bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Beta-Cell Response to Intravenous Exenatide (EXEN) and Arginine (ARG) in Prediabetic Subjects with Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT)
Authors: TERASAWA TOMOKO , TRIPLITT CURTIS L. , ADAMS JOHN M. , CERSOSIMO EUGENIO , DEFRONZO RALPH A. , CHAVEZ VELAZQUEZ ALBERTO O. 
Published: June 2018

Beta cell dysfunction is the main determinant of progression from prediabetes to diabetes. IFG is associated to hepatic insulin resistance, while IGT primarily reflects muscle insulin resistance. The incretin effect is decreased in diabetes, but beta cell response to GLP-1-RA in prediabetic subjects with isolated defects in fasting (i.e., IFG) and postprandial (i.e., IGT) has not been fully characterized. Twenty-five individuals matched for age/BMI: 8 healthy NGT (FPG= 93 mg%±1 2h PG=102±5 mg%, A1c=5.3±0.1%), 11 IFG (FPG=108±2, 2h PG=123±4, A1c=5.7±0.1) and 6 IGT (FPG=95±1 2h PG=162±8, A1c=5.5±0.2) received a two-step hyperglycemic clamp with IV EXENatide and ARGinine infusion. First phase insulin secretion (IS) was calculated as the acute insulin response from 0-15 min; second phase IS and IS after EXEN and EXEN-ARG infusions were calculated as the area under the curve AUC for insulin secretion (IS) during the hyperglycemic clamp (AUC-EXEN and AUC-EXEN/ARG). IS was adjusted for Matsuda index to quantify beta cell function (disposition index). First and second phase insulin secretion in response to EXEN was decreased in both IFG and IGT compared to NGT to a similar extent (p&lt;0.05). IFG individuals exhibited a marked decrease in AUC-EXEN and AUC-EXEN/ARG vs. NGT (52269 vs. 118798, p&lt;0.for EXEN, 15096 vs. 37413 for EXEN-ARG, p&lt;0.01). There was a modest, non-significant decrease in beta cell response in IGT for EXEN and EXEN-ARG vs. NGT (83266 vs. 118798 for EXEN and 22964 vs. 37413 EXEN-ARG, both p=ns).
Conclusion: Individuals with IFG manifest a severe defect in the beta cell response to GLP-1 compared to NGT healthy control subjects. In contrast, the beta cell response to GLP-1 in IGT subject is only minimally impaired. These results suggest that a GLP-1 receptor agonist might be an effective therapy to prevent progression to overt diabetes in subjects with IFG.

Disclosure
T. Terasawa: None. C.L. Triplitt: Speaker0027s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Sanofi, Novo Nordisk Inc.. J.M. Adams: None. E. Cersosimo: Research Support; Self; AstraZeneca, VeroScience, LLC.. Speaker's Bureau; Self; AstraZeneca, Sanofi, Janssen Pharmaceuticals, Inc., Eli Lilly and Company. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc.. A.O. Chavez Velazquez: None.
The Role of Incretins and Insulin Clearance in Postprandial Hyperinsulinemia in Black Women—The Federal Women Study
Authors: CHUNG STEPHANIE T. , COURVILLE AMBER B. , ALDANA PAOLA C. , ONUZURUIKE ANTHONY , BERNSTEIN SHANNA , GALVAN-DE LA CRUZ MIRELLA , MABUNDO LILIAN , WALTER MARY , SUMNER ANNE E. 
Published: June 2018

Postprandial (PP) hyperinsulinemia may be an important cardiometabolic risk factor. Since black compared to white women have greater hyperinsulinemia after IV glucose testing, they may also be at risk for PP hyperinsulinemia. Therefore, we compared by race and menopausal status, early (0-30min) incremental area under the curve for insulin response (insulin:glucose iAUC30), intact glucagon-like peptide-1 (iGLP-1 iAUC30), glucose-dependent insulinotropic peptide (GIP iAUC30) and insulin clearance (insulin:C-peptide iAUC30) in 1federally employed women without diabetes (48% African American, 14% African immigrant, 38% white; age 44±10y (mean±SD), range 24-62y, BMI 30±5 kg/m2, range 21-45 kg/m2) who underwent a 2 hour mixed meal test (52% carbohydrate, 15% protein, 33% fat). Glucose tolerance status was determined by OGTT. No differences by race in glucose tolerance status, BMI, iGLP-1 iAUC30, or GIP iAUC30 were noted in pre- or postmenopausal women (Table). PP insulin response was higher and insulin clearance was lower in blacks (Table). Overall, PP hyperinsulinemia in pre- and post-menopausal black vs. white women was associated with lower insulin clearance, but not differences in incretin response.Table. Postprandial Glucose, Insulin and Incretin Response by Race and Menopausal Status.Pre-menopausalPostmenopausalBlack (n=49)White (n=29)P- valueBlack (n=18)White (n=12)P-valueBMI (kg/m2)30±432± 60.2029±428±50.24Prediabetes n (%)10 (20)6 (21)0.4213 (72)6 (50)0.50iGLP-1 iAUC30 (pg/mL•min)118±83108±880.3973±5989±770.82GIP iAUC30 (pg/mL•min)2704±15142961±33130.842651±13433661±46890.90Insulin response Log Insulin:Glucose iAUC304.9±6.11.9±1.3&lt;0.013.3±1.71.0±0.4&lt;0.01Insulin clearance Log Insulin:C-peptide iAUC30 0.93±0.031.17±0.05&lt;0.011.13±0.081.26±0.040.28

Disclosure
S.T. Chung: None. A.B. Courville: None. P.C. Aldana: None. A. Onuzuruike: None. S. Bernstein: None. M. Galvan-De La Cruz: None. L. Mabundo: None. M. Walter: None. A.E. Sumner: None.
Treatment of Hyperglycemia with Empagliflozin, With or Without Metformin, Improves Islet Endothelial Cell Health and Insulin Secretion in db/db Diabetic Mice
Authors: HOGAN MEGHAN F. , HACKNEY DARYL J. , APLIN ALFRED , MUNDINGER THOMAS O. , ZRAIKA SAKENEH , HULL REBECCA L. 
Published: June 2018

Islet endothelial dysfunction occurs in diabetic mice and results in impaired insulin release in vitro. Previously, we found that 12-week treatment of db/db mice with the SGLT2 inhibitor empagliflozin (EMPA) improved islet endothelial dysfunction. Here, we determined if this occurs with shorter treatment duration, is associated with increased insulin release and whether EMPA combined with metformin (MET) provides additional benefit. 6-week old male diabetic C57BL/KsJ.db/db mice and littermate controls (db/+;+/+) were treated with EMPA (20 mg/kg/d in diet), MET (0.5 g/kg/d in water), EMPA+MET, or vehicle (VEH) for 6 weeks. A subset of mice (n=3-5) underwent IV glucose tolerance tests to determine insulin release. mRNA levels of cell adhesion molecules E-selectin (Sele) and vascular cell adhesion molecule 1 (Vcam1), proinflammatory cytokine interleukin-6 (Il6) and vasoconstrictor endothelin-1 (Edn1), were assessed. EMPA treatment lowered plasma glucose, increased insulin release and improved islet endothelial health (Table). MET had a similar effect, but was less effective than EMPA, while EMPA+MET was more effective in improving endothelial function but did not further increase insulin release. Improving islet endothelial health with EMPA may have beneficial effects on beta-cell function in human type 2 diabetes.

Disclosure
M.F. Hogan: None. D.J. Hackney: None. A. Aplin: None. T.O. Mundinger: None. S. Zraika: None. R.L. Hull: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company.
Increased Gluconeogenesis Is Not an Early Feature of Whole-Body Insulin Resistance in Black Women—The Federal Women Study
Authors: CHUNG STEPHANIE T. , HAYMOND MOREY W. , ONUZURUIKE ANTHONY , MABUNDO LILIAN , GARRAFFO H. MARTIN , WALTER PETER J. , COURVILLE AMBER B. , GHARIB AHMED M. , CHACKO SHAJI , SUMNER ANNE E. 
Published: June 2018

In contrast to white women, fasting hyperglycemia is not an early diabetes risk marker in black women. The etiology of this racial difference in risk is unknown but could be related to differences in rates of gluconeogenesis and hepatic fat in black women. Using stable isotope tracers [2H2O], [6,62H2]glucose, and ([2H5]glycerol), we partitioned basal glucose production into its two components (gluconeogenesis and glycogenolysis) and measured basal whole body lipolysis. Whole body (SI), hepatic (HIS) and adipose tissue insulin sensitivity were calculated in two groups of federally employed pre-menopausal women, without diabetes: 24 black and 19 white; age 37±6 (mean±SD), range 25-50y; BMI 33±6, range 24.9-45.2 kg/m2. Hepatic and visceral fat were measured by proton MRS. The prevalence of prediabetes (17% vs. 26%), age and BMI were similar in blacks and whites, all P&gt;0.4). Black women had less fasting hyperglycemia (4% vs. 22%, P=0.1), lower visceral and hepatic fat (P&lt;0.01) but similar SI, adipose tissue insulin sensitivity and whole body lipolysis (all P&gt;0.5). Basal glucose, insulin and FFA concentrations were similar in both groups (P&gt;0.05). Blacks had lower glucose production (2.52±0.34 vs. 2.75±0.28 mg·kglbm-1·min-1, P&lt;0.05), fractional gluconeogenesis (57.6±10.6 vs. 66.3±11.4%, P=0.02), and absolute gluconeogenesis (1.44±0.28 vs. 1.77±0.31 mg·kglbm-1·min-1, P&lt;0.01). HIS correlated with SI and hepatic fat (both r=0.5, P&lt;0.01) and the relationship did not differ by race (P&gt;0.05). However, at the same SI blacks had higher HIS (intercepts P&lt;0.01).
In summary, black women had relatively preserved HIS and lower hepatic fat, while white women had higher gluconeogenesis and hepatic fat associated with fasting hyperglycemia. Fasting glucose may be a poor early diabetes marker in black women because gluconeogenesis was low despite whole-body insulin resistance.

Disclosure
S.T. Chung: None. M.W. Haymond: Advisory Panel; Self; Zealand Pharma A/S. Other Relationship; Self; Xeris Pharmaceuticals, Inc.. A. Onuzuruike: None. L. Mabundo: None. H. Garraffo: None. P.J. Walter: None. A.B. Courville: None. A.M. Gharib: None. S. Chacko: None. A.E. Sumner: None.
Palmitic Acid Esters of Hydroxy Stearic Acids Are Hepatic Insulin Sensitizers in Chow and High-Fat Diet (HFD)–Fed Mice
Authors: SANTORO ANNA , ZHOU PENG , PERONI ODILE D. , SYED ISMAIL , NELSON ANDREW T. , SIEGEL DIONICIO , SAGHATELIAN ALAN , KAHN BARBARA 
Published: June 2018

Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs), bioactive lipids with potent anti-inflammatory and antidiabetic effects, reduce ambient glycemia and improve glucose tolerance and insulin sensitivity in insulin resistant HFD-fed mice. We aimed to determine the mechanisms by which PAHSAs improve insulin sensitivity. We treated chow- and HFD-fed mice with 5-PAHSA (0.1 mg/day) and 9-PAHSA (0.4 mg/day) by SQ osmotic minipumps for 13 weeks. Serum 5-PAHSA levels increased 3.5 fold and 9-PAHSA 2.5 fold in chow-fed mice, while 5-PAHSA levels increased 17 fold and 9-PAHSA 6 fold in HFD-fed mice. PAHSAs had no effect on weight gain or fat mass. We performed hyperinsulinemic euglycemic clamps (2.5 mU/Kg/min insulin infusion rate). PAHSA treatment increased systemic insulin sensitivity in both chow- [glucose infusion rate (GIR): vehicle 13±2 vs. PAHSA 27±4 mg/kg/min] and HFD-fed mice (GIR: vehicle 2±0.5 vs. PAHSA 10±3 mg/kg/min). Endogenous glucose production (EGP) was suppressed 28% by insulin in vehicle-treated mice and 55% in PAHSA-treated mice on chow diet. Remarkably, while insulin failed to suppress EGP in vehicle-treated HFD-fed mice, PAHSA treatment led to a 37% reduction in EGP. PAHSAs also decreased glycemia during a pyruvate tolerance test, indicating that suppression of hepatic gluconeogenesis contributes to the EGP improvement. Mechanistic studies showed that PAHSAs inhibit basal and glucagon-stimulated EGP and reduce cAMP in isolated hepatocytes. This effect is blocked by pertussis toxin indicating it is mediated by Gα/i protein-coupled receptors. PAHSAs also reduce G6pase activity and phosphorylation of CREB in liver. Sum: PAHSAs are systemic insulin sensitizers and augment insulin action on EGP in vivo. In vitro, PAHSAs reduce EGP through a cAMP dependent pathway involving Gα/i protein-coupled receptors. Thus, PAHSAs could be effective antidiabetic agents and the pathways they engage could provide novel drug targets for type 2 diabetes.

Disclosure
A. Santoro: None. P. Zhou: None. O.D. Peroni: None. I. Syed: None. A.T. Nelson: None. D. Siegel: None. A. Saghatelian: None. B. Kahn: Advisory Panel; Self; Janssen Research & Development. Research Support; Self; Janssen Research & Development. Advisory Panel; Self; Alterna Biotech.
Exenatide Treatment Improves Mitochondrial Metabolism and Hepatic Insulin Sensitivity in Mice with Nonalcoholic Steatohepatitis (NASH)
Authors: KALAVALAPALLI SRILAXMI , BRIL FERNANDO , VERGARA ARIANA , SUNNY NISHANTH , CUSI KENNETH 
Published: June 2018

Exenatide (Exe) is a glucagon-like peptide-1agonist (GLP-1) that enhances insulin production, slows gastric emptying and reduces appetite. Nonalcoholic fatty liver disease (NAFLD), and its more severe form known as NASH, are frequent complications of T2DM. As mitochondrial dysfunction and lipotoxicity are central features of NASH, we tested whether Exe improved mitochondrial oxidative function and hepatic insulin resistance in this setting. Mice (C57/BL6) were fed either a high-fructose, high trans-fat (TFD) diet for 24 weeks to induce NASH or a control diet. After 16 weeks, mice were randomly assigned for the final 8 weeks to subcutaneous Exe (30 µg/kg/day) or vehicle. After an overnight fast, mice received an i.v. infusion of [13C3] propionate and [3,4-13C2] glucose to evaluate mitochondrial metabolism by NMR-based 13C-isotopomer analysis. Targeted metabolic analysis of lipids was measured by LC-MS/MS. Exenatide reduced liver weight and intrahepatic triglyceride content (TFD: 287±23 vs. Exe: 198±27 mg/g liver, p=0.03). Fasting plasma glucose, insulin, FFA and TGs were all significantly lower with Exe. Expression of lipogenic genes and inflammatory markers were significantly lowered by Exe. Moreover, Exe reduced hepatic glucose production, TCA cycle flux, anaplerosis and pyruvate cycling. Exenatide administration improved the lipidomic profile, and decreased hepatic byproducts resulting from incomplete fat oxidation (typically associated with insulin resistance/lipotoxicity), such as diacylglycerols (TFD: 111±13 vs. Exe: 64±13 µmol/g protein, p=0.02) and ceramides (TFD: 1.6±0.1 vs. Exe: 1.3±0.1 µmol/g protein, p=0.02).
Conclusion: In an animal model of NASH, Exe improves hepatic insulin sensitivity, mitochondrial TCA cycle flux and reduces toxic lipid metabolites resulting in an improvement of mitochondrial function. Taken together, these results suggest that Exe may be of clinical value in the management of NASH.

Disclosure
S. Kalavalapalli: None. F. Bril: None. A. Vergara: None. N. Sunny: None. K. Cusi: Consultant; Self; Janssen Global Services, LLC., Eli Lilly and Company. Research Support; Self; Cirius Therapeutics. Other Relationship; Self; Nordic Bioscience. Research Support; Self; Novartis Pharmaceuticals Corporation, Novo Nordisk Inc.. Other Relationship; Self; Quest Diagnostics. Research Support; Self; Zydus Pharmaceuticals (USA) Inc.. Other Relationship; Self; OWL metabolomics, Echosens. Research Support; Self; Janssen Global Services, LLC.. Consultant; Self; Tobira Therapeutics, Pfizer Inc..
Hepatic Insulin/Snail1 Axis Protects against Liver Steatosis and Insulin Resistance through Epigenetically Suppressing Lipogenesis
Authors: LIU YAN , IRELAND NICOLE M. , JIANG LIN , RUI LIANGYOU 
Published: June 2018

Insulin stimulates hepatic lipogenesis that drives nonalcoholic fatty liver disease (NAFLD). Paradoxically, insulin resistance is associated with increased hepatic lipogenesis in obesity, and the underlying mechanism remains poorly understood. Here, we delineate an insulin-PI 3-kinase-Snail1 pathway that links metabolic signals to epigenetic reprogramming of de novo lipogenesis in the liver. We found that insulin robustly upregulated Snail1 in both primary hepatocytes and liver in a PI 3-kinase-dependent manner. Notably, the hepatic insulin-PI 3-kinase-Snail1 pathway was severely impaired in obesity. Overexpression of Snail1 blocked, whereas deletion of endogenous Snail1 enhanced, insulin-stimulated lipogenesis in hepatocytes. Hepatocyte-specific deletion of Snail1 exacerbated, whereas liver-specific overexpression of Snail1 ameliorated, dietary NAFLD in mice. Ablation of hepatic Snail1 also attenuated NAFLD-associated insulin resistance and glucose intolerance; conversely, liver-specific overexpression had the opposite effect. Mechanistically, Snail1 bound to the fatty acid synthase (Fasn) promoter and repressed Fasn promoter activity through histone modifications. Our data suggest that insulin pathways bifurcate into the canonical lipogenic and the noncanonical Snail1 two arms wherein the Snail1 arm puts a brake on the lipogenic arm, curbing excessive lipogenesis, liver steatosis, and lipotoxicity. Thus, insulin-resistance-induced impairment in the Snail1 arm contributes to increased lipogenesis in obesity.

Disclosure
Y. Liu: None. N.M. Ireland: None. L. Jiang: None. L. Rui: None.
Elevated Serum Cytokeratin-18 Levels in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease
Authors: LEE TAO-CHUN 
Published: June 2018

Background: Cytokeratin-18 (CK-18) is a caspase-cleaved fragment released by injured hepatocytes, and serum levels of CK-18 were believed to be a marker of hepatic cell damage such as inflammation. Patients with type 2 diabetes (T2DM) were well known to have a high prevalence of the fatty liver condition. However, rare studies had been reported the serum CK-18 level in patients with T2DM and investigated the association between the levels with metabolic biomarkers.
Material and Methods: Healthy participants and T2DM patients who followed in the specialized diabetes polyclinic were enrolled. Physical and metabolic factors were collected,and NAFLD was screened by abdominal ultrasound and fatty liver index. Cytokeratin 18 level was detected by commercially available immunoassay.
Results: There were 22.8% (29/127) and 35.9%(42/117) participants were diagnosedwith NAFLD in the non-DM group and T2DM group, respectively. Both serum levels of CK-18 M30 and CK-18 M65 were significantly higher in patients with T2DM as compared with those of the non-DM group. Patients with nonalcoholic fatty liver disease (NAFLD) had higher serum CK-18 M30 level whatever withT2DM (205.8±135.1 vs. 108.4±66.19 U/L; P&lt;0.001) or without (177.69±70.53 vs. 87.07±34.57 U/L; P003C0.001). Similarly, serum CK-18 M65 was also higher in patients with NAFLD in theT2DM group (513.9±271.2 vs. 285.4±115.3 U/L; P&lt;0.001)and in the non-DM group (353.5±162.4 vs. 248.51±111.3 U/L; P&lt;0.001).Multi-variate regression analyses demonstrated that fasting plasma glucose was independently and significantly associated with CK-18 M30 (β coefficient: 0.002; P=0.011)) and CK-18 M65 (β coefficient:0.003; P&lt;0.001). These results suggested that CK-18 level was closely connected with diabetes mellitus.
Conclusions: Independent of NAFLD, our result suggests that CK-18 level was closely associated with the hyperglycemic milieu. The association between serum CK-18 and T2DM may worth for further investigation.

Disclosure
T. Lee: None.
The Importance of Metabolic Syndrome in Patient Progression to Type 2 Diabetes Mellitus
Authors: GLASHEEN WILLIAM P. , CORDIER TRISTAN A. , RENDA ANDREW , DONG YANTING , CHIGULURI VINAY , HAUGH GIL 
Published: June 2018

Introduction: Type 2 diabetes mellitus (T2DM) is a common chronic condition associated with significant risk of morbidity and mortality. Metabolic syndrome (MetS) is a chronic prevalent condition, but rarely documented in administrative data. A positive MetS finding comes from tracking five clinical dimensions, and employing a minimum three condition threshold. The aim of this study was to validate a new administrative data MetS algorithm by showing its relevance in tracking progression to T2DM.
Methods: A cohort of 1,321,314 persons enrolled for 3 years in a Medicare Advantage health and wellness company with no evidence of diabetes in the first year were tracked in the subsequent 2 years. Demographic information along with evidence of prediabetes from administrative claims and lab data were documented for the first year. Algorithms to detect MetS and Charlson Comorbidity Index (CCI) were applied to the first year data. For the subsequent 2 years, ICD-10 diagnostic information from administrative data was tracked to identify individuals who progressed into T2DM. Descriptive statistics and Poisson regression analysis were used to assess correlation between first year data and subsequent relative risk for T2DM.
Results: The study population was 87.3% white, 56.4% female, mean age of 70.6, and an overall T2DM progression rate of 8.63%. In the first year, 79.3% had no MetS and no prediabetes (NMNP), 6.9% had MetS but no prediabetes (MNP), 6.8% had no MetS but with prediabetes (NMP), and 7.1% had MetS with prediabetes (MP). Compared to NMNP, the MNP group had an elevated risk of progression to T2DM (RR 1.63 | 95% CL: 1.60, 1.67), as did NMP (1.73 | 1.70, 1.76), and MP (2.47 | 2.43, 2.51). Nonwhite races (1.31 to 1.52), male (1.21), and higher CCI scores (1.02 to 1.45) all were associated with elevated and significant relative risk of T2DM.
Conclusion: Our findings reveal that use of MetS diagnosis and consideration of patient demographics and CCI risk score yield valuable information regarding risk of T2DM.

Disclosure
W.P. Glasheen: None. T.A. Cordier: Employee; Self; Humana Inc.. Stock/Shareholder; Self; Humana Inc.. A. Renda: None. Y. Dong: None. V. Chiguluri: None. G. Haugh: None.
Growth Differentiation Factor 15 Ameliorates Nonalcoholic Steatohepatitis Associated with Metabolic Syndrome in Mice
Authors: LEE MYUNG-SHIK , LEE YONG-HO , KIM SEONG HUN , KIM KOOK HWAN 
Published: June 2018

Growth differentiation factor 15 (GDF15) is an endocrine hormone belonging TGFβ superfamily member. GDF15 administration or GDF15 overexpression has been reported to have anti-obesity and antidiabetic effects. Although nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is frequently associated with metabolic syndrome or diabetes, the functional role of endogenous GDF15 and therapeutic effect of exogenous GDF15 in NASH associated metabolic syndrome have not been addressed. We studied whether GDF15 has therapeutic effects on NASH and associated metabolic syndrome.
To this end, Gdf15-knockout and Gdf15-transgenic mice were employed, and mice were fed Amylin liver NASH (AMLN) diet as a physiologically relevant dietary mouse model of NASH associated with metabolic syndrome.
GDF15 expression was increased in the livers of mice fed AMLN diet and human subjects with NASH. Elevated expression of GDF15 was due to diet-induced endoplasmic reticulum (ER) stress in the liver. Importantly, Gdf15-knockout mice exhibited deteriorated metabolic syndrome and aggravated NASH phenotypes such as increased steatosis, hepatic inflammation, fibrosis and liver injury. Furthermore, we found that GDF15 directly suppresses expression of fibrosis-related genes and osteopontin (OPN) in the liver in vivo. OPN expression was increased in hepatocytes and stellate cells in the liver of Gdf15-knockout mice. Finally, we found that GDF15-transgenic mice showed attenuated NASH phenotypes and improved glucose tolerance in mice fed AMLN diet. Our results suggest that induction of endogenous GDF15 is a compensatory mechanism to protect against NASH associated with metabolic syndrome and that GDF15 could be an attractive therapeutic candidate for treatment of these diseases.

Disclosure
M. Lee: Other Relationship; Self; Jeil Pharmaceutical Co. Ltd.. Y. Lee: None. S. Kim: None. K. Kim: None.