bluuebunny/crossref_metadata_2025_split huggingface dataset:
1902-P: Definition of Nonalcoholic Fatty Liver Disease (NAFLD) Stage by Independent Noninvasive Fibrosis Markers and Elastography
Authors: LAVRYNENKO OLGA , ZEMLIANITSYNA OLHA , KRAVCHUN NONNA , DUNAEVA INNA , KARACHENTSEV IURIY , SINAIKO VADYM , DEFRONZO RALPH A. , CERSOSIMO EUGENIO 
Published: June 2019

Aim: We sought to define the degree of NAFLD with B-mode ultrasound sono-elastography using the discriminant Bonacini scale in type 2 diabetes (T2D) patients.
Materials and Methods: Forty-three patients with T2D and clinically diagnosed NAFLD (26F, 17M) were examined with liver ultrasound in B-mode elastography. The presence and degree of fibrosis was assessed using the Bonacini Classification (Discriminant) Scale. The compliance of the stage of the fibrosis was compared with results of the histological evaluation of METAVIR and Ishak.
Results: An enlarged liver was found in all, often combined with the hyperechogenic, coarse-grained structure. In rare cases, a decrease in the liver echogenicity indicated development of fibrosis. The liver density index was significantly higher in men (2.63 ± 0.05) than in women (2.49 ± 0.06, p = 0.05). In a series of correlation analyses, it was found that sono-elastography strongly correlated with the results of the classification (discriminant) Bonacini score scale (r= 0.68 ± 0.13, p &lt;0.001). The results of the Ishak and METAVIR scales at minimum values have a moderate correlation with sono-elastography data (r= 0.36 ± 0.17, p &lt; 0.05 and r= 0.37±0.16, p&lt;0.05respectively). These scales determine the degree of fibrosis as a range from the less to the greater degree, but the stronger correlation (r= 0.50 ± 0.16, p&lt;0.01and r= 0.47 ± 0.15, p&lt;0.01respectively) with results of sono-elastography was found in patients with severe fibrosis of the liver.
Conclusion: In majority of type 2 DM patients with clinical NAFLD a slight degree fibrosis (F0-F2) was diagnosed. To better assess the degree of liver fibrosis in these patients it is advisable to use sono-elastography and the discriminant Bonacini scale. These have similar significance, can complement each other and allow identification of early manifestations of liver fibrosis in patients with type 2 DM.

Disclosure
O. Lavrynenko: None. O. Zemlianitsyna: None. N. Kravchun: None. I. Dunaeva: None. I. Karachentsev: None. V. Sinaiko: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. E. Cersosimo: None.
191-OR: New Regulators of Insulin-Stimulated GLUT4 Exocytosis
Authors: SHEN JINGSHI 
Published: June 2019

Insulin promotes glucose uptake by triggering the translocation of the glucose transporter GLUT4 from intracellular storage vesicles to the cell surface through exocytosis. Defects in GLUT4 exocytosis are a hallmark of insulin resistance (IR) and type 2 diabetes (T2D). To develop effective and safe treatments for IR and T2D, it is crucial to gain a comprehensive understanding of insulin-stimulated GLUT4 exocytosis at the molecular level. Recently, our group developed new genetic screen platforms to systematically dissect insulin-stimulated GLUT4 exocytosis, taking advantage of the revolutionary CRISPR-Cas9 genome editing system. Our genome-wide CRISPR screens recovered known GLUT4 exocytic regulators but most of the hits were not previously linked to the GLUT4 exocytic pathway. Here, I will focus on AAGAB, a negative regulator of GLUT4 translocation identified in the screens. We discovered that AAGAB plays a dual role in GLUT4 trafficking: 1) it promotes the endocytosis of GLUT4, and 2) it negatively regulates the SNARE-Munc18-mediated GLUT4 vesicle fusion. In addition, I will discuss OSBPL8 and OSBPL10, another two negative regulators identified in our screens. OSBPL8 and OSBPL10 are putative lipid transfer proteins operating between intracellular organelles. We propose that OSBPL8 and OSBPL10 regulate lipid dynamics required for insulin signaling, thereby influencing the activities of GLUT4 exocytic regulators. These genetic studies will facilitate the identification of new therapeutic targets for IR and T2D.

Disclosure
J. Shen: None.

Funding
National Institutes of Health
1915-P: Targeting Remission of Type 2 Diabetes Using a Digital Education and Behavior Change Program Improves Insulin Sensitivity and Liver Fat Content in Type 2 Diabetes
Authors: PESTA DOMINIK , ZAHARIA OANA P. , KUPRIYANOVA YULIYA , HWANG JONG-HEE , MARKGRAF DANIEL F. , TRENELL MICHAEL , SZENDROEDI JULIA , RODEN MICHAEL 
Published: June 2019

Recent controlled trials have demonstrated that type 2 diabetes (T2D) remission is possible with significant weight loss in people with newly diagnosed T2D. However, current programs focus on face-to-face education and behavior change, which limit scalability and inclusivity. We examined the effect of a digital education and behavior change program targeting a very low-calorie diet on metabolic control, insulin sensitivity as well as liver fat and fibrosis.
Patients with diet/metformin controlled T2D (n=8, 50% male, 52±12 years, BMI 33±4 kg/m2) were remotely supported to undertake a very low-calorie (800 kcal/day) diet using digital education, behavior change and tracking with one-to-one tele-coaching for 12 weeks. Insulin sensitivity index was calculated using a mixed-meal tolerance test, liver fat content by 1H-magnetic resonance spectroscopy and liver fibrosis by elastography. After 12 weeks, participants had reduced their body weight by 9.0±3.6 kg and HbA1c (6.6±1.2% vs. 6.0±0.6%, p=0.05) and improved insulin sensitivity (319±61 vs. 355±49 ml.min-1.m-2, p&lt;0.05). Liver fat content declined (9.8±8.2% to 3.3±3.1%, p&lt;0.01) alongside with measures of liver fibrosis (7.0±3.1 to 4.4±1.3 kPa, p=0.05). Changes of liver fat were directly correlated with changes in body weight (r=0.80, p&lt;0.05) as well as changes in fasting plasma glucose (r=0.85, p&lt;0.01) and HbA1c (r=0.91, p&lt;0.01). Within 12 weeks. 38% of participants achieved remission of T2D (HbA1c &lt;6.5%) and 50% normalized liver fat (intrahepatic fat content &lt;5.6%).
In conclusion, this feasibility study demonstrates that digital education, behavior change and tracking can reduce body weight which conveys significant improvements in metabolism and liver health. These preliminary data suggest that care teams should explore how digital education and behavior change can enhance existing care for people with newly diagnosed T2D with a view to achieving remission.

Disclosure
D. Pesta: None. O.P. Zaharia: None. Y. Kupriyanova: None. J. Hwang: None. D.F. Markgraf: Research Support; Self; Sanofi. M. Trenell: Other Relationship; Self; Changing Health Ltd. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc.

Funding
EIT Health; German Ministry of Culture and Science of the State of North Rhine-Westphalia; German Federal Ministry of Health; German Federal Ministry of Education and Research
1922-P: Branched-Chain Ketoacid Dehydrogenase Kinase Inhibition Acutely Improves Glycemia and Alters the Response to Feeding in Mice
Authors: BOLLINGER ELIZA , SIDDALL CHARLES PARKER , GREIZER TIMOTHY , LIBERA JENNA L. , HARIRI GHAZAL , PASHOS EVANTHIA E. , SHIPSTONE ARUN , HADJIPANAYIS ANGELA , SUN ZHONGYUAN , XING GANG , CLASQUIN MICHELLE F. , ZHANG BEI B. , MILLER RUSSELL A. , ROTH FLACH RACHEL 
Published: June 2019

Circulating increases in branched chain amino acid (BCAA) levels have long been associated with type 2 diabetes and metabolic syndrome. Emerging data also suggest that BCAA catabolism may play a role in heart failure progression. It is hypothesized that decreased catabolism, rather than increased consumption of BCAAs, is responsible for these correlations. Branched chain ketoacid (BCKA) dehydrogenase (BCKDH) kinase (BCKDK) is a negative regulator of BCAA catabolism through its inhibitory phosphorylation of the BCKDH E1a subunit. Using the BCKDK inhibitor molecule BT2, we demonstrate here a reduction of BCAA, BCKA and tissue p-BCKDH levels concomitant with improved glucose tolerance and reduced insulin levels in diet-induced obese mice after only one day of treatment. To investigate the mechanisms underlying this protection, we assessed plasma biomarkers and tissue gene expression after fasting and re-feeding in glucose intolerant high fat diet-fed animals. Remarkably, BT2 treated animals demonstrated reduced plasma glucose levels after re-feed, which was accompanied by dramatic reductions in plasma insulin levels, reduced activation of Akt in peripheral tissues, and a failure to suppress plasma free fatty acids and lipolytic machinery in adipose tissue. RNAseq was performed in liver to assess changes in gene expression profiles, and while over 400 genes were differentially regulated in vehicle treated re-fed mice compared with vehicle treated fasted mice, there were no differentially regulated genes in BT2 re-fed animals compared with BT2 fasted animals. These data suggest that activation of BCAA catabolism with the BCKDK inhibitor BT2 impairs the systemic response to feeding.

Disclosure
E. Bollinger: Employee; Self; Pfizer Inc. C.P. Siddall: Employee; Self; Pfizer Inc. Employee; Spouse/Partner; Vertex Pharmaceuticals. T. Greizer: None. J.L. Libera: None. G. Hariri: None. E.E. Pashos: Employee; Self; Pfizer Inc. A. Shipstone: None. A. Hadjipanayis: None. Z. Sun: None. G. Xing: None. M.F. Clasquin: Employee; Spouse/Partner; Merck & Co., Inc. Employee; Self; Pfizer Inc. B.B. Zhang: Employee; Spouse/Partner; Janssen Pharmaceuticals, Inc. Employee; Self; Pfizer Inc. Other Relationship; Self; Eli Lilly and Company. R.A. Miller: Employee; Self; Pfizer Inc. R. Roth Flach: Employee; Self; Pfizer Inc.
1924-P: Praliciguat, a Clinical-Stage sGC Stimulator, Improves Insulin Sensitivity, Lipid Tolerance, and Energy Utilization in a Mouse Diet-Induced Obesity Model Housed at Thermoneutrality
Authors: SCHWARTZKOPF CHAD , HADCOCK JOHN , ROUX JULIEN , LIU GUANG , SHEA COURTNEY , CURRIE MARK , MILNE G. TODD , MASFERRER JAIME , JONES JULI E. 
Published: June 2019

Background: Praliciguat (IW-1973) is a soluble guanylate cyclase (sGC) stimulator under clinical investigation as a potential treatment for diabetic nephropathy. In animal models, praliciguat distributes broadly to tissues and elicits hemodynamic, anti-inflammatory, anti-fibrotic, and metabolic effects. Here, we assessed the metabolic effects of praliciguat in a mouse diet-induced obesity (DIO) model when housed at thermoneutrality.
Methods: Six week old male C57BL/6N mice were maintained on a low-fat diet (LFD, lean mice) or put on a 60% high-fat diet (HFD, obese mice). At 14 weeks of age, one group of obese mice was maintained on HFD (obese controls) while another group of obese mice was switched to HFD formulated with praliciguat to achieve a Cmax similar to a daily oral administration of 6 mg/kg (praliciguat treatment). A group of lean mice were also included (lean controls). Indirect calorimetry was performed on days 8, 9, 20, 21, 32 and 33. On day 35, an oral lipid tolerance test (LTT) was conducted. In a second study under the same dosing paradigm, overnight fasted blood and organs were collected on day 28.
Results: Compared to obese controls, energy expenditure was higher in praliciguat-treated mice throughout a 24h recording period as assessed by AUC (Day 8: +13%, Day 20: +9%, Day 21: +7%, Day 32: +5%, P&lt;0.05) and LTT triglycerides were lower as assessed by AUC (-34%, P&lt;0.01). In the second study, praliciguat-treated mice had lower fasting insulin (-28%, P&lt;0.05), c-peptide (-20%, P&lt;0.05), HOMA-IR (-26%, P&lt;0.05) and triglycerides (-16%, P&lt;0.01) compared to obese controls. Caloric intake, body weight and composition were unaffected by praliciguat treatment.
Conclusions: In a mouse DIO model housed at thermoneutrality, praliciguat increased energy utilization, improved triglycerides in response to an oral lipid challenge, improved insulin sensitivity, and lowered plasma triglycerides.

Disclosure
C. Schwartzkopf: Employee; Self; Ironwood Pharmaceuticals, Inc. J. Hadcock: Employee; Self; Ironwood Pharmaceuticals, Inc. J. Roux: None. G. Liu: None. C. Shea: Employee; Self; Ironwood Pharmaceuticals, Inc. M. Currie: Employee; Self; Ironwood Pharmaceuticals, Inc. G. Milne: Employee; Spouse/Partner; Catabasis Pharmaceuticals. Employee; Self; Ironwood Pharmaceuticals, Inc. Stock/Shareholder; Spouse/Partner; Catabasis Pharmaceuticals. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc. J. Masferrer: Employee; Self; Ironwood Pharmaceuticals, Inc. J.E. Jones: None.
1927-P: Metabolomics of Normal Weight vs. Overweight Diabetics
Authors: FAROQI LIDA ,   IMPACT STUDY
Published: June 2019

The majority of people living with type 2 diabetes mellitus (T2DM) are overweight or obese due to the additional burden of applying insulin to properly control blood sugar levels. However, some people, especially Asian populations, develop T2DM with a low BMI (normal weight). This discrepancy may be resulted from differences in body fat and muscle mass for a given BMI. In order to investigate the influences of body weight on the onset of T2DM, we collected plasma samples from 9 overweight and 17 normal-weight diabetic patients as a pilot study, then applied untargeted metabolomics profiling on these plasma samples. By combining Hydrophilic Interaction (HILIC) and Reverse-Phase Liquid Chromatography (RPLC)-Mass Spectrometry, we comprehensively detected and relatively quantified 5,469 metabolites. We then employed various pattern recognition algorithms (principal component analysis, hierarchical clustering, Welsh t-test, etc.), clearly separated overweight and normal-weight diabetic groups based on their plasma metabolite profiling. Furthermore, we statistically identified 52 significantly different metabolites between these two groups, mainly involved in lipid metabolism. These results not only demonstrate that untargeted metabolomics is able to serve as an efficient diagnostic tool to distinguish overweight and normal-weight diabetic patients, but also provide meaningful insights into molecular mechanisms about tight relationships between diabetes and obesity, further facilitate biomarker discovery for early diagnosis and differentiation of normal/overweight diabetes.

Disclosure
L. Faroqi: None.
1934-P: Acute Hyperglycemia Increases Perfusion of Skeletal and Cardiac Muscle in Healthy Subjects
Authors: HORTON WILLIAM B. , JAHN LINDA , HARTLINE LEE , PATRIE JAMES T. , BARRETT EUGENE 
Published: June 2019

Introduction: Over time, diabetes damages both the micro- and macrovasculature. Acutely, hyperglycemia causes oxidative stress and multiple biochemical abnormalities in endothelial cells. However, initial in vivo functional vascular responses to acute hyperglycemia (AH) are not well-characterized in humans or animals. Measurement of microvascular perfusion (MP) and endothelial function provides in vivo estimates of nutrient and hormone access to tissues and endothelial health, respectively.
Methods: Thirteen healthy adults (18-35 years, BMI 18-25 kg/m2) were fasted overnight. Octreotide was infused with basal insulin replacement and baseline measures of endothelial function by flow-mediated dilation (FMD) and MP (heart and skeletal muscle) by contrast-enhanced ultrasound were obtained after 90 minutes. Glucose was infused to maintain fasting euglycemia (EU) or raise glucose to ∼200 mg/dL (AH) for 4 hours with measures of FMD and MP repeated. Linear mixed model was used for statistical analysis, with Bonferroni correction for between-study comparisons.
Results: Compared to baseline, 4 hours of AH significantly increased skeletal muscle microvascular blood volume (MBV) (p=0.0002), microvascular flow velocity (p=0.047), and microvascular blood flow (p=0.025). MBV significantly increased in comparison to euglycemia (p=0.02). MBV also increased in cardiac muscle during AH (p=0.002). FMD trended towards a significant increase with AH (p=0.058). No changes were observed with EU.
Discussion: First, octreotide had no discernible effect on MP or FMD, which allowed testing the effect of AH while insulin remained at basal. Second, we provide the first evidence that heart and skeletal muscle respond to 4 hours of AH by increasing perfusion in healthy subjects. Whether this response is maintained with chronic hyperglycemia is unknown.

Disclosure
W.B. Horton: None. L. Jahn: None. L. Hartline: None. J.T. Patrie: None. E. Barrett: Research Support; Self; AstraZeneca.

Funding
National Institutes of Health (F32HL142304-01)
1942-P: Intermittent Fasting in Mice Improves Exercise Endurance through Enhancement of Mitochondrial Activating Genes in the Muscle
Authors: MIYASHITA KAZUTOSHI 
Published: June 2019

Background: Intermittent fasting (IF) has been known to increase insulin sensitivity and lower body weight. However, the underlining mechanism for the beneficial effects has not been elucidated enough.
Design and Method: Mice were subjected to a severe IF regimen, in which they were fasted for 72 hours and refed ad libitum for subsequent 96 hours. This cycle was consecutively repeated 4 times to enforce the effects. After 4 cycles of the IF regimen, mice were fed a high-fat diet (HFD) ad-libitum for subsequent 4 weeks of observational period. At the 2 different time points: just after 4 cycles of the IF regimen and after subsequent 4 weeks of observational ad-libitum feeding period, the physical performance was examined.
Result: Glucose tolerance tests showed a significant decrease in the glucose level of IF group just after 4 cycles of the IF regimen. In PCR analysis, expressions of genes responsible for fat oxidation and mitochondrial activation (ACO et al.) were significantly increased in the muscle. The histone acetylation in the promoter region of these mitochondria activating genes was augmented and suggested the significance for enhancement of the expressions of these genes. In addition, we found that exercise endurance was improved in the IF group, without a change in the grip power. After subsequent 4 weeks of observational feeding period, the BW in IF group was significantly lower than ad-libitum feeding group. At the time-point, the exercise endurance, glucose tolerance, histone acetylation and expression of genes maintained the similar changes observed just after 4 cycles of the IF regimen.
Conclusion: The 72 hours fasting IF regimen augmented histone acetylation in the promoter regions of mitochondrial activating genes in the muscle and adipose tissues that would accounts for the prolonged enhancement of the expression. We found that not only glucose tolerance but also exercise endurance was improved through the IF procedure.

Disclosure
K. Miyashita: Research Support; Self; Johnson & Johnson, Merck & Co., Inc., Novo Nordisk Inc.
1943-P: The Sodium-Glucose Cotransporter 2 Inhibitor Luseogliflozin Can Suppress Muscle Atrophy in Db/Db Mice by Suppressing the Expression of Foxo1
Authors: BAMBA RYO , KIMURA TOMONORI , OKAMURA TAKURO , HASHIMOTO YOSHITAKA , OSAKA TAKAFUMI , SENMARU TAKAFUMI , FUKUI MICHIAKI 
Published: June 2019

Here we investigated the effect of the sodium glucose cotransporter-2 inhibitor (SGLT2i) luseogliflozin on skeletal muscle. Eight-week-old mice were fed a standard diet or the standard diet with added luseogliflozin for 8 weeks. The mice were divided into the following four genotype/dietary groups: Db/m mice without (w/o) SGLT2i, Db/m mice with SGLT2i, Db/Db w/o SGLT2i, and Db/Db with SGLT2i. After the 8-week dietary treatment, we investigated the changes in body weight, glucose tolerance, and muscle in each group. Among the mice with and w/o SGLT2i, the ratio of soleus and plantaris muscle to body weight in the Db/Db mice was significantly lower than that in the Db/m mice. The cross-sectional area of soleus muscle in the Db/Db mice w/o SGLT2i was significantly higher than that in the Db/Db mice with SGLT2i. The expression of foxo1 in soleus muscle of the Db/Db mice was significantly higher than that of the Db/m mice, and the foxo1 expression of the Db/Db mice with SGLT2i was significantly lower than that of the mice w/o SGLT2i. The fluorescence intensity of foxo1 in the Db/Db mice fed SGLT2i was significantly lower than that in the Db/Db mice w/o SGLT2i.The administration of luseogliflozin resulted in the suppression of both the increased foxo1 expression and the reduced muscle cross-sectional area in the soleus muscle of Db/Db mice.

Disclosure
R. Bamba: None. T. Kimura: None. T. Okamura: None. Y. Hashimoto: Research Support; Self; Asahi Kasei Pharma. T. Osaka: None. T. Senmaru: None. M. Fukui: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Johnson & Johnson, Kyowa Hakko Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.
1944-P: Muscle a-Parvin Is Not Necessary for Integrin-Linked Kinase Related Insulin Resistance in Diet-Induced Obese Mice
Authors: CAPPEL DAVID A. , POZZI AMBRA , ZENT ROY , WASSERMAN DAVID 
Published: June 2019

High fat diet (HFD) causes obesity and expansion of extracellular matrix (ECM) components and causes insulin resistance. Integrins provide for adhesion between cells and the ECM and signal cells information about the local environment. A major component of signaling through the integrin β1 subunit is the integrin-linked kinase (ILK). Previous studies demonstrated mice that do not express ILK in skeletal muscle (SkM) are resistant to HFD-induced muscle insulin resistance. ILK has no catalytic activity but is the scaffold for signaling molecules, including α-parvin which regulates Rho-GTPases which are involved in actin cytoskeleton and vesicular trafficking. To test the hypothesis that ILK-related insulin resistance is mediated through α-parvin in SkM, we generated a mouse model which lacks α-parvin in SkM (mParKO) using a cre-lox system under control of HSA promoter. mParKO mice and non-transgenic littermates (WT) were fed either chow or HFD for 12 weeks after which insulin sensitivity was assessed in vivo using the hyperinsulinemic-euglycemic clamp combined with 3-[3H]glucose and 2-[14C]deoxyglucose tracers to measure glucose fluxes. Body weight was not different between mParKO and WT mice on either diet, nor was fasting blood glucose. In contrast to previous clamp studies of HFD-fed muscle ILK knockout mice, clamp glucose infusion rate, tracer-determined glucose rates of appearance and disappearance, and an index of SkM glucose uptake were not different between mParKO and WT mice on either diet. These results suggest that the α-parvin unit does not mediate the profound ILK-related susceptibility to insulin resistance in HFD fed mice.

Disclosure
D.A. Cappel: None. A. Pozzi: None. R. Zent: None. D. Wasserman: None.

Funding
National Institutes of Health (DK59637, DK50277, DK54902); American Heart Association