder; Spouse/Partner; Vertex Pharmaceuticals Incorporated. A. J. Sanyal: Advisory Panel; Self; Novo Nordisk, Consultant; Self; Akero Therapeutics, Inc., Alnylam Pharmaceuticals, Inc., Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Genentech, Inc., Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Inventiva Pharma, Lilly Diabetes, Lipocine Inc., Merck & Co., Inc., NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron Genetics Center, Siemens Corporation, Other Relationship; Self; AstraZeneca, UpToDate, Stock/Shareholder; Self; GENFIT, HemoShear Therapeutics, LLC, Indalo Therapeutics, Inc., Tiziana Life Sciences plc.
1183-P: Effect of Dairy Consumption and Its Fat Content on Gut Microbiota in Patients with Type 2 Diabetes: A Secondary Analysis of a Randomized Controlled Trial
Authors: TOMAH SHAHEEN , KOSTIC ALEKSANDAR , MITRI JOANNA , WILKINSON JEREMY E. , LI CHENGCHEN , TASABEHJI MHD WAEL , ELDIB AHMED H. , AL-BADRI MARWA , GARDNER HANNAH , HAMDY OSAMA 
Published: June 2021

Studies have demonstrated differences in gut microbial characteristics in diseases compared to healthy states. Knowledge of how diet alters the gut microbiome is limited by the lack of dietary interventional studies reporting on gut microbial characterization. We explored whether dairy foods differing in fat content alter the gut microbiota of patients with type 2 diabetes (T2D). We randomized 111 subjects with T2D into 3 groups: high-fat (HF) and low-fat (LF) dairy groups (≥ 3 servings/d of HF and LF dairy, respectively), and a control group (CON) maintained baseline dairy intake. Subjects were evaluated at baseline, 12 wk, and 24 wk. Next generation sequencing was performed using an Illumina NextSeq (2x150 bp, high output mode) in 32 subjects (16 in HF, 5 in LF, and 11 in CON). At 24 wk, featurewise testing revealed a higher Faecalibacterium prausnitzii abundance (MaAsLin2 coefficient = 0.0746, FDR-adjusted p = 0.0034; MaAsLin2 coefficient = 0.0691, FDR-adjusted p = 0.0195; respectively) and a higher Bifidobacterium pseudocatenulatum abundance (MaAsLin2 coefficient = 0.0022, FDR-adjusted p = 0.0673; MaAsLin2 coefficient = 0.0022, FDR-adjusted p = 0.1135; respectively) in LF compared to HF and CON in univariable models. Functional analyses revealed 11 significant associations including a lower abundance of UDP-glucose-derived O-antigen building blocks biosynthesis pathway (MaAsLin2 coefficient = –0.0006, FDR-adjusted p = 0.1584) related to lipopolysaccharides (LPS) production in HF compared to CON in a multivariable model and a lower L-methionine biosynthesis III pathway abundance (MaAsLin2 coefficient = –0.0015, FDR-adjusted p = 0.1975) in LF compared to HF in a univariable model.
In conclusion, consumption of ≥ 3 servings/d of LF and HF dairy changed the gut microbiota of patients with T2D compared to CON. Further analysis will reveal whether a decrease in LPS biosynthesis-related pathway in HF influences inflammation.

Disclosure
S. Tomah: Stock/Shareholder; Self; Amarin Corporation plc. O. Hamdy: Advisory Panel; Self; Nestlé, Consultant; Self; Abbott, AstraZeneca, Sanofi, Research Support; Self; Eli Lilly and Company, Gilead Sciences, Inc., National Dairy Council, Novo Nordisk, Stock/Shareholder; Self; Healthimation, LLC. A. Kostic: Other Relationship; Self; DeepBiome Therapeutics, Inc., FitBiomics, Inc. J. Mitri: Consultant; Self; L-Nutra. J. E. Wilkinson: None. C. Li: None. M. Tasabehji: None. A. H. Eldib: None. M. Al-badri: None. H. Gardner: None.

Funding
National Dairy Council; National Institute of Diabetes and Digestive and Kidney Diseases
1187-P: Time to Take Your Steroids: Circadian Regulation of Glucocorticoid Effects on Muscle Metabolism
Authors: QUATTROCELLI MATTIA , WINTZINGER MICHELLE , RATHBUN RICHARD M. 
Published: June 2021

Glucocorticoid steroids are circadian regulators of energy balance and tissue metabolism. Chronic daily intake of synthetic glucocorticoids commonly promotes insulin resistance and metabolic syndrome. In dystrophic mice, we previously showed that frequency of glucocorticoid intake determines their effects on muscle metabolism. We also found that, compared to daily intake, once-weekly intermittent administration of these drugs reduced obesity and metabolic stress biomarkers in persons with muscular dystrophy. In newer experiments, we sought to understand whether the muscle effects of pulsatile glucocorticoids extend to conditions of metabolic stress. We first investigated the muscle-autonomous effects of a single pulse of glucocorticoids. To avoid interferences from other tissues, we developed an ex vivo system to interrogate the steady-state basal metabolism in isolated wildtype muscle. Considering the intrinsic circadian regulation of glucocorticoids, we compared opposite circadian times of drug exposure in muscles isolated at day-time versus night-time of test mice. We found that within 4 hours from ex vivo exposure, prednisone increased the mitochondrial respiratory capacity rate in muscle tissue but, strikingly, only in muscle from the day-time phase. We then restricted in vivo prednisone regimens (intermittent versus daily) to the day-time of mice with dietary obesity, established with 12 weeks of ad libitum high-fat diet (60% kcal from fat). Opposite to daily regimen, intermittent diurnal prednisone promoted strength and mitochondrial oxidation in muscle of obese mice. Moreover, this correlated with partial counteraction of weight accrual and hyperglycemia, while daily prednisone exacerbated dietary obesity.
In summary, our data indicate that circadian time and dosing frequency can upend our current understanding of glucocorticoids and provide a novel strategy to boost nutrient utilization in persons with metabolic stress.

Disclosure
M. Quattrocelli: None. M. Wintzinger: None. R. M. Rathbun: None.

Funding
National Institutes of Health (K01DK121875); Cincinnati Children's Research Foundation
1199-P: The Oncogene MDM2 Induces M1 Macrophage Polarization and Adipose Tissue Inflammation in Obesity
Authors: CHENG KENNETH KING YIP 
Published: June 2021

Obesity is characterized by chronic low-grade inflammation that contributes to the pathogenesis of type 2 diabetes. Adipose tissue macrophages predominantly switch to a pro-inflammatory phenotype known as M1 during obesity. The accumulation of pro-inflammatory M macrophages in obese adipose tissue results in the secretion of a cluster of pro-inflammatory cytokines that instigate adipose tissue inflammation and insulin resistance.
Here we discovered that expression of oncoprotein murine double minute 2 (MDM2) was elevated in obese white adipose tissues. Also, MDM2 protein expression was drastically induced in macrophages activated with lipopolysaccharide (LPS) and interferon-γ (IFNγ). Mice with myeloid cells-specific MDM2 haploinsufficiency (Mye-MDM2 KO mice) were generated and subjected to high-fat-diet (HFD) feeding. After 16 weeks of HFD feeding, obesity-induced glucose intolerance and insulin resistance were alleviated in Mye-MDM2 KO mice with reference to their wild type (WT) controls. Systemic inflammation induced by LPS injection was also reduced in Mye-MDM2 KO mice. In vitro, expression of M1 genes induced by LPS and IFNγ were inhibited in bone marrow-derived macrophages with haplodeficiency of MDM2. Similarly, pharmacological inhibition of MDM2 with the small molecule inhibitor Nutlin-3a attenuates pro-inflammatory cytokines secretion by macrophages. Mechanistically, haplodeletion of MDM2 led to decreased expression of glycolytic genes in BMDM during M1 activation.
Taken together, we demonstrated a novel role of MDM2 in regulating glycolysis and M1 macrophage activation in addition to its role as a negative regulator of p53 tumour suppressor protein, suggesting it as a potential therapeutic target for treating type 2 diabetes.

Disclosure
K. Cheng: None.

Funding
Hong Kong General Research Fund (17100717)
120-LB: The Metabolic Effects of Initiation Pitavastatin vs. Rosuvastatin: Twelve Months Real-World Data on Hyperlipidemic Patients with and without Diabetes (DM)
Authors: LYGNOS DIMITRIOS , PAPAZAFIROPOULOU ATHANASIA , SOTERIADES SOTERIS , LOXAS NIKOLAOS D. , XENOU MARIA , ZOUPAS IOANNIS , FOUSTERIS EVANGELOS 
Published: June 2021

Introduction & Purpose: Statin treatment is an integral part of cardiovascular prevention. Recent studies have highlighted their potential diabetogenic action, mostly in a dose-dependent mode. Pitavastatin has studies showing that this statin may not follow the above rule. The present retrospective study highlights the metabolic effects of initiating pitavastatin vs. rosuvastatin therapy in diabetic and nondiabetic statin-naive patients.
Materials & Methods: A total of 74 hyperlipidemic patients included: 41 with DM, mean age 62.4 years (23 on Pitavastatin + 18 on Rosuvastatin)33 non-DM, mean age 62.2 years (15 on Pitavastatin + 18 on Rosuvastatin)Biochemical data were extracted from the medical records of the participants after consent.
Results: For the group of patients with DM, we found that those on Pitavastatin showed statistically significant difference in increasing HDL and decreasing total cholesterol, LDL, triglycerides and γGT. Those on Rosuvastatin showed decrease in total cholesterol, LDL, triglycerides without HDL increase. For the group of patients without DM, we found that mean fasting blood glucose was 97.2mg/dl before Rosuvastatin initiation and 104.1mg/dL after 1 year. A statistically significant difference was recorded also in reducing total cholesterol and LDL and increasing γGT. Accordingly, blood glucose was 102 before Pitavastatin initiation and 95.6mg/dL after 1 year. A statistically significant difference was recorded in HDL increase and total cholesterol, LDL, triglycerides, γGT and ALT decrease.
Conclusion: In accordance to prospective studies, this retrospective short term “real world” study highlights the rosuvastatin-induced carbohydrate metabolism disorder and the favorable effects of pitavastatin in glucose metabolism and biochemical liver markers, as well as the beneficial effect on lipid profile, regardless the presence of DM.

Disclosure
D. Lygnos: None. A. Papazafiropoulou: None. S. Soteriades: None. N. D. Loxas: None. M. Xenou: None. I. Zoupas: None. E. Fousteris: None.
1210-P: Subcutaneous-Depot Specific Adiposity Change Is Associated with the Ectopic Fat Depot and Tissue Damage in High-Fat High-Sucrose (HFHS) Fed Fabp4 Cre-ERK2 Knockout Mice
Authors: ISHINODA YUKI , IDO YASUO , NOGUCHI MIDORI , YUMITA YUSUKE , KAGAMI KAZUKI , OSAKI AYUMU , SATOH YASUSHI , ENDO SHOGO , KASUGA AKIRA , ADACHI TAKESHI , KUMAGAI HIROO 
Published: June 2021

Previous reports suggested that low subcutaneous adiposity increases the risk of cardiovascular events and diabetes. Mechanisms of depot-specific differences are still unknown. During studying tissue-specific roles of ERK2 (MAPK1), we observed Fabp4Cre mediated adipocyte-specific ERK2 knockout mice (AE2KO) with HFHS diet showed diminished the size of adipocytes in an only subcutaneous depot and increased ectopic fat depot and fibrotic steatohepatitis. The male AE2KO was created by crossing the C57BL/6 background Fabp4-Cre with ERK2flox/flox mouse. ERK2flox/flox Cre- mouse was used as a control. ERK2KO was observed only in white adipose tissues. With a normal diet, AE2KO mice showed no phenotype. HFHS diet started at age 6 weeks for 18 weeks. AE2KO exhibited 18% increase in body weight (n=8 each, p&lt;0.05). Whereas HFHS increased adipose weight, the distribution of adipocyte size showed a significant decrease in subcutaneous depot (30 vs. 60 µm in mode, p&lt;0.05 by 2-way ANOVA, n=8 each), but not in gonadal. RNA-sequence analysis (n=4, each) revealed a significant increase in expression of lipolysis gene (Prkaca, Tshr, and Adcy) and of the genes reported to cause a defect in fat storage (L3mbtl3, Pik3r1). Fasting glucose was increased and the Insulin tolerance test showed no change in plasma glucose in AE2KO compared to control (105% vs. 75% at 60 min, p&lt;0.05, n=8 each). Liver weight increased 1.8-fold (n=8, p&lt;0.05). NAS score increased (6.2 vs. 4.4, p&lt;0.05, n=6) with prominent fibrosis. The increased ectopic fat depot was also observed in skeletal muscle and kidney. Oxygen consumption and RER was not changed. ERK2 knockout in human subcutaneous preadipocyte by Crispr Cas9 decreased adipocyte differentiation by 50%, suggesting an involvement of ERK2 in adipogenesis. These results strongly indicated that ERK2 is involved in subcutaneous depot abnormality which causes ectopic fat depot and organ damage by a high caloric diet.

Disclosure
Y. Ishinoda: None. T. Adachi: None. H. Kumagai: None. Y. Ido: None. M. Noguchi: None. Y. Yumita: None. K. Kagami: None. A. Osaki: None. Y. Satoh: None. S. Endo: None. A. Kasuga: None.
1215-P: Effects of Exogenous Secretin on Postprandial Plasma Glucose and Lipids and Gallbladder Motility and Hemodynamics in Man
Authors: BENTZEN MARIA J. , HEIMBÜRGER SEBASTIAN M. NGUYEN , HARTMANN BOLETTE , HOLST JENS J. , CHRISTENSEN MIKKEL B. , KNOP FILIP K. 
Published: June 2021

Secretin is best known for its effect on pancreatic exocrine secretion. It also has osmoregulatory effects and was recently identified as a potential target for the treatment of obesity. We investigated the effects of a 5-hour intravenous (iv) secretin infusion on postprandial plasma glucose and lipids and gallbladder motility as well as hemodynamics in healthy males.
In a randomized, double-blind, placebo-controlled, crossover study, 25 healthy males (25.7 ± 6.1 (mean ± SD) years; BMI 23.4 ± 1.8 kg/m2) underwent two 5-hour iv infusions of secretin (1 pmol/kg/min) or placebo (saline), with an interposed 8-week washout period. After 30 minutes of infusion, a standardized liquid mixed meal was ingested. Prior to and with regular intervals during the 5-hour infusions, blood samples were drawn, ultrasonography of the gallbladder performed, and hemodynamics measured.
Steady-state plasma concentrations of secretin amounted to 113 ± 2 pmol/L, i.e., ~20-fold higher than physiological levels. Postprandial plasma triglyceride excursions were higher during secretin than placebo infusions (baseline-subtracted area under curve: 111 ± 49 vs. 83 ± 36 min × pmol/L [P = 0.012]), whereas excursions in glucose, glycerol and free fatty acids were similar during placebo and secretin infusions. Compared to placebo, secretin reduced maximum gallbladder ejection fraction by 32 ± 27% (P &lt;0.001) and increased mean systolic and diastolic blood pressure by 5.3 ± 4.5 (P &lt;0.039) and 2.2 ± 3.2 mmHg (P &lt;0.001), respectively, and increased heart rate by 5.5 ± 3.6 bpm (P &lt;0.001).
We conclude that a 5-hour iv infusion of secretin in healthy males has no effect on fasting and postprandial glucose levels, but reduces postprandial gallbladder contraction, while increasing plasma triglycerides, blood pressure and pulse.

Disclosure
M. J. Bentzen: None. S. M. Nguyen heimbürger: Speaker’s Bureau; Self; AstraZeneca. B. Hartmann: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. M. B. Christensen: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S.
122-LB: In Vitro Pharmacodynamic Studies of IDG-16177, a Potent GPR40 Agonist, for the Treatment of Type 2 Diabetes
Authors: YOON JONGMIN , SONG HAENGJIN , LEE DON-GIL , KIM JUNG HO , HONG DAHAE , SHIN CHORONG , JANG EUNHYE , KIM JISU , LEE SEOLHEE , JUN YEARIN , AN KYUNGMI , HONG CHANG-HEE , KWAK HYUN-JUNG , JE IN-GYU , SONG HYO-JUNG 
Published: June 2021

G-protein-coupled receptor 40 (GPR40/FFA1/FFAR1), a clinically validated anti-diabetes target, enhances insulin secretion in type 2 diabetes. It is known that the effect of glucose-stimulated insulin secretion (GSIS) in pancreatic β cells is mediated primarily through Gq. However, in a recent study, it was found that GPR40 plays a role in both G protein-mediated and β-arrestin-mediated mechanisms, and fasiglifam (TAK-875), a partial GPR40 agonist discontinued in phase 3 clinical trials, induces insulin secretion by mediating β-arrestin rather than Gq. Therefore, by using stable GPR40 cell lines and β cells, we tried to confirm the signaling mechanism and efficacy of IDG-16177, which is being developed by Ildong Pharma in first-in-human study, as a GPR40 agonist. In cells expressing recombinant human, rat, and cynomolgus monkey GPR40, IDG-16177 dose-dependently increases intracellular free Ca2+ level, with EC50 of 114.3, 103.9, and 758.8 nM, respectively, showing no significant differences between human and rat (fasiglifam EC50= 75.2, 140.4, and 906.2 nM). IDG-16177 enhances β-arrestin recruitment, which has been shown to contribute to GPR40-mediated GSIS, with an EC50 of 68.0 nM and Emax of 99.4%, and is more efficacious and potent than fasiglifam (EC50= 154.0 nM; Emax= 88.0%). IDG-16177 exhibits EC50 of 0.8 nM and 110.6 nM, in inositol phosphate 1 (IP1) accumulation assay and extracellular signal-regulated kinase (ERK) activation assay, respectively. Although IDG-16177 shows no signal at the cAMP pathway like fasiglifam, IDG-16177 (0.1~3 μM)-treated group enhances more insulin secretion than fasiglifam (1~10 μM) in HIT-T15 β cells. These studies support the potential utility of IDG-16177 for the treatment of type 2 diabetes.

Disclosure
J. Yoon: None. Y. Jun: None. K. An: None. C. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. H. Song: None. D. Lee: None. J. Kim: None. D. Hong: None. C. Shin: None. E. Jang: None. J. Kim: None. S. Lee: None.