bluuebunny/crossref_metadata_2025_split huggingface dataset:
1887-P: Intermittent Hypoxia Increased the Expressions of Interleukin (IL)-8, Osteonectin, and Myonectin via OCT1 and Nrf2 Binding to the Promoters in Muscle Cells
Authors: TAKASAWA SHIN , SHOBATAKE RYOGO , ITAYA-HIRONAKA ASAKO , MAKINO MAI , SAKURAMOTO-TSUCHIDA SUMIYO , UCHIYAMA TOMOKO , OTA HIROYO , YAMAUCHI AKIYO 
Published: June 2020

Sleep apnea syndrome (SAS) is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for insulin resistance/type 2 diabetes. However, the mechanisms linking IH stress and insulin resistance remain elusive. We exposed human RD and mouse C2C12 muscle cells either to 70 cycles/24 h of IH (5 min hypoxia [1% O2]/10 min normoxia [21% O2]), mimicking SAS patients, or normoxia for 24 h, measured mRNA levels by real-time reverse transcription polymerase chain reaction, and found that IH significantly increased the mRNA levels of interleukin-8 (IL-8), osteonectin (ON), and myonectin (MN). IL-8, ON, and MN in IH-treated RD cell medium were also increased (P&lt;0.0001, P&lt;0.0001, and P=0.0079, respectively). We further analyzed the IH-induced expression mechanisms of IL-8, ON, and MN genes in RD muscle cells. Deletion analyses revealed that -152 to -151 region in IL-8, -105∼-99 region in ON, and -3,741∼-3,738 region in MN promoter(s) were responsible for the activation by IH. The promoters contain consensus transcription factor binding sequences for octamer binding transcription factor 1 (OCT1) in IL-8 and MN, and for nuclear factor erythroid 2-related factor 2 (NRF2) in ON, respectively. The introduction of siRNA for OCT1, and NRF2 abolished the increase of mRNAs for IL-8 and MN, and ON, respectively. As IL-8, ON, and MN are reported to be myokines and associated with glucose intolerance, insulin resistance, and diabetes, the results could well explain a mechanism of glucose intolerance, insulin resistance, and diabetes in SAS patients.

Disclosure
S. Takasawa: None. R. Shobatake: None. A. Itaya-Hironaka: None. M. Makino: None. S. Sakuramoto-Tsuchida: None. T. Uchiyama: None. H. Ota: None. A. Yamauchi: None.
1889-P: Light Exercise and Liraglutide Synergistically Improve Muscle Insulin Action in Diet-Induced Obesity
Authors: LIU JIA , AYLOR KEVIN W. , LIU ZHENQI 
Published: June 2020

Insulin recruits muscle microvasculature which contributes to insulin’s metabolic action but is blunted in humans with obesity. Both exercise and glucagon-like peptide 1 (GLP-1) are potent enhancers of muscle microvascular perfusion and their actions are preserved in the insulin resistant states. To examine whether light exercise and GLP-1 receptor agonism modulate insulin’s microvascular and metabolic actions during the development of obesity, adult male rats were fed a high-fat diet (HFD) for 2 weeks with either free access to running wheel (light exercise), liraglutide (200 mcg/kg subcutaneously twice daily), or light exercise + liraglutide. Rats were then fasted overnight and received a euglycemic insulin clamp (3 mU/kg/min) for 120 min. Insulin-mediated muscle microvascular recruitment was measured using contrast-enhanced ultrasound. Rats on HFD alone (control) displayed marked microvascular insulin resistance. Light exercise increased basal plasma nitric oxide levels and fully rescued insulin’s microvascular action. Liraglutide similarly increased basal plasma NO contents but did not reverse microvascular insulin resistance. Both light exercise and liraglutide improved insulin-stimulated whole body glucose disposal in the first 30 min but did not significantly increase the steady-state glucose infusion rates. Combined light exercise and liraglutide treatment not only fully restored microvascular insulin responses but also significantly enhanced insulin-stimulated whole body glucose disposal (&gt;50%, p&lt;0.01). We conclude that light exercise and liraglutide differentially modulate microvascular insulin responses but synergistically enhance metabolic insulin actions during the development of obesity. Our findings provide a novel insight into the exercise and liraglutide interplay and support the early use of exercise and GLP-1 receptor agonism to correct microvascular and metabolic insulin resistance during the development of obesity.

Disclosure
J. Liu: None. K.W. Aylor: None. Z. Liu: None.

Funding
American Diabetes Association (1-17-ICTS-059 to Z.L.); National Institutes of Health (R01HL094722, R01DK102359)
1890-P: Glycemic Control and Ultrasonic Measures of Muscle Mass in Older Adults with Type 2 Diabetes
Authors: MADDEN KENNETH M. , FELDMAN BORIS , ARISHENKOFF SHANE , SY SARAH , MENEILLY GRAYDON S. 
Published: June 2020

Background: Skeletal muscle is the biggest ’glucose sink’ in the body. Sarcopenia (age-related loss of muscle mass) is extremely common in older adults and is one of the factors responsible for the increased prevalence of type 2 diabetes in this population. We examined the association between bedside ultrasonic measures of muscle thickness and measures of glycemic control in older adults with type 2 diabetes.
Methods: 72 older adults (age &gt;= 65) with type 2 diabetes were recruited sequentially from a geriatric medicine clinic (mean age 80.5±0.6 years, 26 women, 46 men). Each subject had glycosylated hemoglobin (HgAIC) lean body mass (LBM, by bioimpedance assay), and ultrasonic measures of muscle quantity (MT, vastus medialis muscle thickness) measured. Our initial models contained age, sex, bmi, and MT as predictor variables, and our outcome variable was HgAIC.
Results: In our final parsimonious models, HgAIC showed a significant positive association with increasing MT(Standardized β=0.237±0.116, R2 = 0.06, p=0.045) and a trend towards a negative correlation with LBM(Standardized β = -0.239±0.126, R2 = 0.07, p=0.063).
Conclusions: Unexpectedly, increased measures of muscle thickness were associated with worse, instead of improved, glycemic control. This suggests that other factors, such as muscle quality (myosteatosis) need to be considered in the older adult population with type 2 diabetes.

Disclosure
K.M. Madden: None. B. Feldman: None. S. Arishenkoff: None. S. Sy: None. G.S. Meneilly: Advisory Panel; Self; Merck & Co., Inc., Novo Nordisk Inc.

Funding
Allan M. McGavin Foundation
1893-P: The Integrative Role of ER Protein Quality Control Pathways (ERQC) in Prohormone Maturation
Authors: SHI GUOJUN , PAN XUYA , WANG HETING , ARVAN PETER , QI LING 
Published: June 2020

Background: Peptide hormones are crucial regulators of metabolism. However, maturation of hormone precursors (prohormones) in the endoplasmic reticulum (ER) in vivo remains largely unexplored.
Aims: This project aims to study the integrative role of the two major protein quality control pathways in the ER, ER-Associated Degradation (ERAD) and autophagy, in regulating prohormone maturation under physiological conditions. Taking vasopressin precursor (proAVP) as a model, this project will provide novel insights on hormone maturation and the physiological function of ERQC pathways.
Methods: We generated AVP neuron specific ERAD and Autophagy deficient mouse models by deleting Sel1L and Atg7, respectively. We also generated Sel1L and Atg7 deficient cell models. We used immunostaining, sucrose sedimentation, and Western blots to dissect the roles of ERAD and autophagy in proAVP folding and maturation.
Results: Mice with Atg7 deficiency in AVP neurons maintain normal water homeostasis, while Sel1L deficient mice develop central diabetes insipidus. Further, Atg7 deficient neurons show reduced proAVP protein and altered subcellular distribution, but its ER export remains functional. Mechanically, unlike Sel1L deficiency, Atg7 deficiency alone shows amber accumulation of misfolded proAVP in vitro; however, further blocking autophagy with ERAD deficiency shows increased portion of misfolded proAVP comparing with ERAD deficiency along. Further, combined deletion of Atg7 and Sel1L in AVP neurons leads to earlier development of Diabetes Insipidus comparing with Sel1L deficiency alone, suggesting a critical role of autophagy in maintaining AVP maturation with compromised ERAD.
Conclusions: Here we demonstrate that autophagy alone is dispensable for the maturation of proAVP in the ER, but is indispensable in the event of compromised ERAD function both in vivo and in vitro. This study points to the differential roles and crosstalk between ERAD and autophagy in neuroendocrine cells.

Disclosure
G. Shi: None. X. Pan: None. H. Wang: None. P. Arvan: None. L. Qi: None.

Funding
National Institutes of Health (R01DK120047); University of Michigan (U064133)
1905-P: Downregulation of HMGCS2 Expression in Small Intestinal Mucosa Biopsies after Roux-en-Y Gastric Bypass Surgery: A Possible Contributor to GLP-1 Hypersecretion?
Authors: LEGART CHRISTIAN , JORSAL TINA , HAGEMANN CHRISTOFFER A. , WORM DORTE , JUHL CLAUS B. , ANDRIES ALIN R. , ZHANG CHEN , VRANG NIELS , RIGBOLT KRISTOFFER , JELSING JACOB , VILSBØLL TINA , KNOP FILIP K. 
Published: June 2020

Background and Aims: Roux-en-Y gastric bypass (RYGB) surgery significantly improves glucose metabolism independently of surgery-induced weight loss; partly due to the increased postprandial secretion of the insulinotropic gut hormone glucagon-like peptide 1 (GLP-1). Mouse studies have shown that intestinally derived ketone bodies inhibit GLP-1 secretion from enteroendocrine L cells, and it was recently suggested that RYGB-induced downregulation of intestinal ketogenesis contributes to the increased GLP-1 secretion after RYGB. We investigated the intestinal expression of genes involved in ketogenesis and postprandial plasma GLP-1 responses before and after RYGB.
Materials and Methods: Twenty obese individuals underwent mixed meal tests and anterograde enteroscopy with gut mucosal biopsy retrieval before and 3 months after RYGB. A global gene expression analysis was performed on the mucosal biopsies. Here, we report the expression of genes involved in ketogenesis and postprandial plasma GLP-1 responses.
Results: We observed a significant 7.6-fold downregulation of the gene encoding 3-hydroxy-3- methylglutaryl-CoA synthase 2 (HMGCS2) (the rate-determining enzyme in ketogenesis) in the alimentary limb after RYGB. The proglucagon gene encoding GLP-1 was significantly upregulated after surgery and postprandial plasma GLP-1 responses increased significantly after RYGB.
Conclusions: RYGB-induced downregulation of intestinal HMGCS2 gene expression in obese individuals may indicate reduced intestinal ketogenesis; supporting the notion (originating from animal studies) that reduced ketone body-mediated inhibition of L cells constitute a contributor to postprandial hypersecretion of GLP-1 after RYGB.

Disclosure
C. Legart: None. T. Jorsal: None. C.A. Hagemann: Employee; Self; Gubra. D. Worm: None. C.B. Juhl: None. A.R. Andries: None. C. Zhang: Employee; Self; Gubra. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. K. Rigbolt: Employee; Self; Gubra. J. Jelsing: Board Member; Self; Gubra. Stock/Shareholder; Self; Gubra. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S.
1908-P: Glucagon Receptor Expression Evaluated by Antibody-Dependent and -Independent Approaches
Authors: KJELDSEN SASHA , GALSGAARD KATRINE D. , WINTHER-SOERENSEN MARIE , SERIZAWA REZA , PEDERSEN JENS , ORSKOV CATHRINE , ALBRECHTSEN REIDAR , SORENSEN CHARLOTTE M. , GLUUD LISE , HOLST JENS J. , WEWER ALBRECHTSEN NICOLAI J. 
Published: June 2020

Glucagon regulates metabolic functions through the glucagon receptor (GCGR). Agonists as well as antagonists of GCGR are evaluated as treatments of diabetes and obesity. To understand the role of glucagon, knowledge of GCGR localization is important but limited. Twelve commercially available GCGR antibodies were evaluated using HEK293 cells transfected with mouse or human GCGR cDNA transcripts. Eleven of the 12 GCGR antibodies showed staining of GCGR protein from both species, but not in cells transfected with a scrambled vector. Several of the antibodies stained liver sections from both GCGR+/+ and GCGR-/- mice. Staining was absent in fat and muscle tissues but present in the distal tubuli of the kidney. Two antibodies did not react with tissue from GCGR-/- and were further evaluated by western blotting of GCGR transfected cells. Bands corresponding to the predicted size of the GCGR (62kDa) were identified but larger bands were also observed. Liver tissue from healthy subjects and individuals with nonalcoholic steatohepatitis (NASH) was stained using same GCGR antibodies and based on qualitative intensities GCGR staining did not seem to vary between healthy and NASH liver sections. We used autoradiography to confirm the immunohistochemistry findings. In mice injected with 125I-labeled glucagon, grains were found in the liver and in the distal tubuli of the kidney, whereas fat and muscle sections were negative. To investigate the role of renal GCGR’s, we infused glucagon (1µg) in rats with and without blockade of the GLP-1 receptor (GLP-1R) (Exendin 9-39). Glucagon increased diuresis and renal blood flow, but not blood pressure, in a GLP-1R dependent manner. Urea excretion was numerically increased by glucagon (P=0.08).
In conclusion, glucagon receptor localization is challenging due to the lack of suitable commercially available GCGR antibodies. The actions of glucagon on renal parameters may be mediated by the GLP-1R. Glucagon’s role in kidney physiology needs further investigation.

Disclosure
S. Kjeldsen: None. K.D. Galsgaard: None. M. Winther-Soerensen: None. R. Serizawa: None. J. Pedersen: None. C. Orskov: None. R. Albrechtsen: None. C.M. Sorensen: None. L. Gluud: 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. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Novo Nordisk Foundation. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp.

Funding
Novo Nordisk Foundation (NNF19OC0055001)
1909-P: The Natriuretic Action of Glucagon-Like Peptide-1 in Humans Is Abolished by the GLP-1 Receptor Antagonist Exendin 9-39
Authors: ASMAR ALI , CRAMON PER K. , ASMAR MEENA , SIMONSEN LENE , MADSBAD STEN , SORENSEN CHARLOTTE M. , HARTMANN BOLETTE , HOLST JENS J. , HOVIND PETER , JENSEN BOYE L. , BÜLOW JENS 
Published: June 2020

We have recently demonstrated that renal extraction of GLP-1 is ∼45% and that extracellular fluid volume expansion in healthy participants uncovered a natriuretic action of GLP-1 probably via a tubular mechanism secondary to suppression of angiotensin II (ANG II) and independent of changes in renal hemodynamics. It is not known whether the high extraction is due to receptor binding. The present study was designed to test the hypotheses that the renal extraction and natriuretic effect of GLP-1 are mediated via GLP-1 receptor. Under fixed sodium intake for 4 days before each study day, 6 healthy male participants were recruited from our recent study1 and examined during a 3-h infusion of GLP-1 (1.5 pmol/kg/min) together with a 3.5-h infusion of the GLP-1 receptor antagonist, exendin 9-39 (Ex 9-39) (900 pmol/kg/min), initiated 30 minutes before start of GLP-1 infusion. Timed urine collections were conducted throughout the experiments. Renal plasma flow (RPF), glomerular filtration rate (GFR), and renal extraction of GLP-1 were measured via Fick’s principle after catheterization of a renal vein. Renal extraction of GLP-1 was ∼45% during infusion of GLP-1 alone and decreased significantly to ∼25% during co-infusion of GLP-1 and Ex 9-39. Urinary sodium and osmolar excretions remained at baseline levels during co-infusion of GLP-1 and Ex 9-39 compared to a mean 2-fold natriuretic effect during GLP-1 infusion alone. Arterial plasma ANG II levels were unaffected during the co-infusions, whereas ANG II decreased significantly during GLP-1 alone. Arterial plasma renin levels decreased similarly on the two study days, and arterial aldosterone levels remained unchanged on both days. RPF and GFR remained unchanged on both days.
In conclusion, renal extraction of GLP-1 is partially and natriuresis is fully dependent on GLP-1 receptor activation, probably via GLP-1-mediated ANG II suppression. 1Asmar A et al. J Clin Endocrinol Metab. 2019 Jul 1;104(7):2509-2519.

Disclosure
A. Asmar: None. P.K. Cramon: None. M. Asmar: None. L. Simonsen: None. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. C.M. Sorensen: None. B. Hartmann: 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. P. Hovind: None. B.L. Jensen: None. J. Bülow: None.
1916-P: Postprandial Glucagon Metabolism in Healthy Subjects: Use of 13C 15N Glucagon
Authors: RUCHI FNU , YADAV YOGESH R. , ROMERES DAVIDE , SAWLEH SAFIA , BENSON LINDA M. , JOHNSON KENNETH L. , SCHIAVON MICHELE , MAN CHIARA DALLA , COBELLI CLAUDIO , MCCORMICK DANIEL J. , BASU RITA , BASU ANANDA 
Published: June 2020

Glucagon metabolism in humans is poorly understood and is currently under active investigation. We have recently developed a new isotope dilution method using nonradioactive, stable human glucagon (Phe 6 13C9, 15N; Phe 22 13C9, 15N) tracer to measure glucagon fluxes. To estimate postprandial glucagon turnover using this novel technique, we present data from the first 5 healthy subjects (3 males, age 26.2±7.9 years, BMI 25.4±2.6 kg/m2, fasting plasma glucose 4.7±0.2 mM, HbA1c 5.1±0.2 %) done thus far. After IRB approval and informed consent, subjects presented to the clinical research unit in the morning after an overnight fast. A catheter was inserted in a forearm vein for glucagon tracer infusion and another catheter placed in the contralateral hand and the hand kept in a heated box for periodic draws of arterialized venous samples for measurements of glucagon tracer (tandem mass spectrometry), glucagon and glucose concentrations during the study. A mixed meal (75 grams carb, 15% protein, 35% fat; 8 kcal/kg) was ingested at time 0 and the glucagon tracer infusion rate adjusted to mimic the anticipated changes in postprandial circulating glucagon concentrations for 6 hours. Systemic glucagon appearance rate (Ra glucagon) was calculated by the isotope dilution method. Fig 1 shows the Ra glucagon in all subjects. These initial data show that postprandial glucagon turnover can be calculated in humans applying this novel technique.

Disclosure
F. Ruchi: None. Y.R. Yadav: None. D. Romeres: None. S. Sawleh: None. L.M. Benson: None. K.L. Johnson: None. M. Schiavon: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. C. Cobelli: None. D.J. McCormick: None. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca.

Funding
National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)
1918-P: YWHAB Inhibits Hepatic Gluconeogenesis through Suppression of Glucagon Signaling Pathway
Authors: WEI LI , JI LINLIN , ZHU CHAOYU 
Published: June 2020

Aims/Introduction: Hyperglycemia serves as a central factor in the development and progression of metabolic diseases. Since the glucagon receptor and its antagonism have been reported to be associated with the development and progression of hyperglycemias, the factors and proteins involved in the regulation of glucagon activity and signaling are still unclear.
Materials and Methods: We examined the role of YWHAB in vivo (in hepatocyte-selective Ywhab knockout and overexpressing mice) and in vitro (in mouse primary hepatocytes and human HepG2 cells).
Results: In this study, we found that YWHAB was down-regulated in ob/ob mice and db/db mice. To establish function of YWHAB in glucose metabolism in vivo, we generated hepatocyte-selective Ywhab knockout mice. The knockout mice displayed impaired blood glucose homeostasis in isolated mouse primary hepatocytes, as well as the increase in glucagon-mediated hepatocytic glucose production. Overexpressing YWHAB markedly decreases the expression of key enzymes in gluconeogenesis and inactivates the glucagon signaling. Similarly, the magnifying effect on glucagon signaling of Ywhab knockout in mouse primary hepatocytes were significantly changed by the treatment of PKA inhibitor H89.
Conclusions: The regulatory role of YWHAB in hepatocytes can protect against the glucagon-induced glucose production by attenuating the activation of cAMP/PKA and the expression of key enzymes in gluconeogenesis. Thus, YWHAB is a new target site identified in the control of glucagon signaling and associated metabolic diseases.

Disclosure
L. Wei: None. L. Ji: None. C. Zhu: None.

Funding
National Natural Science Foundation of China (81870603)
192-OR: Association between Gestational Diabetes and the Risk of Short Interpregnancy Intervals
Authors: ANGUZU RONALD , EGEDE LEONARD E. , SHOUR ABDUL R. , PALATNIK ANNA 
Published: June 2020

Objective: Short interpregnancy intervals are associated with a number of adverse perinatal outcomes and their prevention is a public health priority. Among women with a history of gestational diabetes (GDM), short interpregnancy intervals further decrease the timeframe for postpartum glucose optimization and testing for type 2 diabetes prior to the next conception. The objective of this study was to evaluate whether women with GDM have higher rates of short interpregnancy intervals.
Methods: Data from the 2011-2017 National Survey on Family Growth were analyzed. Study sample included 28,443 women aged 18-44y. Primary outcome was short interpregnancy intervals, defined as pregnancies conceived within 18 months after a previous birth. The rates of short interpregnancy intervals were compared between women with and without GDM using bivariate analysis. Multivariable logistic regression was done to assess independent association between GDM and short interpregnancy intervals.
Results: Out of 28,443 women included in the analysis, 2,827 (9.9%) had diagnosis of GDM. Short interpregnancy intervals rates were higher in women with GDM compared to controls (56.4% vs. 43.6%, p&lt;0.001). In bivariate analysis, GDM significantly increased the odds of short interpregnancy intervals compared to controls (OR=1.43, 95% CI 1.22-1.66). After controlling for maternal age, body mass index, race/ethnicity, marital status, education, insurance, family income, contraception use and history of sexually transmitted infections, GDM remained to be independently associated with a higher rate of short interpregnancy intervals (aOR=1.49, 95% CI 1.26-1.76).
Conclusion: Women with GDM have higher rates of short interpregnancy intervals. Reducing short interpregnancy intervals in this population will not only reduce perinatal risks of short interpregnancy intervals but will also allow time for adequate preconception counseling for screening and management of type 2 diabetes prior to future pregnancy.

Disclosure
R. Anguzu: None. L.E. Egede: None. A.R. Shour: None. A. Palatnik: None.