bluuebunny/crossref_metadata_2025_split huggingface dataset:
1917-P: Primary Weight Loss Failure after Gastric Bypass Is Characterized by Impaired Gut-Hormone-Mediated Suppression of Food Intake
Authors: BOJSEN-MOLLER KIRSTINE N. , SVANE MARIA S. , MARTINUSSEN CHRISTOFFER , DIRKSEN CARSTEN , JØRGENSEN NILS B. , KRISTIANSEN VIGGO BJERREGAARD , HARTMANN BOLETTE , HOLST JENS J. , MADSBAD STEN 
Published: June 2019

Roux-en-Y gastric bypass (RYGB) induces large and sustained weight loss in most patients. However, a minority of patients (5-10%) never obtain a successful weight loss after RYGB. The aim of this study was to characterize the role of gut hormones for appetite regulation in patients with primary weight loss (WL) failure defined as maximal excess BMI loss (EBLmax= ΔBMIpreoperative-postoperative/ΔBMIpreoperative-25) &lt;50% compared with patients with successful WL (EBLmax &gt;60%) after RYGB. Twenty women with primary WL failure (EBL 24% [9;27], median [IQR]) were matched to 20 women with successful WL (EBL 74% [70;83]) on age (51±9 vs. 51±9 years, mean ± sd), preoperative BMI (43.1±4.0 vs. 43.0±3.6 kg/m2) and time from RYGB (4.8±2.0 vs. 4.8±1.4 years). On separate days, a patient blinded subcutaneous injection of the somatostatin analogue Octreotide (Oct) 1 µg/kg bodyweight (max 100 µg) or saline (placebo) was given in randomized order followed by a mixed meal test at T=30 min and an ad libitum meal with measurement of food intake at T=270 min. The WL failure group had similar GLP-1 (tAUC, median [IQR], 4039 [3336;6018] vs. 4669 [3006;5891] pM·min, p=0.30) and PYY secretion (tAUC, 1935 [1493;2783], 1778 [1163;2756] pM·min, p=0.65) on the placebo day compared with the successful WL group. Injection of Oct diminished GLP-1 and PYY secretion in both groups. Oct had no effect on ad libitum food intake in the WL failure group (-0.5% [-13, 12], mean [95% CI]), while food intake was increased after Oct in the successful WL group (+23% [1.6, 44]) (ANOVA Group x Oct p=0.04).
In conclusion, primary WL failure after RYGB was not explained by lower secretion of GLP-1 or PYY. However, inhibition of hormone secretion with octreotide increased food intake only in patients with successful WL, whereas the effect was absent in patients with primary WL failure. These results support that an impaired gut-hormone mediated suppression of appetite could contribute to primary weight loss failure after RYGB.

Disclosure
K.N. Bojsen-Moller: None. M.S. Svane: None. C. Martinussen: None. C. Dirksen: None. N.B. Jørgensen: Stock/Shareholder; Self; Novo Nordisk A/S. V. Kristiansen: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. S. Madsbad: None.

Funding
Danish Council for Independent Research
192-OR: A CRISPR Screen Identifies Rfwd2 as a Regulator of Brown Fat Glucose Transport
Authors: LYNES MATTHEW , HUANG QIAN , YI PENG , TSENG YU-HUA 
Published: June 2019

Brown adipose tissue (BAT) generates heat to regulate body temperature, and to support this energy expending activity it takes up glucose from circulation. Cold exposure regimens that activate BAT improve insulin sensitivity, presumably by decreasing circulating glucose levels. Interestingly, glucose uptake during cold is specific to BAT and occurs at low circulating insulin levels, suggesting alternative pathways that do not exist in other insulin sensitive tissues may regulate brown adipocyte glucose uptake. To identify putative regulators of brown adipocyte glucose uptake, we performed a whole genome CRISPR screen using the uptake of the fluorescent glucose analog 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) as the readout on mouse brown adipocytes differentiated in vitro. By sorting single brown adipocytes according to their fluorescence, we separated the top 5%, bottom 5% and the remainder of cells using fluorescence activated cell sorting (FACS) and then sequenced to identify genes acting as both putative positive and negative regulators of glucose uptake. Genes identified as potential hits could be classified by gene ontology and belonged mostly to groups related to metabolism and energy homeostasis. A list of 25 potential regulatory genes were validated using the same 2-NBDG strategy used to identify them as well as radiolabeled glucose uptake in vitro. From these genes, 5 were further validated using a second CRISPR based strategy to block gene function. One gene that we identified is the E3 ubiquitin ligase Rfwd2, which is highly expressed in BAT and is known to regulate lipid metabolism. When Rfwd2 was deleted from brown adipocytes the global ubiquitination pattern was changed and glucose uptake was increased in both the basal and insulin stimulated states. These data suggest that targets of this ligase may play a role in the cell-signaling cascade that activates glucose uptake and these targets could further regulate BAT glucose uptake in vivo.

Disclosure
M. Lynes: None. Q. Huang: None. P. Yi: None. Y. Tseng: Other Relationship; Self; Chugai Pharmaceutical Co., Ltd.

Funding
National Institutes of Health (P30DK036836, R01DK077097, R01DK102898, F32DK102320, K01DK111714)
1923-P: Quantitative Measurement of Whole-Body Glycogen Metabolism and Gluconeogenic Flux
Authors: TESLAA TARA 
Published: June 2019

Circulating glucose levels are maintained during fasting by endogenous production of glucose through: 1) the breakdown of glycogen and 2) from gluconeogenesis. Recently published work from our lab has utilized stable isotope tracing with cutting edge LC-MS methods to determine metabolic fluxes in vivo. During these studies we observed a surprising lack of labeling in glycolytic intermediates in the majority of tissues when infusing 13C-glucose. Based on these results we hypothesized that glycogen metabolism and gluconeogenesis were active in more tissues than was previously thought. To gain a holistic understanding of glycolysis, glycogenolysis, and gluconeogenesis in vivo, we performed a series of intravenous infusions to determine the flux through these pathways. To measure the contribution of glycogen breakdown to glycolytic intermediate we performed pulse chase infusions of glucose (16h pulse of glucose infusion followed by an 8-hour chase with no infusion) and measured labeling in key glycolytic intermediates. To determine contribution from gluconeogenic, we infused stable isotope labeled lactate, glycerol, alanine, and glutamine. Finally, by utilizing a linear algebra approach to account for substrate interconversion, we were able to determine the direct contribution of glucose, glycogen breakdown, and different gluconeogenic substrates to glycolytic intermediate in 11 tissues.

Disclosure
T. TeSlaa: None.

Funding
National Institutes of Health
1925-P: Apparent Plateau in Diabetes Diagnosis Explained by Misuse of Updated Diagnosis Criteria in Simulation Modeling Study of Macronutrient Consumption Trends in U.S.
Authors: MOHANTY SMITA , CHELINI COLLEEN M. , D'ALESSANDRO PAUL , DWIVEDI GAURAV 
Published: June 2019

Introduction: Increase in diabetes prevalence in the U.S. is likely due to demographic and dietary changes, but epidemiological studies do not show large enough changes in either to explain the magnitude of diabetes increase. We used a validated diabetes model to decompose the impact of diet on diabetes prevalence from 2001-2014, while considering demographics data and new diabetes diagnosis criteria.
Methods: We used a published model of diabetes that considers macronutrient intake, demographics and individual physiology to simulate a virtual population matched to U.S. demographics in 2001 and advanced it annually by updating demographic distribution (matched to U.S. Census) and diet (estimated by training the model to CDC-estimated diabetes prevalence from ‘01-’06). Prevalence was forecast for ‘07-’14 assuming the estimated diet trend continued linearly.
Results: Predicted prevalence was within 0.24% (absolute error) of CDC estimates between ‘07-‘14. Diabetes rates were largely explained by increase in carbohydrate (5%) and decrease in fat intake (11%) between ‘01-’14. The apparent plateau in diagnosed diabetes after 2010 (Figure) is inconsistent with model prediction unless both high HbA1c and glucose are used to diagnose diabetes, suggesting possible misuse of the ‘10 criteria in clinical practice.

Disclosure
S. Mohanty: None. C.M. Chelini: Employee; Self; Pwc. P. D'Alessandro: None. G. Dwivedi: None.
1931-P: Skeletal Muscle (SM) Insulin Resistance (IR) in Coronary Artery Disease (CAD) in Type 1 Diabetes (T1D)
Authors: WILLIAMS KATHERINE V. , SHAY CHRISTINA M. , PRICE JULIE , ORCHARD TREVOR J. , KELLEY DAVID 
Published: June 2019

IR in T1D may contribute to CAD risk. We recently reported that SM IR in T1D primarily involves oxidative SM while glycolytic SM is comparable to healthy controls. This study compared systemic glucose disposal (GD) and SM IR in T1D with and without CAD. Insulin-infusion glucose clamps measured systemic GD concurrent with positron emission tomography (PET) imaging of SM glucose uptake with [18F]fluorodeoxyglucose (FDG) to profile glucose transport and phosphorylation, rate-limiting steps for GD. PET images were co-registered with MRI of the calf to determine FDG uptake (Patlak K) in soleus (SO) SM (largely oxidative muscle, type 1 fibers) vs. tibialis anterior (TA) SM (largely glycolytic muscle, type 2 fibers). Subjects with (n=9) and without (n=10) CAD were from the Epidemiology of Diabetes Complications (EDC) study, a 30-year prospective study of childhood onset T1D. Those CAD+ were older (52.4 vs. 43.1 years, p &lt;0.01), heavier (BMI 28.0 vs. 24.3 kg/m2, p&lt;0.05), and had higher systolic blood pressure (137 vs. 116 mmHg, p &lt;0.05), each a factor disposing to IR. Groups did not differ in HbA1c (7.6 vs. 7.6%), insulin dose (0.59 vs. 0.59 U/kg), waist circumference (91.7 vs. 85.2 cm, p=0.07 controlled for sex), creatinine (1.0 vs. 0.9 mg/dL), CKD-EPI (78.9 vs. 93.1 mL/minute/1.73m2), or lipids. Those CAD+ did not differ from CAD- in systemic GD (5.40 vs. 4.95 mg/kg-FFM, p=0.59). In SM, FDG uptake in SO did not differ in T1D CAD+ vs. CAD- (0.0080 vs. 0.0075 mL/cm3-minute), though these values were reduced by 40% compared to controls (n=13). FDG uptake in TA SM was greater in T1D CAD+ vs. CAD- (0.0133 vs. 0.0077 mL/cm3-minute, p&lt;0.01), and was also higher than in controls. Neither systemic nor SM IR were more severe in T1D with CAD compared to T1D without CAD. SM IR in T1D is present in oxidative type SM regardless of CAD, yet IR in T1D is not evident in glycolytic SM. Moreover, insulin-stimulated glucose transport/phosphorylation is increased in TA SM of T1D with CAD, perhaps as a compensatory heightening of insulin action in glycolytic SM.

Disclosure
K.V. Williams: None. C.M. Shay: None. J. Price: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH. D. Kelley: Consultant; Self; Kallyope, Regeneron Pharmaceuticals, Takeda Pharmaceutical Company Limited. Other Relationship; Self; Merck & Co., Inc.

Funding
National Institutes of Health (DK071487)
1937-P: miR-23b-3p Upregulates Glucose Uptake in C2C12 Myotube Cells by Regulating the Expression of PTEN
Authors: OKAMURA TAKURO , HASHIMOTO YOSHITAKA , OSAKA TAKAFUMI , SENMARU TAKAFUMI , HAMAGUCHI MASAHIDE , FUKUI MICHIAKI 
Published: June 2019

Sarcopenia, i.e., the loss of muscle mass and degradation of muscle that can occur with aging, increases an individual's risk of death. MicroRNAs are negative regulators of gene expression that have been implicated in many biological processes, including metabolism. Here we investigated the role of microRNA in sarcopenia. Orchiectomized (ORX) mice have decreased body weight and muscle mass, a smaller cross-sectional area of muscle, and impaired glucose tolerance. In our microarray analysis of the microRNA expression in skeletal muscle, the expression of miR-23b-3p in ORX mice was significantly higher than that in Sham mice; the expression in ORX mice treated with androgen was conversely lower. The overexpression of miR-23b-3p in C2C12 myotube cells significantly upregulated the expression of myosin heavy chain, protein synthesis, ATP activity, and glucose uptake. Reporter assays revealed direct post-transcriptional regulation involving miR-23b-3p and the 3'-untranslated region of PTEN mRNA. Among male subjects with type 2 diabetes, the serum miR-23b-3p levels in the subjects with sarcopenia was significantly higher compared to the levels of the subjects without sarcopenia. Our results indicate that miR-23b-3p negatively regulates the expression of PTEN in myotube cells and induces the upregulation of glucose uptake. In addition, the serum level of miR-23b-3p can be a surrogate marker of sarcopenia.

Disclosure
T. Okamura: None. Y. Hashimoto: Research Support; Self; Asahi Kasei Pharma. T. Osaka: None. T. Senmaru: None. M. Hamaguchi: 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.
1941-P: The Relationship among Intramyocellular Lipid, Peak Oxygen Consumption, and Insulin Resistance in Nonobese Japanese Men
Authors: YAMASAKI NOZOMU , TAMURA YOSHIFUMI , TAKENO KAGEUMI , KAKEHI SAORI , SOMEYA YUKI , FUNAYAMA TAKASHI , FURUKAWA YASUHIKO , KAGA HIDEYOSHI , SUZUKI RURIKO , SUGIMOTO DAISUKE , KADOWAKI SATOSHI , SATO MOTONORI , KAWAMORI RYUZO , WATADA HIROTAKA 
Published: June 2019

Accumulation of intramyocellular lipid (IMCL) is observed not only in insulin resistant obese subjects with low peak oxygen consumption (VO2peak), but also in insulin sensitive endurance athletes with high VO2peak (athlete’s paradox). While the relationship among intramyocellular lipid, peak oxygen consumption and insulin resistance is variable among the different subjects, its relation within non-obese non-athlete subject has not been elucidated yet. To investigate this relation, we studied 61 non-obese (BMI&lt;25kg/m2) non-athlete Japanese men. We evaluated muscle insulin sensitivity (M-IS) by a 2-step hyperinsulinemic euglycemic clamp. We divided the subjects into 4 groups based on the median value of VO2 peak (31.4 ml/kg per min) and the IMCL in soleus muscles (14.3 s-fat/Cre), then we compared M-IS. Compared with Low-VO2peak/High-IMCL group, M-IS was significantly higher in High-VO2peak/Low-IMCL group and High-VO2peak/High-IMCL group (Fig). On the other hand, M-IS was comparable between High-VO2peak/Low-IMCL group and High-VO2peak/High-IMCL group. These results suggest that in non-obese non-athlete Japanese men, VO2peaklevel is an important determinant of muscle insulin sensitivity in IMCL accumulated subjects. In addition, IMCL accumulation is not an important determinant of muscle insulin sensitivity in subjects with high VO2peak.

Disclosure
N. Yamasaki: None. Y. Tamura: None. K. Takeno: None. S. Kakehi: None. Y. Someya: None. T. Funayama: None. Y. Furukawa: None. H. Kaga: None. R. Suzuki: None. D. Sugimoto: None. S. Kadowaki: None. M. Sato: None. R. Kawamori: None. H. Watada: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kissei Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanwa Chemical Industry Co. Ltd., Takeda Pharmaceutical Company Limited.
1945-P: The Mitochondrial Protein DRP1 Is Required for Endogenous Fatty Acid Oxidation
Authors: KING WILLIAM T. , AXELROD CHRISTOPHER L. , DAVULURI GANGARAO , NOLAND ROBERT C. , KIRWAN JOHN P. 
Published: June 2019

Introduction: Mitochondria are organelles that routinely undergo fission and fusion in a process known as mitochondrial dynamics. Increased mitochondrial fission is implicated in the pathogenesis of obesity, type 2 diabetes, and metabolic disease. DRP1 has been identified as a key regulator of mitochondrial fission. We and others have demonstrated that loss of DRP1 is associated with improvements in glucose homeostasis, however, the role of DRP1 in mitochondrial fatty acid oxidation is unknown. The purpose of this study was to measure endogenous fatty acid oxidation in DRP1-deficient skeletal muscle cells.
Methods: C2C12 myoblasts were stably transfected with DRP1 shRNA (KO) or a scrambled control (CT). Myoblasts were then cultured in a substrate-limited DMEM (0.5mM glucose, 0.5mM carnitine, 1mM glutamine, and 1% FBS) overnight. 15 minutes prior to assay, etomoxir was added to inhibit endogenous fatty acid oxidation (FAO). Cells were then challenged with either bovine serum albumin (BSA) or palmitate (PA) and assessed for mitochondrial function using whole cell respirometry (Agilent XFe24). Additionally, cells were treated with 14C-labeled PA in the absence and presence of increasing glucose concentrations to assess metabolic flexibility and fatty acid oxidation.
Results: Basal whole cell (P&lt;0.05) and endogenous fatty acid (P&lt;0.05) oxygen consumption were reduced in KO cells relative to CT (P&lt;0.05). Furthermore, ATP linked fatty acid oxidation was blunted in the KO cells (P&lt;0.05).
Conclusion: Here, we show that DRP1 is required for FAO. After inhibition of FAO with etomoxir, basal and ATP-linked respiration were ablated in DRP1-deficient cells. These findings suggest that loss of DRP1 ablates the ability of cells to use endogenous fatty acids as substrate when carbohydrate is not available. These data suggest that impaired lipid metabolism, rather than inhibition of mitochondrial fission, may explain improvements in glucose homeostasis with the loss of DRP1.

Disclosure
W.T. King: None. C.L. Axelrod: None. G. Davuluri: None. R.C. Noland: None. J.P. Kirwan: None.

Funding
National Institutes of Health (R01DK108089, U54GM104940, R01DK103860)
1952-P: Glucagon Receptor Antagonism Increases Plasma Amino Acids and Glucagon
Authors: HAEDERSDAL SOFIE , WEWER ALBRECHTSEN NICOLAI JACOB , LUND ASGER B. , GALSGAARD KATRINE D. , WINTHER-SOERENSEN MARIE , HOLST JENS J. , KNOP FILIP K. , VILSBØLL TINA 
Published: June 2019

Hyperglucagonemia in type 2 diabetes (T2D) may result from impaired hepatic glucagon signaling and consequent reduced glucagon-induced amino acid (AA) turnover leading to higher AA concentrations and stimulation of glucagon secretion. In a double-blinded, cross-over study, blood was sampled from 10 overnight fasted patients with T2D (BMI [mean±SD]: 33.0±5.4 kg/m2; HbA1c: 46.2±6.1 mmol/mol, 6.4±0.6%) and 10 matched healthy controls (BMI: 31.7±4.2 kg/m2; HbA1c: 33.9±3.0 mmol/mol, 5.3±0.3%) after a single-dose of the glucagon receptor antagonist (GRA) LY2409021 or placebo. Total AA and glucagon concentrations are means of 3 samples (15 minutes apart) on 3 GRA and 3 placebo days. Fractioned AA were analyzed from one sample per day. Total AA concentrations were increased by GRA compared to placebo by 1.4 fold in T2D and 1.3 fold in controls (P≤0.001) with threonine, proline and the glucagonotropic AAs alanine and tyrosine exhibiting the greatest increases in T2D (1.6-2 fold) and controls (1.4-1.5 fold). GRA also increased plasma glucagon concentrations by more than 3-fold (P≤0.0001), and the glucagonotropic AAs alanine (R2 0.24, P=0.0012) and tyrosine (R2 0.30, P=0.0002) were correlated to glucagon.
In conclusion, acute inhibition of glucagon receptor signaling by GRA causes hyperaminoacidemia linked to hyperglucagonemia, supporting the importance of the liver-alpha cell axis in regulating circulating glucagon and AA in humans.

Disclosure
S. Haedersdal: None. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. A.B. Lund: None. K.D. Galsgaard: None. M. Winther-Soerensen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S. T. Vilsbøll: None.

Funding
Novo Nordisk Foundation
1957-P: The Role of Glucose-Dependent Insulinotropic Polypeptide in Regulation of Splanchnic Blood Flow and Lipid Metabolism in Humans
Authors: ASMAR ALI , HOLST JENS J. , ASMAR MEENA 
Published: June 2019

The aim of this study was to investigate the effect of glucose-dependent insulinotropic polypeptide (GIP) per se and in combination with hyperglycemia and hyperinsulinemia on splanchnic blood flow and further to investigate the role of GIP in splanchnic lipid metabolism in humans. Eight healthy lean males were examined in a randomized order on four different occasions. Splanchnic blood flow and lipid metabolism were measured by Fick’s Principle using indocyanine green as indicator during GIP (1.5 pmol/kg/min) or saline infused intravenously alone or in combination with a hyperglycemia and hyperinsulinemia (Hygluc-Hyinsu) clamp. During all four experiments, splanchnic blood flow increased similarly. Splanchnic triglyceride output decreased similarly during the Hygluc-Hyinsu clamp with and without GIP (8.6 ± 1.8 and 10.3 ± 2.6 µmol/min, respectively, P=NS). Likewise, during the clamp alone and with GIP, free fatty acids uptake decreased similarly (3.5 ± 3.8 and 6.7 ± 4.6 µmol/min, respectively, P=NS). GIP does not seem to play a key role in the acute regulation of splanchnic blood flow or lipid metabolism under these particular conditions in vivo.

Disclosure
A. Asmar: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. M. Asmar: None.