bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retinol Binding Protein 4 Impairs Pancreatic Beta-Cell Function, Leading to the Development of Type 2 Diabetes
Authors: HUANG RONG , BAI XINXIU , LI XUEYAN , ZHAO LINA , XIA MIN 
Published: June 2018

Circulating Retinol binding protein 4 (RBP4), the specific transport protein for vitamin A, has been implicated in insulin resistance and type 2 diabetes. Pancreatic beta cell failure plays a decisive role in the onset and the progression of type 2 diabetes. However, the effect of RBP4 on beta cell function and the molecular mechanisms are far from clear. The direct effect of RBP4 on islet function was assessed by treating primary isolated islets from C57BL/J mice with different dose of RBP4 (0, 20, 40, 60 μg/ml) for 24 hour or with 60ug/ml RBP4 for different time points (0, 12, 18,24 hours). We found that RBP4 could dose and time dependently inhibit the glucose stimulated insulin secretion (GSIS). To further identify the role of RBP4 on islet beta cell function. RBP4-overexpressing mice (RBP4-Tg) were generated. Compared to the wild type group, the islets isolated from RBP4-Tg mice showed a significant decrease of insulin secretion in response to glucose (∼50%) and KCl (∼70%). The Dynamic insulin secretion of the isolated islets of RBP4-tg mice in response to glucose was further characterized. RBP4 could dramatically inhibit first-phase GSIS by up to 80%. In consistent to these in vitro findings, RBP4-tg mice showed a progressive decrease of GSIS (8weeks, 12weeks, 16weeks) which appeared as early as 8weeks. While the glucose tolerance of these mice was not significantly impaired until 12 weeks by intraperitoneal glucose tolerance test and the insulin sensitivity was not changed until 16 weeks by intraperitoneal insulin tolerance test respectively.
In conclusion, RBP4 could impair pancreatic beta cell function which may lead to the onset and the development of T2DM.

Disclosure
R. Huang: None. X. Bai: None. X. Li: None. L. Zhao: None. M. Xia: None.
Sodium-Glucose Cotransporter 2 Inhibitors Improve Pancreatic ß-Cell Function by the Relief of ß-Cell Distress in Japanese Type 2 Diabetes
Authors: YAMAMOTO TSUNEHIKO 
Published: June 2018

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapies have demonstrated efficacy and safety in the treatment of type 2 diabetes (T2D). Recent studies suggested the potential roles of SGLT2i in the restoration of pancreatic β-cell function. SGLT2i is a new class of antidiabetic agent, independent from insulin action, however, its mechanism are not enough elucidated. We investigated the effects of SGLT2i on pancreatic β-cell function in T2D patients. This open-label, single-arm trial was conducted in our single medical hospital. A total of 30 patients (mean age 57.9±9.0 years, hemoglobin A1c 8.35±1.09%, BMI 29.2±4.5 kg/m2, diabetes duration 9.6±7.0 years) received some kinds of SGLT2i, canagliflozin, dapagliflozin or empagliflozin. Any change in the medication of oral hypoglycemic agents was not prohibited during the period of this trial. After 3 months of treatment, changes in hemoglobin A1c,body weight, fat mass, proinsulin-to-C-peptide ratio (ProINS/CPR, as an indicator of distressed pancreatic β-cell) and secretory units of islets in transplantation index (SUIT, as a marker of pancreatic β-cell function) were evaluated. Mean hemoglobin A1c decreased from 8.35 to 7.39% (p&lt;0.01), and body weight decreased from 81.3 to 79.3 kg (p&lt;0.01), significantly. ProINS/CPR ratio decreased from 0.037 to 0.031 (p=0.022), whereas SUIT index restored from 35.3 to 47.8 (p&lt;0.01). We found a linear negative relationship between δProINS/CPR ratio and δSUIT index (r(2)=0.338, p&lt;0.01). Multivariate analysis revealed that only baseline ProINS/CPR ratio was independently associated with SUIT index restoration (β=0.673, p&lt;0.01), whereas older age, longer diabetic duration, body weight, fat mass, hemoglobin A1c were not associated. These results suggest that SGLT2i improves pancreatic β-cell function by the relief of β-cell distress, independent of the efficacy of glycemic control and body weight loss effect.

Disclosure
T. Yamamoto: None.
Risk Factors for Major Atherosclerotic Cardiovascular Events (MACE) in Type 1 Diabetes (T1D)—The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study
Authors: MILLER RACHEL G. , ORCHARD TREVOR J. 
Published: June 2018

The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications follow-up study (EDIC) recently reported that after age mean HbA1c was the strongest predictor of MACE over 27 year of follow-up. The DCCT/EDIC cohort had a short T1D duration at baseline (mean 6 yr) and those with high blood pressure or cholesterol were excluded so it is unclear if these results apply to longer T1D durations and without risk factor exclusion. We thus replicated these analyses in the Pittsburgh EDC study a prospective cohort study of childhood onset (&lt;17 yr) T1D with 25 year of follow-up and similar age (mean 27 year in both studies) but longer T1D duration (mean 18 yr) at baseline. EDC participants were diagnosed 1950-1980 (n=658 49% women) and examined at 1986-88 baseline. Follow-up exams occurred at 2, 4, 6, 8, 10, 18 and 25 years. MACE incidence (CVD death, MI, stroke) was ascertained by death certificate or self reported and confirmed with medical records. Participants with prevalent CVD were excluded (n=54). Baseline (BL), time varying updated mean (UM) and time varying most recent (MR) risk factors were assessed in Cox models as in DCCT/EDIC. In EDC 18% (107) developed MACE vs. 6% in DCCT/EDIC. The final multivariable model for MACE comprised BL T1D duration (HR 1.1, p&lt;.001), MR albumin excretion rate (AER) (HR 1.3, p&lt;.001), UM SBP (HR 1.03, p&lt;.001), BL smoking (HR 1.9, p=0.003), UM LDLc (HR 1.01, p=0.03) and UM HbA1c (HR 1.2, p=0.03). In DCCT/EDIC the HbA1c effect size was larger while T1D duration, UM SBP, MR (not UM as in EDC) LDLc and MR (not BL as in EDC) smoking predicted with similar effect sizes. ACE inhibitors (protective) and pulse rate also predicted MACE in DCCT/EDIC. While AER was a strong predictor in EDC no renal markers were significant in DCCT/EDIC. These results suggest that at longer T1D duration much of the HbA1c effect on MACE risk is mediated through other factors as recently reported by DCCT/EDIC.

Disclosure
R.G. Miller: None. T.J. Orchard: None.
IGFBP2 Is Increased after Gastric Bypass in Humans—Potential Impact on Hepatic Metabolism
Authors: YUCHI YIXING , CAI WEIKANG , TAKAGI TOKIYO , PAN HUI , DREYFUSS JONATHAN , FOSTER KATHLEEN , VERNON ASHLEY H. , SIMONSON DONALD C. , GOLDFINE ALLISON , HOEFLICH ANDREAS , PATTI MARY E. 
Published: June 2018

To identify molecular mechanisms contributing to postoperative metabolic improvements after Roux-en-Y gastric bypass (RYGB), we performed comprehensive proteomic analysis of fasting human plasma samples obtained from the SLIMM-T2D longitudinal clinical trial, which randomized obese individuals with T2D to RYGB surgery or a one-year intensive medical diabetes and weight management (DWM) program, and followed them for 3 years. Somalogic proteomic analysis was performed on plasma collected in the fasting state at baseline and during longitudinal follow-up, and proteins differentially abundant in RYGB vs. DWM at each time point were identified. The protein with highest magnitude of differential abundance at 3 years was insulin-like growth factor binding protein 2 (IGFBP2), upregulated by 2.2-fold in RYGB vs. DWM (p=4.37E-06); differences were confirmed by ELISA. IGFBP2 inversely correlated at 3 years with BMI (r=-0.74, p=5.31E-05) and HbA1c (r=-0.68, p=0.00004). Notably, IGFBP2 levels were increased at the first postoperative study visit (10% weight loss) following RYGB or at similar weight loss for the DWM group, suggesting an early weight-independent contribution.
IGFBP2 is predominantly expressed in liver and upregulated after RYGB in mice (2.8-fold at 8 weeks, GSE68812). To identify IGFBP2-dependent mechanisms contributing to improved hepatic metabolism, we overexpressed mouse IGFBP2 or control vector in mouse AML12 hepatocytes, achieving a 6-fold increase in IGFPB2 protein. qPCR revealed 15-30% downregulation of lipogenic genes (e.g., Fasn, Srebp1) with a 2-fold increase in expression of genes regulating fatty acid oxidation (e.g., Ppara, Ppargc1a). Analysis of metabolism (Seahorse flux analyzer) revealed increased fatty acid oxidation (3-fold, p&lt;0.01 for IGFBP2 vs. control).
In conclusion, increased IGFBP2 expression may contribute to improved hepatic lipid oxidative metabolism, and thus induce systemic metabolic improvement after RYGB surgery.

Disclosure
Y. Yuchi: None. W. Cai: None. T. Takagi: None. H. Pan: None. J. Dreyfuss: None. K. Foster: None. A.H. Vernon: None. D.C. Simonson: Advisory Panel; Self; GI Windows, Inc.. Stock/Shareholder; Self; GI Windows, Inc.. Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. A. Goldfine: Employee; Self; Novartis AG. A. Hoeflich: None. M.E. Patti: Research Support; Self; Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Xeris Pharmaceuticals, Inc.. Research Support; Self; Ethicon US, LLC., Coviden, MedImmune. Other Relationship; Self; Novo Nordisk Inc., XOMA Corporation, AstraZeneca, Nestlé. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eiger BioPharmaceuticals.
The SGLT2 Inhibitor Canagliflozin Induces Catabolic Transcriptional and Metabolic Switching and Increases FGF-21 in Mice with Dietary Obesity
Authors: OSATAPHAN SORAVIS , MACCHI CHIARA , SALES VICENCIA , KOZUKA CHISAYO , CHIMENE-WEISS JEREMY I. , TANGJAROENPAISAN YANIN , MORNINGSTAR JORDAN , GERSZTEN ROBERT , PATTI MARY E. 
Published: June 2018

Given the impact of SGLT2 inhibitors to reduce overall mortality and CV risk in T2D, improved understanding of cellular and transcriptional mechanisms responsible for metabolic effects is required. We fed C57BL/6J mice a 60% high fat diet (HFD) for 4 weeks prior to assignment to one of 3 groups: (1) 60% HFD, (2) HFD with canagliflozin (CANA, 25 mg/kg/day), and (3) HFD weight-matched (WM) to CANA via caloric restriction. Mice were analyzed after 4-8 weeks. CANA reduced fasting glucose by 47% (P&lt;0.0001), improved glucose tolerance, and 25% lower body weight vs. HFD (p&lt;0.0001). CANA promoted shift toward lipid utilization, with respiratory quotient &lt;0.7 even during feeding, and a 3.7 and 2.0-fold increase in plasma and liver β-hydroxybutyrate (both p&lt;0.01 vs. HFD). In parallel, liver glycogen and cholesterol were reduced by 55% and 28%, and triglycerides were shifted toward polyunsaturated species.
To identify potential mechanisms responsible for these fasting-like phenotypes, we analyzed the molecular impact of CANA. Liver transcriptomic analysis revealed marked downregulation of lipogenesis, glycolysis, and steroid synthesis pathways (p&lt;0.01), while the lipid oxidative regulatory genes PPARα and PGC1α were increased by 2.8 and 4-fold, respectively. CANA significantly increased hepatic FAD+ (2.4-fold) and AMP (1.3-fold), in parallel with a 12-fold increase in AMPK phosphorylation and 50% reduction in Tor-dependent phosphorylation of S6. Hepatic gene expression of FGF-21, a hormonal regulator of fatty acid oxidation and ketogenesis, was increased by 4.5-fold, with parallel 2.2-fold increase in plasma FGF-21 in CANA-treated mice (p&lt;0.vs. HFD for both). These effects were independent of insulin sensitivity or glucagon signaling. Collectively, these data demonstrate CANA induction of a fasting-like state by coordinated transcriptional-metabolic reprogramming, and identify FGF-21 as a potential molecular metabolic switch.

Disclosure
S. Osataphan: None. C. Macchi: None. V. Sales: None. C. Kozuka: None. J.I. Chimene-Weiss: None. Y. Tangjaroenpaisan: None. J. Morningstar: None. R. Gerszten: None. M.E. Patti: Research Support; Self; Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Xeris Pharmaceuticals, Inc.. Research Support; Self; Ethicon US, LLC., Coviden, MedImmune. Other Relationship; Self; Novo Nordisk Inc., XOMA Corporation, AstraZeneca, Nestlé. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eiger BioPharmaceuticals.
The Association of Impaired Fasting Glucose and Serum Fibroblast Growth Factor-21 (FGF-21)
Authors: KIM HANBYUL , CHO HOCHAN 
Published: June 2018

Prediabetes includes impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) and there is a strong probability that prediabetes will lead to diabetes mellitus (DM). Serum fibroblast growth factor 21 (FGF-21) is known to increase as a compensatory response to metabolic imbalance under conditions such as obesity, metabolic syndrome, and DM. This study aimed to identify the relationship of serum FGF-21 to prediabetes and to biomarkers of related metabolic diseases. Three hundred five Korean adult patients participated in a cohort study from June 2012 to December 2015. Study subjects comprised of those with normal glucose tolerance(n=165), prediabetes(IFG, IGT, n=87) and type 2 diabetes(n=54). The biochemical parameters were analyzed using auto-analyzer, and the level of FGF-21 was estimated using an ELISA kit. The analysis revealed that FGF-21 levels were significantly higher in the Prediabetes group compared to those in the normal group(193.94±10.62, 343.49±60.94)(P=0.004). One-way ANCOVA was conducted on the correlations between serum FGF-21 levels and other parameters, dyslipidemia(F=7.428, P=0.007), HbA1c(F=11.874, P=0.001) was show statistical significance.
In conclusion, our results revealed that serum FGF-21 level serves as a marker predicting IFG.

Disclosure
H. Kim: None. H. Cho: None.
Low Hepatic Fat and Stearoyl-CoA Desaturase Activity Contribute to Paradoxically Normal Triglyceride-Rich Lipoproteins in Insulin Resistant Black Women—The Federal Women Study
Authors: CHUNG STEPHANIE T. , GALVAN-DE LA CRUZ MIRELLA , BERNSTEIN SHANNA , ONUZURUIKE ANTHONY , MATTHAN NIRUPA R. , OUWERKERK RONALD , MABUNDO LILIAN , SAMPSON MAUREEN L. , COURVILLE AMBER B. , GHARIB AHMED M. , LICHTENSTEIN ALICE H. , REMALEY ALAN , SUMNER ANNE E. 
Published: June 2018

In black women, triglycerides (TG) are paradoxically normal in the presence of insulin resistance (IR). This TG paradox while partially explained by low visceral fat, might be further clarified by delineating the association of triglyceride rich lipoprotein (TRLP) subclasses with hepatic fat, IR and stearoyl-CoA enzyme activity (SCD-116, a marker of de novo lipogenesis). We hypothesized that fasting TRLP, hepatic fat and SCD-116 activity would be lower in black vs. white women. In 122 federally employed women without diabetes, we compared fasting TRLP number and size (measured with NMR) in 73 black (58 African American and 15 African immigrant) and 49 white; age 44±10 (mean±SD), range 24- 62y; BMI 30.0±5.6, range 20.3-45.2 kg/m2. Hepatic and visceral fat were measured by proton MRS. RBC fatty acid profiles were measured by gas chromatography (mol %) and used to estimate SCD-116 (16:1n-7/to 16:0). Total, large, medium and small TRLPs, visceral fat, SCD-116 were similar in blacks and lower than in whites before and after adjustment for age and body fat (P&lt;0.001). Blacks had lower SI (2.28 (1.52) vs. 2.74 (2.81), median(IQR) P=0.05, and hepatic fat (0.7 (1.1) vs. 1.2 (2.1), P=0.03. SCD-116 correlated with hepatic fat (r=0.34, P&lt;0.01). Habitual physical activity, dietary fatty acid profiles were similar (P&gt;0.1). In multivariate linear models, age, SCD-116, body fat, visceral fat and SI, but not race or liver fat, were independently associated with total TRLP (adjR2=0.44, P&lt;0.01). Medium and large TRLP number was independently predicted by visceral fat and SCD-116 activity (adjR2=0.37, P&lt;0.01); race was the only predictor for small TRLPs (adjR2=0.14, P&lt;0.01). Therefore, lower hepatic fat and SCD-116 maybe important contributors to the paradoxically normal fasting TRLP in insulin resistant black women.

Disclosure
S.T. Chung: None. M. Galvan-De La Cruz: None. S. Bernstein: None. A. Onuzuruike: None. N.R. Matthan: None. R. Ouwerkerk: None. L. Mabundo: None. M.L. Sampson: None. A.B. Courville: None. A.M. Gharib: None. A.H. Lichtenstein: None. A. Remaley: None. A.E. Sumner: None.
Canagliflozin, an SGLT2 Inhibitor, Prevents Development of Hepatocellular Carcinoma (HCC) from Nonalcoholic Steatohepatitis (NASH) in a Mouse Model of NASH-HCC Under Diabetic State
Authors: JOJIMA TERUO , WAKAMATU SYO , IIJIMA TOSHIE , USUI ISAO , ASO YOSHIMASA 
Published: June 2018

Nonalcoholic steatohepatitis (NASH) can result in liver cirrhosis and hepatocellular carcinoma (HCC). Several studies have shown that some SGLT2 inhibitors alleviate hepatic steatosis or steatohepatitis in type 2 diabetic mice or rats. First, we investigated the effects of canagliflozin (CANA), an SGLT2 inhibitor, on steatohepatitis and fibrosis in a novel diabetes nonalcoholic steatohepatitis (NASH) -HCC progression model mice. We next investigated inhibitory effects of CANA on development of HCC in this model mice. Mice aged 5 weeks were divided into two groups (vehicle and CANA 30 mg/kg) and fed for 3 more weeks. The histological nonalcoholic fatty liver disease activity score (NAS) was lower in the CANA group than in the vehicle group. The expression of type 1 and 3 collagen mRNA was reduced in the CANA group. Mice aged 5 weeks were divided into three groups of 9 animals: vehicle, CANA initial administration 30mg/kg (5 to 9 W), CANA continuous administration 30 mg/kg (5 to 16W). At the age of 16 weeks, the NAS was significantly lower in the CANA continuous administration group than in the vehicle or the CANA initial administration groups. The number of hepatic tumors was significantly smaller in the CANA continuous administration group than in the vehicle group. Immunohistochemistry showed that expression of glutamine synthetase, a marker of HCC, was reduced in the CANA continuous administration group compared with the vehicle group. Furthermore, the CANA continuous administration significantly decreased expression of mRNAs for α-fetoprotein, a tumor maker of HCC, compared with the vehicle administration.
In conclusion, canagliflozin attenuates development of NASH showing anti-steatotic and anti-inflammatory effects, and prevents progression of HCC from NASH.

Disclosure
T. Jojima: Research Support; Self; mitsubishi tanabe phama corporation. S. Wakamatu: None. T. Iijima: None. I. Usui: None. Y. Aso: None.
Lactobacillus Pentosus Strain S-PT84 Attenuates Insulin Resistance and Steatohepatitis by Maintaining Gut Permeability and Polarizing M2 Macrophages
Authors: SAKAI YURIKO , NAGASHIMADA MAYUMI , OTA TSUGUHITO 
Published: June 2018

Obesity or high-fat diet enhances gut permeability and metabolic endotoxemia, which can trigger insulin resistance and NASH. However, there are few promising treatments targeting lipotoxicity-mediated endotoxemia in NASH. The Lactobacillus pentosus strain S-PT84 has immunomodulatory functions including Th1/Th2 balance modulatory effects and natural killer (NK)/NKT cell activation. In this study, we examined the effect of S-PT84 on diet-induced NASH. C57BL/6 mice were fed a high-cholesterol/high-fat diet (CL) alone or with 1×1010 S-PT84 (CL + S-PT) for 22 weeks. We quantified intrahepatic immune cells using a fluorescence-activated cell sorter (FACS). S-PT84 administration improved hepatic steatosis by decreasing TG and FFA levels by 34% and 37%, respectively. S-PT84 also inhibited the development of hepatic inflammation and fibrosis, lowering F4/80+ macrophage/Kupffer cell infiltration and the hydroxyproline content of the liver. S-PT84 administration in mice fed a CL diet led to improved hyperinsulinemia as well as enhanced hepatic insulin signal assessed by phospho-Akt. FACS analysis revealed that mice fed the CL+S-PT had 71% more CD11c-CD206+ M2 macrophages than mice fed the CL diet, resulting in a predominance of the M2 over the M1 macrophage population. S-PT84, however, showed little effect on NK/NKT cell and T regulatory cell populations in the liver. Furthermore, CL diet increased intestinal permeability as measured with the carboxyfluoresce assay and increased plasma lipopolysaccharide binding protein (LBP) levels. S-PT84 diminished increased intestinal permeability and plasma LBP levels. Additionally, S-PT84 reduced IL-17 producing T cells and increased ZO-1, occludin, and claudin proteins constituting tight junction in colon.
In conclusion, S-PT84 treatment attenuated lipotoxicity-induced insulin resistance and NASH by maintaining gut permeability and polarizing M2 liver macrophages.

Disclosure
Y. Sakai: None. M. Nagashimada: None. T. Ota: None.
Development of In Vitro NASH Model with Mechanically Compliant Substrate
Authors: MORISHIMA MASAKI , HORIKAWA KAZUKI , FUNAKI MAKOTO 
Published: June 2018

Although a sedentary lifestyle is known to play a role in nonalcoholic steatohepatitis (NASH), understanding of the molecular mechanism of NASH development is incomplete and effective treatment is still greatly sought. Part of this challenging situation in tackling NASH is a lack of an appropriate in vitro hepatocyte culture that reproduces in vivo cellular functions ex vivo. Emerging evidence suggests that matching the stiffness of substrates with that of tissues helps reproducing in vivo functions of cells derived from them. Thus, we hypothesized that primary hepatocytes on 500 Pa polyacrylamide (PAA) gels, whose stiffness matches that of the liver, may exhibit steatosis and a pro-inflammatory response when treated with either fructose or palmitate to model over-nutrition. To this end, rat primary hepatocytes were seeded on either 500 Pa PAA gels or glass coverslips, which represent a conventional but unphysiological stiff culture device. Cells were cultured in low glucose Dulbecco’s Modified Eagle’s medium, whose glucose concentration matches the normal blood glucose level, with or without addition of 5.5 mM fructose or 0.5 mM palmitate. Addition of fructose or palmitate induced lipid accumulation in cells on 500 Pa gels and increased ROS (reactive oxygen species) accumulation in hepatocytes on 500 Pa PAA gels, but not in hepatocytes on glass. Fructose or palmitate treatment also caused HMGB1 (High Mobility Group Box 1) secretion by hepatocytes, implicating a proinflammatory response by these cells. These results suggest that exposure of hepatocytes on a mechanically compliant substrate to either fructose or palmitate may serve as an excellent ex vivo model of the initial phase of NASH development by showing ability to initiate an inflammatory process.

Disclosure
M. Morishima: None. K. Horikawa: None. M. Funaki: Research Support; Self; Otsuka Holdings Co., Ltd., The Knowledge Cluster from the Ministry of Education, Science, and Culture of Japan. Board Member; Self; Mechanogenic C.C..