bluuebunny/crossref_metadata_2025_split huggingface dataset:
1770-P: Role of Prolactin Rhythm in the Development of Nonalcoholic Fatty Liver Disease
Authors: YAN BI , ZHANG PENGZI , ZHU DALONG 
Published: June 2020

Circadian disorder such as light exposure at night are risk factors for NAFLD Prolactin (PRL), a pituitary derived hormone, is recently shown to improve fatty liver. Noteworthy, PRL is secreted in an oscillating pattern. We aimed to explore the role of PRL rhythm in hepatic lipid metabolism. Serum PRL levels in 8:00, 16:00, and 24:00 of subjects without or with NAFLD were evaluated. A cosine model was fitted to the curve of dynamic PRL levels. Luciferase report assay, ChIP and EMSA were used to examine the mechanism of PRL rhythm. Hight fat diet (HFD) C57BL/6 mice were categorized into HFD, HFD+jet-lag group for 16 weeks and serum PRL levels at ZT0, ZT4, ZT8, ZT12, ZT16, ZT20 were determined. Then mice in HFD+jet-lag group were randomly assigned to HFD+ jet lag and HFD+jet-lag+PRL for 14 days. Hepatic lipid content, clock genes and lipid metabolic genes in liver were detected. PRL in 8:00, 16:00 and 24:00 were all significantly lower in NAFLD group than in controls. Cosine curve analysis showed that NAFLD patients had reduced amplitude and delayed phase shift of PRL levels. After adjusted for confounders, light exposure at night is a risk factor for NAFLD, yet this association was dampened after adjusted for PRL rhythm. Luciferase report assay in 293T cell and EMSA assay in human pituitary tissue showed that Prl can be transactivated by core clock gene Rorα via RORα response element RORE. In mice, dynamic PRL attained highest levels at ZT12 in HFD mice but remained low in HFD+jet-lag mice. ChIP analysis showed that binding of Rorα and Prl promoter in HFD mouse pituitary at ZT12 was inhibited under HFD+jet-lag. Furthermore, hepatic lipid content was significantly higher in HFD+jet-lag group than that in HFD, and can be mitigated after 14 days PRL intervention at ZT12. We also found that PRL injection reversed changes of clock and lipid metabolic gene rhythm caused by jet-lag. PRL can serve as an endocrine sensor that transmits rhythmic signals from central nervous system to liver and thus regulating hepatic lipid metabolism.

Disclosure
B. Yan: None. P. Zhang: None. D. Zhu: None.

Funding
National Natural Science Foundation of China (81900787, 81770819)
1772-P: Reversibility of Altered Brain Glucose Kinetics in T2DM
Authors: RANGEL ELIZABETH SANCHEZ , GUNAWAN FELONA , JIANG LIHONG , SAVOYE MARY , DAI FENG , ROTHMAN DOUGLAS L. , MASON GRAEME F. , HWANG JANICE J. 
Published: June 2020

Poor glycemic control is associated with central nervous system complications. We have previously shown that compared to healthy controls, individuals with uncontrolled T2DM have a blunted rise in brain glucose levels measured by 1H magnetic resonance spectroscopy (MRS). In this study, we investigate whether reduction in HbA1C improves intracerebral glucose levels. Six T2DM subjects with poor glycemic control were recruited (4F, age 46.0 ± 8.8 yrs, BMI 34.2 ± 4.1 kg/m2, HgbA1c 9.6 ± 1.1%) to participate in 1HMRS scanning at 4 Tesla during a hyperglycemic clamp (∼220 mg/dl) before and after a 12-week intervention to improve glycemic control through use of continuous glucose monitoring, intensification of diabetes regimen, and frequent visits with an endocrinologist and nutritionist. Following the intervention, HbA1c decreased by 2.1%±1.5 (P=0.02) with minimal BMI changes (P=0.10). Using a hierarchical linear regression model to compare glucose time courses during the clamp pre and post intervention, brain glucose levels were modestly and significantly higher during the clamp after the intervention (P=0.02) despite no differences in plasma glucose levels during the clamp (P=0.45). These findings suggest that brain glucose levels increase after improvement of glycemic control and provide evidence that reducing HbA1C may improve brain glucose transport and/or metabolism.

Disclosure
E. Sanchez Rangel: None. F. Gunawan: None. L. Jiang: None. M. Savoye: None. F. Dai: None. D.L. Rothman: None. G.F. Mason: None. J.J. Hwang: Research Support; Self; General Electric.

Funding
National Institutes of Health (DK109284)
1785-P: Drug-Induced Blockade of the Herg-Voltage-Gated Potassium Channel Decreases Glucose-Stimulated Insulin and GLP-1 Secretion in Healthy Participants: A Crossover Study
Authors: JUHL CHRISTIAN R. , BURGDORF JOSEPHINE , KNUDSEN CECILIE , VEEDFALD SIMON , HOLST JENS J. , KANTERS JØRGEN , TOREKOV SIGNE S. 
Published: June 2020

Background: Patients with Long-QT syndrome (LQTS) due to a loss-of-function mutation in hERG, encoding the hERG-voltage-gated potassium channel (Kv11.1), exhibit increased glucose-stimulated insulin secretion, defective glucagon secretion, and postprandial hypoglycemia. Recently, LQTS has been reported to be associated with an increased risk of type 2 diabetes. We aimed to investigate the effect of drug-induced (moxifloxacin) blockade of the hERG-channel on glucose homeostasis.
Methods: Using a double-blinded, randomized, placebo-controlled, crossover design, 40 healthy young participants underwent two 6-hours oral glucose tolerance tests (OGTT). The intervention was a 4-day treatment period with a selective hERG-blocker (the antibiotic moxifloxacin 800 mg/day) or placebo, final dose two hours before the OGTT, separated by a 3-week washout period.
Results: Moxifloxacin prolonged the QTc interval by 25 ms. Figure 1 shows the means and 95% CI from the moxifloxacin/placebo 6-hour OGTTs. Insulin and GLP-1 levels were reduced the first 90 min and glucose was reduced the first 15 min with moxifloxacin blockade, thereby increasing the Matsuda-index by 1.16 (95% CI -1.9;-0.4).
Conclusion: Moxifloxacin-induced hERG blockade reduced peak postprandial glucose excursions and decreased the secretion of insulin and GLP-1.

Disclosure
C.R. Juhl: None. J. Burgdorf: None. C. Knudsen: None. S. Veedfald: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. J. Kanters: None. S.S. Torekov: Research Support; Self; Novo Nordisk Inc.

Funding
Independent Research Fund Denmark; Danish Heart Association; Lundbeck Foundation
1790-P: ACE2-Ang1-7-Mas Axis Protects Islets from Endoplasmic Reticulum Stress
Authors: SHI TING-TING , LU JING 
Published: June 2020

The derangement of endoplasmic reticulum (ER) homeostasis triggers β-cell dysfunction and apoptosis, leading to diabetes. The angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) [Ang-(1-7)]/Mas axis has been evidenced to protect islet function, but its role in ER stress remains undefined. Here we confirmed that upon treatment with the ER stress inducers thapsigargin (TG) or palmitic acid (PA), the protein levels of ACE2 rapidly increased in mouse islets. ACE2 overexpression and Ang-(1-7) treatment in islets reduced EIF2α-ATF4-mediated ER stress induced by TG or PA. On the contrary, islets from aged Ace2−/y mice (20-month old) were substantially more sensitive to ER stress and cell loss compared with Ace2+/y mice. ACE2 overexpression improved glucose-stimulated insulin secretion (GSIS) and ACE2 ablation resulted in impaired GSIS in mice islets. In vitro, the defective GSIS and ER stress in Ace2−/y islets were rescued by replenishment of ACE2. Furthermore, PI3K-Akt signaling was activated by ACE2 and participated in ER stress in islets. The present study is the first to clarify the possible mechanisms of ACE2/Ang-(1-7)/Mas axis regulate ER stress in islets.

Disclosure
T. Shi: None. J. Lu: None.

Funding
National Natural Science Foundation of China (81561128015, 81370946, 81400824)
1792-P: Measures of ß-Cell Function from Two-Step Hyperglycemic Clamps: Relation to Glycemia
Authors: XIANG ANNY , HANNON TAMARA S. , MATHER KIEREN J. , BARENGOLTS ELENA , CREE-GREEN MELANIE , NADEAU KRISTEN J. , SAM SUSAN , KAHN STEVEN E. , BUCHANAN THOMAS A. ,   THE RISE CONSORTIUM
Published: June 2020

We derived β-cell measures compensating for insulin resistance (disposition indices [DI]) from two-step hyperglycemic clamps with arginine stimulation, and examined their associations with glycemia cross-sectionally and longitudinally after treatment. Data included 355 adults (age 23-66 y; 51% female) and 89 youth (age 10-19 y; 71% female) from the RISE Consortium studies. Clamps were done at baseline and after 12 mo treatment with medications or gastric banding. Insulin sensitivity was quanitfied as M/I. β-cell responses included acute insulin (AIRg) and C-peptide (ACPRg) responses to glucose; steady-state C-peptide (SSCP) at glucose ∼11.1 mmol/L; and maximum insulin (AIRmax) or C-peptide (ACPRmax) responses to arginine at glucose &gt;25 mmol/L. DIs were calculated from M/I and β-cell responses as [responses x (M/I)-b ]. The Table shows the correlations between each DI and glucose at baseline, and changes after treatment. The correlations were higher in youth than adults, except for changes in AIRmax or ACPRmax and 2-hour glucose. The correlations for ACPRg and AIRg were generally higher, followed by SSCP and then maximal responses. Thus, in the RISE cohorts, measures of early β-cell response were more strongly associated with glycemia than were late responses, with stronger correlations in youth. This underscores different contributions of early and late insulin secretion in the regulation of glycemia.

Disclosure
A. Xiang: None. T.S. Hannon: None. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. E. Barengolts: None. M. Cree-Green: Advisory Panel; Self; Novo Nordisk Inc. K.J. Nadeau: None. S. Sam: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc. T.A. Buchanan: None. T. Consortium: None.

Funding
American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases
1822-P: Regulation of Trafficking of Lipids from Liver to Fat by ApoA4 in a Mouse Model of Nonalcoholic Steatohepatitis
Authors: LI XIAOMING , LIU XIAO-HUAN , CHENG CHENG , ZHOU JING-TING , FAN JING-NA , LI SHENGBIN 
Published: June 2020

Lipogenesis and lipolysis largely determining adipose tissues and liver lipid content, and the imbalance between them contributes to fatty liver disease and metabolic syndromes. Lipogenesis and lipolysis are regulated by nutritional signals and metabolic hormones such as insulin through multiple mechanisms. Apolipoprotein A-IV (ApoA4), secreted largely by intestine, is existed as the composition of HDL and as the free form mostly in blood. ApoA4 plays the important roles in anti-atherosclerosis and lowering blood glucose. After we found its suppressing hepatic gluconeogenesis via NR1D1/NR4A1, and promoting glucose uptake in adipose tissues through PI3K-Akt-GLUT4, we have studied the action of ApoA4 on lipid metabolism with ApoA4 knock-out mice (A4KO). We found that ApoA4 deficiency resulted in worse fatty liver in diet induced obesity (DIO) mice. ApoA4 deficiency lowered the expression of hepatic ATGL, the rate-limiting enzyme for lipolysis, but enhanced the expression of key lipogenic enzymes such as ACC and SCD1. However, the expression of ATGL was increased and the expression of ACC, SCD1, FAS as well as their transcriptional activator SREBP1 were decreased from both BAT and WAT in A4KO mice. Furthermore, ApoA4 deletion also resulted in the inhibited expression of key proteins in thermogenesis pathway SIRT1, PGC1 and UCP1. Moreover, either overexpression of ApoA4 by delivery of AAV-ApoA4 or one time injection of ApoA4 protein resulted in reversed expression of key enzymes for lipogenesis and lipolysis both in liver and adipose tissues from A4KO DIO mice. These data suggest that ApoA4 may promote lipolysis in liver, but inhibited lipolysis and enhance lipogenesis and energy metabolism in adipose tissues, implying ApoA4’s action of regulating the trafficking of lipids from liver to fat and then turn fat into energy for burning.

Disclosure
X. Li: None. X. Liu: None. C. Cheng: None. J. Zhou: None. J. Fan: None. S. Li: None.

Funding
National Natural Science Foundation of China (81770798, 81700691)
1827-P: Pioglitazone Improves Nonalcoholic Steatohepatitis (NASH) in a Diet-Induced Cynomolgus Monkey Model
Authors: CAMACHO RAUL , POLIDORI DAVID , CHEN TAO , GAO BIN , WONG PEGGY , GABRIEL JOSEPH A. , ZHU EDWARD , WANG TONY , NAWROCKI ANDREA R. 
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) ranges in severity from steatosis to NASH. NASH, which is characterized by steatosis, ballooning, inflammation (NAFLD Activity Score [NAS]), and frequently fibrosis, can progress to cirrhosis and hepatocellular carcinoma. Despite the unmet medical needs of NASH leading to end stage liver disease and increased risk for cardiovascular death, there are no approved treatments to date. In clinical trials, pioglitazone treatment (6-24 months) has led to NASH resolution and/or reduction in fibrosis. We developed a cynomolgus monkey (cyno) model of NASH by feeding a high fat/cholesterol diet for 2+ years and demonstrated accelerated disease progression by adding fructose to this diet. A total of 31 obese (mean±SD, 10.4±1.8 kg), insulin resistant (HOMA-IR: 29±32) cynos with NASH were used. Histological assessments of liver biopsies were used to characterize disease progression and response to therapy and compared to human studies. Baseline NAS of 5.6±0.9 was similar to those in NASH patients, whereas baseline fibrosis scores of 1.2±0.5 were slightly lower than values of ∼2 typically enrolled in Phase 2 trials. Cynos were treated daily with vehicle (n=10) or pioglitazone (3 mg/kg; n=21) for 6 months. Drug exposures 24 hours post-dose averaged 233±145 ng/mL, similar to that seen in humans (∼200 ng/mL) dosed with 45 mg. Adiponectin, a biomarker for PPARγ activation, increased ∼2-fold in treated cynos. NAS improvement (a decrease in NAS of ≥2 with changes in 2 or more components of NAS) was seen in 30% of treated cynos (p=0.08). No vehicle animals showed NAS improvement. Treated cynos showed significant decreases in ballooning, trends in decreases (p=0.07) in steatosis and inflammation, but no change in fibrosis whereas vehicle animals showed no changes or worsening. We have validated and benchmarked a novel cyno model for NASH that has characteristics similar to human pathology and responds to a treatment known to improve NASH in clinical trials.

Disclosure
R. Camacho: Employee; Self; Janssen Pharmaceuticals, Inc. D. Polidori: Employee; Self; Janssen Research and Development. Stock/Shareholder; Self; Janssen Research and Development. T. Chen: Employee; Self; Janssen Pharmaceuticals, Inc. B. Gao: Employee; Self; Janssen Pharmaceuticals, Inc. P. Wong: Employee; Self; Johnson & Johnson. Stock/Shareholder; Self; Merck & Co., Inc. J.A. Gabriel: Employee; Self; Kunming Biomed International (KBI). E. Zhu: None. T. Wang: None. A.R. Nawrocki: Employee; Self; Janssen Pharmaceuticals, Inc.
1870-P: Glucose Metabolism after Overnight and Prolonged Fasting in Participants with Different Glucose Tolerances
Authors: TRIPOLT NORBERT J. , PFERSCHY PETER N. , OBERMAYER ANNA , ECKSTEIN MAX L. , KOJZAR HARALD , SOURIJ CAREN , MOSER OTHMAR , OBERMAYER-PIETSCH BARBARA M. , RIEDL REGINA , SOURIJ HARALD 
Published: June 2020

Background: Metabolic regulation of glucose can be altered by fasting periods. The aim of our study was to examine the glucose metabolism after an overnight fast (12 hours) as well as after prolonged fasting (36 hours of fasting) in non-obese people, people with obesity and people with type 2 diabetes (T2DM).
Material and Methods: Glucose metabolism was assessed by a 75 g oral glucose tolerance test after 12 and 36 hours fasting, respectively. Area under the curve (AUC) was calculated according to the trapezoidal rule. Insulin sensitivity was estimated by using QUICKI and HOMA-IR.
Results: In total 60 participants (age 43±16 years, 62% women) were included. Fasting levels of glucose, insulin and c-peptide were significantly lower in all cohorts after 36 hours vs. 12 hours of fasting (p&lt;0.05). However, in non-obese people mean 2h-glucose level was significant higher after prolonged fasting [108.7±31.1 mg/dL vs. 79.4±18.4mg/dL after 12h fasting; p&lt;0.05] with significantly lower 30 minutes insulin levels following prolonged fasting, while within the two other cohorts no change in this 2h-glucose was observed. Indices of insulin sensitivity improved in all groups after prolonged fasting.
Conclusion: Our data demonstrate higher glucose excursions and a reduced early insulin response after 36 hours of fasting compared to an overnight fasting period in participants with various glucose tolerance levels.

Disclosure
N.J. Tripolt: None. P.N. Pferschy: None. A. Obermayer: None. M.L. Eckstein: Research Support; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi-Aventis. H. Kojzar: None. C. Sourij: None. O. Moser: Other Relationship; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi. B.M. Obermayer-Pietsch: None. R. Riedl: None. H. Sourij: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi.
1871-P: Dietary Iron and Hypoxia Interact to Alter Glucose Homeostasis and ß-Cell Activity in a Fast Food Diet Mouse Model
Authors: HARRISON ALEXANDRIA V. , SINK SANDY T. , LORENZO FELIPE , JAIN SHALINI , MCCLAIN DONALD A. 
Published: June 2020

Dietary iron overload is linked to increase risk of type 2 diabetes (T2D), with iron significantly affecting insulin sensitivity/secretion, hepatic glucose production, as well as other physiological responses altered in T2D. These effects are in part mediated through the iron-dependent hypoxia sensing pathway. The interactions between iron and hypoxia in T2D have yet to be elucidated. We therefore fed mice a fast food (FF) diet with varying iron concentrations, from a low 4 mg/kg to a high 2000 mg/kg, under normoxic and hypoxic conditions. There was a reduction in weight for hypoxic mice (by 30% for 4mg-Fe diet, 20% for 35mg-Fe diet, and 15% for 2000mg-Fe diet; p&lt;0.05) as compared to normoxic mice, independent of food consumption. ECHO-MRI measurements revealed higher fat mass with increased iron in normoxic mice. Hypoxic mice had significantly lower fat mass and increased leaner muscle mass. Both fasting glucose (FG) and glucose tolerance were significantly improved under hypoxia (improvement of 15-45% for FG, p&lt;0.05 and 25-40% for glucose tolerance, p&lt;0.01). High iron decreased the homeostasis model assessment of insulin resistance (HOMA-IR) in normoxic mice, and hypoxic mice were less insulin resistant than those in normoxia (p&lt;0.05). Higher iron also decreased the homeostasis model assessment of beta-cell function (HOMA-B) for both normoxic and hypoxic mice. Consistent with the HOMA-B results, islet perifusion shows that glucose-stimulated insulin secretion (GSIS) is comparatively lower under the combination of high iron and hypoxia. We conclude that while iron is able to independently affect glucose tolerance in mice on a FF diet, the effects of dietary iron still depend on oxygen level. Our perifusion data suggests that iron and hypoxia work in synergy to alter β-cell activity. The synergistic effects of iron and hypoxia may be mediated by the two HIF regulatory arms, iron-dependent dioxygenases prolyl-hydroxylase (PHD) and factor inhibiting HIF (FIH).

Disclosure
A.V. Harrison: None. S.T. Sink: None. F. Lorenzo: None. S. Jain: None. D.A. McClain: None.
1875-P: The Impact of Carbohydrate/Fat Intake Balance on Beta-Cell Dedifferentiation and Fatty Liver in Obese Mouse Model
Authors: ISHIDA EMI , LEI XIAO , YAMADA EIJIRO , OKADA SHUICHI , YAMADA MASANOBU 
Published: June 2020

In clinical, the ’fatigue’ of the pancreatic beta cells is a famous phenomenon in type 2 diabetes. Nowadays, researchers describe the several mechanisms of beta cell dysfunction, such as glucolipotoxicity, endoplasmic reticulum stress and oxidative stress. In 2012, Talchai et al. revealed that the beta cells were dedifferentiated in diabetes, and previously we showed that food restriction had the most manifold good effects to restore beta cell gene expression, among the known diabetic treatments that we tested. In the current study, we aimed to unveil which nutrients should be cut down to protect beta cell differentiation, sugar or fat. First, we performed the pair-feeding with db/+ and db/db to reduce food intake of db/db mice. We utilized the high-fat/low carbohydrate diet (HF) or low-fat/high carbohydrate (HC) diet which were adjusted to the same total calorie intake. Pair fed-db/db mice had better body weight and glucose tolerance control than ad libitum db/db group, as previously we reported, and there was no significant difference between HF and HC diet. Albeit the same metabolic profile, HC diet group had more enlarged islets and more dedifferentiated beta cell features, which indicated the compensatory beta cell response in HC diet group. Moreover, HC diet group showed more severe fatty liver than HF diet group, along with the elevated synthesis and accumulation of triglycerides and cholesterol in liver. We are now investigating the relationship between sugar load, insulin resistance in liver and beta cell dedifferentiation.

Disclosure
E. Ishida: None. X. Lei: None. E. Yamada: None. S. Okada: None. M. Yamada: None.

Funding
Japan Society for the Promotion of Science (18K16222)
1881-P: Separate Free Fatty Acid (FFA) Pools Are Involved in Muscle Lipid Utilization
Authors: CHOW LISA S. , MASHEK DOUGLAS G. , JENSEN MICHAEL D. 
Published: June 2020

Despite discrepant phenotypes, the insulin resistant (IR) and trained states have high levels of intramyocellular lipid. We hypothesize that higher muscle lipid turnover in the trained state may explain this discrepancy.
Obese, IR subjects and trained subjects were fasted overnight (Table1). To characterize muscle lipid turnover, we conducted a pulse-chase experiment using sequential [U-13C]palmitate and [9-2H]palmitate infusions (6 h each) with a 1 hour overlap to label endogenous and exogenous FFA pools. Biopsy#1 (Bx#1 -s/p 14 hr fast) was performed at the time of the overlap (last hour of the 6 h [U-13C]palmitate infusion, after 1 h of starting the [9-2H]palmitate). Bx#2 was performed at the study conclusion (last hour of the [9-2H]palmitate infusion-s/p 20 hr fast). Plasma and muscle samples were analyzed for palmitate enrichment and concentration.
Regardless of phenotype, muscle triglyceride (IMTG) synthesis at Bx#1 was not different as assessed by either [U-13C]palmitate or [9-2H]palmitate; IMTG synthesis assessed by [9-2H]palmitate was 9-fold higher than [U-13C]palmitate. At Bx#2, IMTG breakdown as assessed by [U-13C]palmitate was similar between groups, whereas [9-2H]palmitate showed IMTG synthesis in the obese, IR group and IMTG breakdown in the trained group.
IMTG synthesis was higher with recent (1 hour) FFA exposure than more prolonged (6 hour) FFA exposure supporting separate FFA pools in lipid utilization.

Disclosure
L.S. Chow: None. D.G. Mashek: None. M.D. Jensen: None.

Funding
National Institutes of Health (R01DK098203, UL1TR000114)