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https://www.readbyqxmd.com/read/28213092/prediction-of-thyroid-c-cell-carcinogenicity-after-chronic-administration-of-glp1-r-agonists-in-rodents
#1
Willem van den Brink, Annette Emerenciana, Francesco Bellanti, Oscar Della Pasqua, Jan Willem van der Laan
Increased incidence of C-cell carcinogenicity has been observed for glucagon-like-protein-1 receptor (GLP-1r) agonists in rodents. It is suggested that the duration of exposure is an indicator of carcinogenic potential in rodents of the different products on the market. Furthermore, the role of GLP-1-related mechanisms in the induction of C-cell carcinogenicity has gained increased attention by regulatory agencies. This study proposes an integrative pharmacokinetic/pharmacodynamic (PKPD) framework to identify explanatory factors and characterize differences in carcinogenic potential of the GLP-1r agonist products...
February 16, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28202906/bar502-a-dual-fxr-and-gpbar1-agonist-promotes-browning-of-white-adipose-tissue-and-reverses-liver-steatosis-and-fibrosis
#2
Adriana Carino, Sabrina Cipriani, Silvia Marchianò, Michele Biagioli, Chiara Santorelli, Annibale Donini, Angela Zampella, Maria Chiara Monti, Stefano Fiorucci
Non-alcoholic steatohepatitis (NASH) is a highly prevalent chronic liver disease. Here, we have investigated whether BAR502, a non-bile acid, steroidal dual ligand for FXR and GPBAR1, reverses steato-hepatitis in mice fed a high fat diet (HFD) and fructose. After 9 week, mice on HFD gained ≈30% of b.w (P < 0.01 versus naïve) and were insulin resistant. These overweighting and insulin resistant mice were randomized to receive HFD or HFD in combination with BAR502. After 18 weeks, HFD mice developed NASH like features with severe steato-hepatitis and fibrosis, increased hepatic content of triacylglycerol and cholesterol and expression of SREPB1c, FAS, ApoC2, PPARα and γ, α-SMA, α1 collagen and MCP1 mRNAs...
February 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28191525/obesity-diabetes-and-the-role-of-bile-acids-in-metabolism
#3
Gerald H Tomkin, Daphne Owens
Bile acids have many activities over and above their primary function in aiding absorption of fat and fat soluble vitamins. Bile acids are synthesized from cholesterol, and thus are involved in cholesterol homeostasis. Bile acids stimulate glucagon-like peptide 1 (GLP1) production in the distal small bowel and colon, stimulating insulin secretion, and therefore, are involved in carbohydrate and fat metabolism. Bile acids through their insulin sensitising effect play a part in insulin resistance and type 2 diabetes...
June 1, 2016: Journal of Translational Internal Medicine
https://www.readbyqxmd.com/read/28164753/evaluation-of-the-influence-of-the-conjugation-site-of-the-chelator-agent-hynic-to-glp1-antagonist-radiotracer-for-insulinoma-diagnosis
#4
Bluma Linkowski Faintuch, Daniele Seo, Érica Aparecida De Oliveira, Roselaine Campos Targino, Ana Maria Moro
Radiotracer diagnosis of insulinoma, can be done using somatostatin or glucagon-like peptide 1 (GLP-1). Performance of GLP-1 antagonists tends to be better than of agonists. We investigated the uptake of the antagonist exendin (9-39), radiolabeled with technetium-99m. Two different sites of the biomolecule were selected for chelator attachment. HYNIC-βAla chelator attached to serine (C- terminus) of exendin, was associated with higher tumor uptake than to aspartate (N- terminus). In conclusion the chelator position in the biomolecule influenced receptor uptake...
January 26, 2017: Current Radiopharmaceuticals
https://www.readbyqxmd.com/read/28133368/obesity-5-ht2a-in-glp1-mediated-weight-loss
#5
Alan Morris
No abstract text is available yet for this article.
January 30, 2017: Nature Reviews. Endocrinology
https://www.readbyqxmd.com/read/28105738/glucagon-like-peptide-1-agonists-and-risk-of-acute-pancreatitis-in-patients-with-type-2-diabetes
#6
Heidi Storgaard, Frederik Cold, Lise L Gluud, Tina Vilsbøll, Filip K Knop
Glucagon-like peptide-1 receptor agonist (GLP-1RAs) labels warn about acute pancreatitis (AP) and impose doctors to inform patients about symptoms of AP. Here we systematically reviewed the risk of AP in randomized placebo-controlled trials (RCTs) investigating the effect of GLP-1RAs in type 2 diabetes. We performed a systematic review with meta-analysis of long-term (minimum 24 months), placebo-controlled GLP-1RA RCTs in which AP was a predefined adverse event and adjudicated by blinded and independent adjudicating committees...
January 20, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28077257/real-world-effectiveness-and-safety-of-dapagliflozin-therapy-added-to-a-glp1-receptor-agonist-in-patients-with-type-2-diabetes
#7
J J Gorgojo-Martínez, C Serrano-Moreno, A Sanz-Velasco, G Feo-Ortega, F Almodóvar-Ruiz
BACKGROUND AND AIM: To evaluate the effectiveness and safety of a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, dapagliflozin, in patients with type 2 diabetes mellitus (T2DM) and background glucagon-like peptide-1 receptor agonist (GLP1-RA) therapy. METHODS AND RESULTS: This is a 12-month, real-world observational study, which assessed the effectiveness and safety of dapagliflozin in patients with T2DM and background GLP1-RA therapy. The main outcome measures were changes in A1C and weight at 6 and 12 months from baseline...
November 23, 2016: Nutrition, Metabolism, and Cardiovascular Diseases: NMCD
https://www.readbyqxmd.com/read/28059593/clinical-relevance-of-epigenetics-in-the-onset-and-management-of-type-2-diabetes-mellitus
#8
Linda Sommese, Alberto Zullo, Francesco Paolo Mancini, Rossella Fabbricini, Andrea Soricelli, Claudio Napoli
Epigenetics is involved in the altered expression of gene networks that underlie insulin resistance and insufficiency. Major genes controlling β-cell differentiation and function, such as PAX4, PDX1, and GLP1 receptor, are epigenetically controlled. Epigenetics can cause insulin resistance through immunomediated pro-inflammatory actions related to several factors, such as NF-kB, osteopontin, and Toll-like receptors. Hereafter, we provide a critical and comprehensive summary on this topic with a particular emphasis on translational and clinical aspects...
January 6, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/27982680/distinct-response-of-fat-and-gastrointestinal-tissue-to-glucose-in-gestational-diabetes-mellitus-and-polycystic-ovary-syndrome
#9
D Vejrazkova, O Lischkova, M Vankova, S Stanicka, J Vrbikova, P Lukasova, J Vcelak, G Vacinova, B Bendlova
Gestational diabetes mellitus (GDM) and polycystic ovary syndrome (PCOS) are distinct pathologies with impaired insulin sensitivity as a common feature. The aim of this study was to evaluate the response of fat tissue adipokines and gastrointestinal incretins to glucose load in patients diagnosed with one of the two disorders and to compare it with healthy controls. Oral glucose tolerance test (oGTT) was performed in 77 lean young women: 22 had positive history of GDM, 19 were PCOS patients, and 36 were healthy controls...
December 16, 2016: Physiological Research
https://www.readbyqxmd.com/read/27980002/the-role-of-nutrient-sensing-in-the-metabolic-changes-after-gastric-bypass-surgery
#10
Sandra Steensels, Matthias Lannoo, Bert Avau, Jorien Laermans, Laurien Vancleef, Ricard Farré, Kristin Verbeke, Inge Depoortere
Taste receptors coupled to the gustatory G-protein, gustducin, on enteroendocrine cells sense nutrients to regulate gut hormone release. During Roux-en-Y gastric bypass (RYGB) surgery, the altered nutrient flow to more distal regions can affect gustducin-mediated gut hormone release, and hence energy and glucose homeostasis. We studied the role of gustducin-mediated signaling in the metabolic improvements and intestinal adaptations along the gut after RYGB surgery in wild-type (WT) and α-gustducin(-/-) (α-gust(-/-)) mice...
December 15, 2016: Journal of Endocrinology
https://www.readbyqxmd.com/read/27957723/low-kidney-uptake-of-glp-1r-targeting-beta-cell-specific-pet-tracer-18-f-labeled-nle-14-lys-40-exendin-4-analog-shows-promise-for-clinical-imaging
#11
Kirsi Mikkola, Cheng-Bin Yim, Paula Lehtiniemi, Saila Kauhanen, Miikka Tarkia, Tuula Tolvanen, Pirjo Nuutila, Olof Solin
BACKGROUND: Several radiometal-labeled, exendin-based tracers that target glucagon-like peptide-1 receptors (GLP-1R) have been intensively explored for β cell imaging. The main obstacle has been the high uptake of tracer in the kidneys. This study aimed to develop a novel GLP1-R-specific tracer, with fluorine-18 attached to exendin-4, to label β cells for clinical imaging with PET (positron emission tomography). We hypothesized that this tracer would undergo reduced kidney uptake. (18)F-labeled [Nle(14),Lys(40)]exendin-4 analog ([(18)F]exendin-4) was produced via Cu-catalyzed click chemistry...
December 2016: EJNMMI Research
https://www.readbyqxmd.com/read/27927266/enzymatically-modified-starch-up-regulates-expression-of-incretins-and-sodium-coupled-monocarboxylate-transporter-in-jejunum-of-growing-pigs
#12
B U Metzler-Zebeli, R Ertl, D Grüll, T Molnar, Q Zebeli
Dietary effects on the host are mediated via modulation of the intestinal mucosal responses. The present study investigated the effect of an enzymatically modified starch (EMS) product on the mucosal expression of genes related to starch digestion, sugar and short-chain fatty acid (SCFA) absorption and incretins in the jejunum and cecum in growing pigs. Moreover, the impact of the EMS on hepatic expression of genes related to glucose and lipid metabolism, and postprandial serum metabolites were assessed. Barrows (n=12/diet; initial BW 29 kg) were individually fed three times daily with free access to a diet containing either EMS or waxy corn starch as control (CON) for 10 days...
December 8, 2016: Animal: An International Journal of Animal Bioscience
https://www.readbyqxmd.com/read/27917862/purslane-portulaca-oleracea-seed-consumption-and-aerobic-training-improves-biomarkers-associated-with-atherosclerosis-in-women-with-type-2-diabetes-t2d
#13
Firouzeh Dehghan, Rahman Soori, Khadijeh Gholami, Mitra Abolmaesoomi, Ashril Yusof, Sekaran Muniandy, Sara Heidarzadeh, Parvin Farzanegi, Mohammad Ali Azarbayjani
The aim of this study was to investigate the responses of atherosclerosis plaque biomarkers to purslane seed consumption and aerobic training in women with T2D. 196 women with T2D were assigned into; (1) placebo (PL), (2) aerobic training+placebo (AT + PL), 3) purslane seeds (PS), aerobic training+purslane seeds (AT + PS). The training program and purslane seeds consumption (2.5 g lunch and 5 g dinner) were carried out for 16 weeks. The components of purslane seed were identified and quantified by GC-MS...
December 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27903028/-cardiovascular-morbidity-and-mortality-in-patients-with-kidney-disease
#14
Ivo Quack, Ralf Westenfeld
Patients with kidney disease have a significantly increased cardiovascular morbidity and mortality. Especially diabetics have an increased risk to develop renal insufficiency and cardiovascular events. Two recent studies show that the SGLT2 inhibitor Empagliflozin and the GLP1 agonist Liraglutid are able to lower the cardiovascular risk of type2 diabetics with renal insufficiency. Recent observations suggest that bradycardia and asystole are main triggers for sudden cardiac death in patients with chronic kidney disease...
November 2016: Deutsche Medizinische Wochenschrift
https://www.readbyqxmd.com/read/27898183/effect-of-exenatide-on-postprandial-glucose-fluxes-lipolysis-and-%C3%A3-cell-function-in-nondiabetic-morbidly-obese-patients
#15
Stefania Camastra, Brenno Astiarraga, Andrea Tura, Silvia Frascerra, Demetrio Ciociaro, Andrea Mari, Amalia Gastaldelli, Ele Ferrannini
AIMS: To investigate the effect of exenatide on glucose disposal, insulin secretion, ß-cell function, lipolysis, and hormone concentrations in non-diabetic, morbidly obese subjects under physiological conditions. MATERIALS AND METHODS: Patients were assigned to exenatide 10 µg twice daily (EXE, n = 15) or control (CT, n = 15) for 3 months. Patients received a meal test/tracer study (MTT) to measure endogenous glucose production (EGP), rate of oral glucose appearance (RaO), insulin secretion rate (ISR), ß-cell function, hepatic (HIR) and adipose tissue insulin resistance (AT-IR) and insulin sensitivity (IS)...
November 29, 2016: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/27872157/exendin-4-increases-oxygen-consumption-and-thermogenic-gene-expression-in-muscle-cells
#16
Jin-Seung Choung, Young-Sun Lee, Hee-Sook Jun
Glucagon-like peptide-1 (GLP1) has many anti-diabetic actions and also increases energy expenditure in vivo As skeletal muscle is a major organ controlling energy metabolism, we investigated whether GLP1 can affect energy metabolism in muscle. We found that treatment of differentiated C2C12 cells with exendin-4 (Ex-4), a GLP1 receptor agonist, reduced oleate:palmitate-induced lipid accumulation and triglyceride content compared with cells without Ex-4 treatment. When we examined the oxygen consumption rate (OCR), not only the basal OCR but also the OCR induced by oleate:palmitate addition was significantly increased in Ex-4-treated differentiated C2C12 cells, and this was inhibited by exendin-9, a GLP1 receptor antagonist...
February 2017: Journal of Molecular Endocrinology
https://www.readbyqxmd.com/read/27780892/diabetes-negatively-affects-cortical-and-striatal-gabaergic-neurons-an-effect-that-is-partially-counteracted-by-exendin-4
#17
Martin Larsson, Grazyna Lietzau, David Nathanson, Claes-Göran Östenson, Carina Mallard, Maria E Johansson, Thomas Nyström, Cesare Patrone, Vladimer Darsalia
Type 2 diabetic (T2D) patients often develop early cognitive and sensorimotor impairments. The pathophysiological mechanisms behind these problems are largely unknown. Recent studies demonstrate that dysfunctional γ-aminobutyric acid (GABAergic) neurons are involved in age-related cognitive decline. We hypothesized that similar, but earlier dysfunction is taking place under T2D in the neocortex and striatum (two brain areas important for cognition and sensorimotor functions). We also hypothesized that the T2D-induced effects are pharmacologically reversible by anti-diabetic drugs targeting the glucagon-like peptide-1 receptor (GLP-1R)...
December 2016: Bioscience Reports
https://www.readbyqxmd.com/read/27748385/adipose-tissue-key-role-for-fgf21-in-glp1-mediated-weight-loss
#18
David Holmes
No abstract text is available yet for this article.
December 2016: Nature Reviews. Endocrinology
https://www.readbyqxmd.com/read/27699898/adipose-tissue-regulates-insulin-sensitivity-role-of-adipogenesis-de-novo-lipogenesis-and-novel-lipids
#19
U Smith, B B Kahn
Obesity, the major cause of the current global epidemic of type 2 diabetes (T2D), induces insulin resistance in peripheral insulin target tissues. Several mechanisms have been identified related to cross-talk between adipose tissue, skeletal muscle and liver. These mechanisms involve both increased free fatty acid release and altered secretion of adipokines from adipose tissue. A major determinant of metabolic health is the ability of subcutaneous adipose tissue (SAT) to store excess fat rather than allowing it to accumulate in ectopic depots including liver (i...
November 2016: Journal of Internal Medicine
https://www.readbyqxmd.com/read/27689014/fibroblast-activation-protein-fap-as-a-novel-metabolic-target
#20
Miguel Angel Sánchez-Garrido, Kirk M Habegger, Christoffer Clemmensen, Cassie Holleman, Timo D Müller, Diego Perez-Tilve, Pengyun Li, Archita S Agrawal, Brian Finan, Daniel J Drucker, Matthias H Tschöp, Richard D DiMarchi, Alexei Kharitonenkov
OBJECTIVE: Fibroblast activation protein (FAP) is a serine protease belonging to a S9B prolyl oligopeptidase subfamily. This enzyme has been implicated in cancer development and recently reported to regulate degradation of FGF21, a potent metabolic hormone. Using a known FAP inhibitor, talabostat (TB), we explored the impact of FAP inhibition on metabolic regulation in mice. METHODS: To address this question we evaluated the pharmacology of TB in various mouse models including those deficient in FGF21, GLP1 and GIP signaling...
October 2016: Molecular Metabolism
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