bluuebunny/crossref_metadata_2025_split huggingface dataset:
1847-P: SGLT2 Inhibition Reduces Paternal Intergenerational Transmission of Metabolic Disease in Mice with Dietary Obesity
Authors: OSATAPHAN SORAVIS , CHIMENE-WEISS JEREMY , MACCHI CHIARA , SU LEI , LORANGER NICOLE , KRITSANAVIPARKPORN CHAWAN , KOZUKA CHISAYO , PATTI MARY E. 
Published: June 2019

Risk for metabolic disease can be transmitted via both the maternal and paternal lineage, potentially through both genetic and non-genetic mechanisms. This may contribute to the exponential rise in obesity and type 2 diabetes worldwide. We hypothesized that preconception interventions to improve paternal metabolism could improve offspring health and reduce adult offspring metabolic disease. We have developed a model of glucolipotoxicity, induced by chronic overnutrition, and its reversal by SGLT2 inhibitors (SGLT2i). Male C57BL/6J mice fed a 60% high fat diet (HFD) were subjected to (1) continued HFD ad libitum (HFD), or (2) HFD ad libitum, supplemented with canagliflozin (CANA, 30mg/kg/day) for 4 weeks. CANA significantly (1) reduced body weight and hepatic steatosis, (2) improved glucose tolerance and (3) reprogrammed hepatic transcription to favor catabolism in adult males. HFD and CANA males were bred with control females, and offspring were fed chow diet ad libitum throughout life. At 13 months male offspring of CANA-treated fathers had 18% lower body weight and 32% lower fat mass (all p&lt;0.05, vs. offspring of HFD fathers). Improved glucose tolerance and improved insulin sensitivity were also observed at age 9-12 months (26% and 18% lower AUC respectively, P&lt;0.05). Remarkably, at 13 months all male offspring of HFD-exposed fathers had mild to severe liver steatosis; however, 57% of CANA-treated fathers were free of liver steatosis. At a transcriptional level, expression of genes encoding key lipogenic enzymes (e.g., Fasn, Pkl and Scd1) were reduced in offspring of CANA-treated males Together these data demonstrate that improvement of paternal metabolism prior to conception protects against obesity, hepatic steatosis, and diabetes risk later in life in offspring.

Disclosure
S. Osataphan: None. J. Chimene-Weiss: None. C. Macchi: None. L. Su: None. N. Loranger: None. C. Kritsanaviparkporn: None. C. Kozuka: None. M.E. Patti: Consultant; Self; Eiger BioPharmaceuticals. Research Support; Self; Dexcom, Inc., Janssen Pharmaceuticals, Inc., MedImmune, Xeris Pharmaceuticals, Inc.

Funding
National Institutes of Health
185-LB: Repeatability and Reproducibility of Pancreas Volume Measurements Using MRI
Authors: WILLIAMS JONATHAN M. , HILMES MELISSA A. , ARCHER BRANCH T. , DU LIPING , KANG HAKMOOK , RUSSELL WILLIAM E. , MOORE DANIEL J. , POWERS ALVIN C. , VIROSTKO JOHN 
Published: June 2019

Pancreas volume, as measured by magnetic resonance imaging (MRI), is smaller in individuals with newly-diagnosed type 1 diabetes (T1D) and declines over the first year after diagnosis. However, the repeatability and reproducibility of these MRI measurements is not established, and for MRI to be utilized to measure pancreas volume, the variation between measurements of pancreas volume must be determined. To determine the test-retest repeatability of pancreas volume measurements by MRI, we performed two or three same-day repeat MRIs in the same individuals with or without T1D (n = 8, mean age 24 y, range 11-40 y). A single radiologist, blinded to whether the subject had T1D or not, outlined the pancreas on these repeat images. Pancreas volume was determined by multiplying the area of the pancreatic regions of interest by the MRI slice volume (5 mm). The repeatability of test-retest scans had an intraclass correlation coefficient (ICC) of 0.979 (95% CI 0.928 to 0.996). To determine the inter-reader reliability of pancreas volume measurements, the pancreas was independently outlined by two board-certified radiologists (n = 11). Comparing results from multiple radiologists yielded an ICC of 0.931 (95% CI 0.776 to 0.981), with greater differences in measurement in larger pancreases (p &lt; 0.005). The mean DICE coefficient, a measurement of the degree overlap between pancreas regions of interest between the two readers, was 0.77. These data show that measurements of pancreas volume obtained using MRI are both repeatable and reproducible across multiple readers with ICCs corresponding to excellent clinical significance (ICC &gt; 0.9). These results indicate that MRI measurements of T1D pancreatic volume can be reliably determined and could be useful for clinical investigation.

Disclosure
J.M. Williams: None. M.A. Hilmes: None. B.T. Archer: None. L. Du: None. H. Kang: None. W.E. Russell: None. D.J. Moore: None. A.C. Powers: None. J. Virostko: None.

Funding
JDRF (3-SRA-2015-102-M-B)
1859-P: Autophagy Promotes Gluconeogenesis in Hepatocytes through Forkhead/winged Helix Transcription Factor (FoxO1) Biosynthesis by Supporting Intracellular Amino Acids Turnover
Authors: SHEN ZHENG , PAN QUAN , YANG WANBAO , CHEN YUNMEI , LI XIAOPENG , AI WEIQI , GUO SHAODONG 
Published: June 2019

Autophagy is one of cellular survival mechanisms under starvation condition. When eukaryotic cells are in poor nutritional state, such as starvation, cells tend to utilize intracellular autophagic substrates (e.g., defective, surplus or damaged cellular macromolecules, or organelles) to generate building blocks such as amino acids for temporal adaptation to adverse condition. The forkhead/winged helix transcription factor FoxO1 promotes hepatic glucose production (HGP) by increasing expression of genes responsible for gluconeogenesis. In this study, we propose a possible mechanism how autophagy regulates gluconeogenesis in hepatocytes under starvation condition. Using an autophagy inhibitor, chloroquine (CQ) and mice primary hepatocytes, we found that HGP was suppressed under autophagy deficiency. Interestingly, the effect of autophagy inhibitor on HGP suppression was significantly reduced in FoxO1-knockout mice primary hepatocytes. Furthermore, autophagy deficiency decreased FoxO1 protein amount and expression of genes encoding gluconeogenesis rate-limiting enzymes Pck1 and G6pc, but barely affected FoxO1 mRNA level and FoxO1-S253 phosphorylation. Immunofluorescent data also suggested that less FoxO1 was translocated into nuclear under CQ-treatment. By analyzing the amino acid profile in hepatocytes in vitro with HPLC, we found that CQ-treatment significantly decreased the concentration of amino acids for leucine, isoleucine, alanine, phenylalanine, tyrosine, glutamine, glycine and valine. Importantly, when complete 20 amino acids mixture was added in CQ-treated hepatocytes under starvation, the reduction of FoxO1 protein levels was largely attenuated. Thus, we conclude that autophagy regulates gluconeogenesis in hepatocytes through supporting intracellular amino acids turnover which helps biosynthesis of FoxO1.

Disclosure
Z. Shen: None. Q. Pan: None. W. Yang: None. Y. Chen: None. X. Li: None. W. Ai: None. S. Guo: None.

Funding
American Diabetes Association (1-15-CD-09 to S.G.)
1864-P: p38α MAPK Mediates Glucagon-Induced Hepatic Glucose Production through Phosphorylation of Foxo1 at Ser273
Authors: YANG WANBAO , AI WEIQI , LI XIAOPENG , PAN QUAN , SHEN ZHENG , CHEN YUNMEI , SUN YUXIANG , GUO SHAODONG 
Published: June 2019

Glucagon is involved in glucose homeostasis via triggering gluconeogenesis and glycogenolysis. In addition to activation of protein kinase A (PKA), p38α MAPK (p38) is activated by glucagon and promotes glucagon-induced hepatic glucose production. However, underlying mechanisms by which p38 mediates the effect of glucagon are not well elucidated. Previously, we established that glucagon increases the phosphorylation of Foxo1 at Ser273 via PKA to promote hepatic glucose production. In this study, we investigated the potential role of p38 in the action of glucagon by phosphorylation of Foxo1 at Ser273. Using the mouse primary hepatocytes, we showed that activation of p38 by glucagon promoted phosphorylation of Foxo1 at Ser273, which results in both increased stability and nuclear translocation of Foxo1. In vivo kinase assay shows that the active p38 enzyme increased the phosphorylation of Foxo1 at Ser273. Moreover, p38 promoted glucagon-induced PKA activity to increase the phosphorylation of Foxo1 at Ser273. Suppression of p38 by siRNA and SB203580 decreased hepatic glucose production by glucagon in control mouse primary hepatocytes; however, such an effect was diminished in the hepatocytes isolated from the Foxo1-S273D knock-in mice, where Foxo1-Ser273 was replaced by the aspartate mutation (D). In mice, we further showed that injection of p38 inhibitor SB203580 decreased the fasting blood glucose and hepatic glucose production in wild type control mice, while this effect was not observed in Foxo1-S273D mice. These results revealed the novel role of p38 in control of Foxo1 phosphorylation at Ser273 to regulate the action of glucagon in glucose homeostasis.

Disclosure
W. Yang: None. W. Ai: None. X. Li: None. Q. Pan: None. Z. Shen: None. Y. Chen: None. Y. Sun: None. S. Guo: None.

Funding
American Diabetes Association (1-15-CD-09 to S.G.); National Institutes of Health (R01DK095118)
188-LB: MicroRNA-126-3p Impacts Insulin Signaling in Smooth Muscle Cells
Authors: TRYGGESTAD JEANIE B. 
Published: June 2019

Human umbilical vein endothelial cells (HUVEC) are a rich source of miRNA-126-3p. HUVEC package miR-126-3p into exosomes and secrete them into the extracellular space, potentially influencing other cells. Smooth muscle cells (SMC) take up miR-126-3p in a co-culture model with endothelial cells. miR-126-3p targets mRNAs in the insulin signaling pathway impacting their protein abundance. To test the hypothesis that miRNA-126-3p would decrease abundance of IRS1 and Akt, targets of miR-126-3p, SMC were isolated from the umbilical veins of infants born to women with (DM group; n=2) and without (control group; n=3) diabetes during pregnancy. miR-126-3p or a non-coding control mimic (NTC; 50 nM per miRNA) was transfected into SMC. After 48 h, SMC were stimulated for 10 min with 0 or 10 nM insulin. For analysis, abundance of all proteins was set relative to the NTC-transfected, unstimulated control group SMC (set at 100%). The fold change in IRS1 abundance was 85% +/- 72% and 85% +/- 30% for the control and DM groups, respectively. Abundance of Akt was 107% +/- 32% and 112% +/- 19% for the control and DM groups, respectively. pAkt abundance was 67% +/- 21% and 40% +/- 9% for the control and DM groups, respectively. Upon insulin stimulation, pAkt abundance in the control group increased to 114% +/- 29% of NTC, while in the DM group, abundance only reached 68% +/- 27% of control NTC. Furthermore, pAS160, necessary for GLUT4 translocation, was largely unchanged in the control group with or without insulin stimulation (96% +/- 23% and 99% +/- 45%, respectively). However, pAS160 abundance in the DM group was 45% +/- 4% of NTC and this reduction was not rescued by insulin stimulation (42% +/- 28%). These data suggest that miRNA-126-3p can decrease abundance of insulin signaling pathway proteins, and these decreases are more substantial in DM-exposed SMC. miRNA-126-3p appears to exert its affects through a decrease in IRS1, rather than through Akt. Future studies are planned to examine the impact of miRNA-126-3p on SMC function.

Disclosure
A.M. Teague: None. J.B. Tryggestad: None.

Funding
National Institutes of Health (1K23DK106533-01A1 to J.B.T.); Children's Medical Research Institute Metabolic Research Program; Harold Hamm Diabetes Center; University of Oklahoma Health Sciences Center
1890-P: Lipocalin-Type Prostaglandin D2 Synthase Deficient Mice Develop Dyslipidemia Resulting in Nonalcoholic Fatty Liver Disease Independent of Obesity
Authors: SRIVASTAVA ANKITA , PALAIA THOMAS , HALL CHRIS , LEE JENNY , STEVENSON MATTHEW , RAGOLIA LOUIS 
Published: June 2019

Nonalcoholic fatty liver disease (NAFLD) is an emerging risk factor for type 2 diabetes mellitus (T2DM), cardiovascular disease, and all-cause mortality. Obesity is a major determinant of the high prevalence of NAFLD and T2DM worldwide. Previously, we demonstrated that lipocalin-type prostaglandin D2 synthase (L-PGDS) knockout mice show increased glucose intolerance and accelerated atherosclerosis. In the present study, we investigated the role of L-PGDS in causing NAFLD in L-PGDS knockout (KO) and control C57BL/6 mice (n=6/group) on both low fat and high fat diets for 14 weeks. We observed that L-PGDS KO mice remain slightly lighter in weight compared to control mice, yet develop NAFLD faster, even on the low fat diet. In addition, we found elevated fasting glucose and insulin levels in L-PGDS KO mice with increased lipid accumulation in the liver with time on both diets as compared to controls. We also found total cholesterol and LDL levels were significantly elevated in L-PGDS KO mice. Finally, lipogenesis marker proteins such as SREBP-1c and LXRα, and CD36, a fatty acid transporter protein, were also found to be increased in L-PGDS KO mice on both diets as compared to control mice. These data confirm that absence of L-PGDS results in hyperinsulinemia and dyslipidemia. Therefore, we conclude that L-PGDS plays a significant role in developing NAFLD independent of obesity and may serve as a novel therapeutic target for the treatment of NAFLD.

Disclosure
A. Srivastava: None. T. Palaia: None. C. Hall: None. J. Lee: None. M. Stevenson: None. L. Ragolia: None.

Funding
George Link, Jr. Foundation, Inc.; American Heart Association
1894-P: HIF-2α Induced by Hypoxia Exacerbates Nonalcoholic Fatty Liver Disease Progression via Suppressing PPARα
Authors: CHEN JIANDI , CHEN JIANXU , FU HUIRONG , LI YUN , LUO SHUNKUI , WANG LINGLING , LU HONGYUN 
Published: June 2019

Background: Hypoxic condition induced by obstructive sleep apnea syndrome (OSAS) involves in the development of NAFLD. Previous studies indicated HIF-2α was correlated with lipid metabolism. However, the potential mechanisms of HIF-2α in the progress of NAFLD was unclear. Our study aimed to detect the molecular mechanisms.
Methods: We established steatosis LO2 cells model and mouse NAFLD model, then exposed to intermittent hypoxia (IH) treatment, We detected the lipid accumulation in liver and the expression of HIF-1α and HIF-2α. Furthermore, we treated steatosis hepatocytes with hypoxia, HIF-2α siRNA, PPARα agonists and inhibitors respectively. Meanwhile, we exposed mouse NAFLD mode to IH or IH with PPARα agonists.
Results: Steatosis hepatocytes exhibited more sensitive to hypoxia and more likely to occur lipid accumulation. Moreover, we found lipid accumulation in hepatocytes was ameliorated by HIF-2α silence or PPARα agonist. HIF-2α overexpression suppressed PPARα leading to PGC-1α, NRF-1, ESRRα downregulation and impaired mitochondrial function. We also found lipolysis genes such as CPT1α, CPT2α, ACOX1, ACOX2 were downregulated, and lipogenesis genes including LXRα, FAS, SCD1 were upregulated.
So we concluded HIF-2α induced by hypoxia exacerbates NAFLD progression by suppressing β-oxidation via PPARα.

Disclosure
J. Chen: None. J. Chen: None. H. Fu: None. Y. Li: None. S. Luo: None. L. Wang: None. H. Lu: None.

Funding
National Natural Science Foundation of China (81670815); Natural Science Foundation of Guangdong Province (2016A030313279); Sun Yat-sen University (17YKZD23)
1901-P: CK1 δ/ε Inhibitor PF-05006739 Ameliorates Hepatic Steatosis and Hyperinsulinemia in Dio Mice
Authors: PELOQUIN MATTHEW , LITCHFIELD JOHN , ZHANG BEI B. , CHANG CHENG , MILLER RUSSELL A. , BERNARDO BARBARA , LUTHRA SUMAN , CORTES CHRISTIAN , LI XIANGPING , ZOU CHANG J. 
Published: June 2019

The circadian rhythm allows for metabolic processes to be primed to anticipate the expected daily cycling of behaviors like food consumption and lipid storage. Previous genetic and epidemiological studies have implicated circadian disruption as a potential causal determinant for metabolic diseases such as obesity, diabetes and fatty liver. Here we leverage diet induced obese (DIO) mice to test the potential for circadian modulation by inhibition of casein kinase 1δ/ε (CK1 δ/ε) to improve endpoints in metabolic disease models. Our data reveal that the CK1 δ/ε inhibition with small molecule PF-05006739 was able to significantly lower fasted and fed insulin levels, fasted glucose and hepatic lipid content with a concomitant ∼9% decrease in body weight. PF-05006739 was also capable of shifting the gene expression of circadian oscillating transcripts in the liver, consistent with reported actions of this compound in previous preclinical evaluations. Furthermore, this shift in gene expression also correlated with a shift in respiratory exchange ratio (RER) and energy expenditure (EE) in vivo. Taken together these data suggest CK1 δ/ε inhibition as a potential therapeutic approach for metabolic diseases, specifically hyperinsulinemia and NAFLD/NASH.

Disclosure
M. Peloquin: Employee; Self; Pfizer Inc. J. Litchfield: Employee; Self; Pfizer Inc. B.B. Zhang: Employee; Spouse/Partner; Janssen Pharmaceuticals, Inc. Employee; Self; Pfizer Inc. Other Relationship; Self; Eli Lilly and Company. C. Chang: Employee; Self; Pfizer Inc. R.A. Miller: Employee; Self; Pfizer Inc. B. Bernardo: Employee; Self; Pfizer Inc. Employee; Spouse/Partner; Pfizer Inc. S. Luthra: None. C. Cortes: None. X. Li: Employee; Self; Pfizer Inc. C.J. Zou: None.
1904-P: The Hepatocyte Integrin ß1 Subunit Links ECM-Integrin Signaling to Insulin Resistance in Obese Mice
Authors: TREFTS ELIJAH , ROBY DEBORAH A. , POZZI AMBRA , ZENT ROY , WASSERMAN DAVID 
Published: June 2019

Insulin resistance (IR) is a primary contributor to obesity related pathologies including type 2 diabetes. Hepatic IR manifests as a loss of insulin’s suppressive action on hepatic glucose output, and correlates with extracellular matrix (ECM) expansion. Integrin receptors are the primary input for ECM derived signals to the intracellular environment. Given the correlation of ECM deposition with hepatic IR our goal is to define contributions of integrin signaling to this pathologic process.
Integrin receptors are heterodimeric membrane receptors with an α and β subunit. Hepatocytes are involved in hepatic insulin responsiveness and express four integrin subunits. Utilizing mice with hepatocyte specific knockout of integrin α5 (hepα5-KO) or β1 (hepβ1-KO) we aimed to determine contributions of these integrin subunits to IR.
A high-fat (HF) fed model of diet induced obesity (DIO) caused weight gain in hepα5-KO, hepβ1-KO, and respective control littermates. Using hyperinsulinemic-euglycemic clamps in the conscious catheterized mouse we demonstrate that hepα5-KO mice on a standard diet (chow) have normal insulin sensitivity and develop IR during DIO similar to controls. While insulin sensitivity of chow fed hepβ1-KO is no different from controls, DIO hepβ1-KO mice are protected from IR. Significant increases in glucose disappearance (Rd) and suppression of endogenous glucose appearance (EndoRa) during the clamp drive preservation of insulin sensitivity in these mice. Interestingly the primary hepatocyte knockout of the β1 subunit has effects on extrahepatic tissue as DIO hepβ1-KO mice also demonstrate increased glucose metabolic indexes (Rg) in several tissues, likely contributing to enhanced Rd.
Overall, these findings demonstrate the direct link between IR and ECM-integrin signaling through integrin β1. This further establishes the involvement of ECM-integrin signaling during metabolic disease and the potential for this pathway as a novel therapeutic avenue.

Disclosure
E. Trefts: None. D.A. Roby: None. A. Pozzi: None. R. Zent: None. D. Wasserman: None.

Funding
National Institutes of Health (DK007563), (DK112553 to E.T.), (DK069221, DK083187 to R.Z.), (CA162433, DK095761 to A.P.), (DK050277, DK054902 to D.W.)
1905-P: Artificial Decline in HbA1c Level during Treatment of Hepatitis C with Interferon-Free, Direct-Acting Antiviral Regimen Combined with Ribavirin
Authors: MORIYA AKIO , IWASAKI YOSHIAKI , ANDO MASAHARU 
Published: June 2019

HbA1c is an important marker for glycemic control; however, not only plasma glucose levels but also RBCs' lifespan determines the value. Some of interferon-free, direct-acting antiviral regimens for hepatitis C are combined with ribavirin, which causes hemolytic anemia. Hemolytic anemia shortens the RBCs' lifespan and lowers HbA1c levels. We monitored HbA1c levels in 28 patients during and after antiviral therapy with daily sofosbuvir (400 mg) plus weight-based ribavirin for hepatitis C. Five cases (18%) had antidiabetic medication. The hemoglobin concentration, 13.9 ± 1.4 g/dl at the baseline, significantly fell to 12.0 ± 1.3 g/dl at the 4th week of treatment (P &lt; 0.001). It hardly declined further during the treatment and immediately recovered after the end of treatment. Although there was no significant change in the random plasma glucose levels, the HbA1c level, 5.8% ± 0.7% at the baseline, gradually declined to 4.3% ± 0.7% (- 1.5% ± 0.7%, P &lt; 0.001) at the end of treatment. It partly recovered to 4.8% ± 0.6% at the 4th week after treatment, then further increased to 6.2% ± 0.9% at the 12th week, and eventually returned to 5.7% ± 0.7%, which was similar to the value at baseline.
Conclusions: interferon-free, direct-acting antiviral regimen combined with ribavirin temporally causes artificial declines in HbA1c levels.

Disclosure
A. Moriya: None. Y. Iwasaki: None. M. Ando: None.
1906-P: Effects of a Carbohydrate-Restricted Diet on Hepatic Lipid Content in Adolescents with Nonalcoholic Fatty Liver Disease
Authors: GOSS AMY M. , DOWLA SHIMA , ASHRAF AMBIKA P. , BOLDING MARK , MORRISON SHANNON A. , GOWER BARBARA 
Published: June 2019

Background: NAFLD has emerged as the most common liver disease among adolescents in industrialized countries. Results from trials in adults with NAFLD suggest that reducing CHO intake may deplete liver fat to a greater extent than other dietary approaches, even when there was no difference in weight loss between diet groups. The objective of this study was to determine the effects of a CHO-restricted vs. fat-restricted diet in adolescents with NAFLD on reduction in hepatic lipid and insulin resistance.
Methods: Twenty-three adolescents (age 9-17) with obesity (BMI ≥85th percentile) and confirmed NAFLD were randomized to a CHO-restricted (&lt;10:25:&gt;65% energy from CHO:protein:fat) or fat-restricted diet (55:25:20) for 8 weeks. Caloric intakes were calculated to be weight maintaining. Participants and one parent attended bi-weekly counselling with a registered dietitian. To encourage compliance, groceries were delivered to participants’ families during the first 2 weeks of the study. Both diets included minimally processed foods with limited added sugar. Change in hepatic lipid content was measured via MRI, body composition via DXA, and insulin resistance via a fasting blood sample.
Results: After 8 weeks, the CHO-restricted diet group experienced a significant decrease in hepatic lipid content (-6.0±4.7%, p&lt;0.001), whereas the fat-restricted diet group showed no change. We found significantly greater decreases in insulin resistance (HOMA-IR, -1.2±5.1, &lt;0.05), abdominal fat mass (-1.7 ±1.1 kg, p&lt;0.01), and body fat mass (-3.1±4.0 kg, p&lt;0.01) in response to the CHO-restricted vs. fat-restricted diet.
Conclusion: The CHO-restricted diet approach may be markedly beneficial in improving fatty liver, body composition, and insulin resistance in adolescents with NAFLD even in the absence of intentional caloric restriction. Practitioners should consider recommending this diet approach to effectively improve disease course in this patient population.

Disclosure
A.M. Goss: None. S. Dowla: None. A.P. Ashraf: Research Support; Self; Opko. Speaker's Bureau; Spouse/Partner; Bristol-Myers Squibb Company, Celgene Corporation, Insys, Pfizer Inc. M. Bolding: None. S.A. Morrison: None. B. Gower: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases; Thrasher Research Fund