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Ranka Kanda, Haruko Hiraike, Osamu Wada-Hiraike, Takayuki Ichinose, Kazunori Nagasaka, Yuko Sasajima, Eiji Ryo, Tomoyuki Fujii, Yutaka Osuga, Takuya Ayabe
BACKGROUND: A previous report showed that a glucagon-like peptide-1 receptor (GLP-1R) agonist (exenatide) induced apoptosis in endometrial cancer cells. However, the pathophysiological role of GLP-1R in endometrial cancer has not been fully elucidated. Here, we investigated the effects of the GLP-1R agonist liraglutide in endometrial cancer cells and examined the association between GLP-1R expression and clinicopathological characteristics in endometrial cancer patients. METHODS: Human Ishikawa endometrial cancer cells were treated with different concentrations of liraglutide...
June 15, 2018: BMC Cancer
Megan E Capozzi, Richard D DiMarchi, Matthias H Tschöp, Brian Finan, Jonathan E Campbell
Glucagon-like peptide-1 (GLP-1) receptor agonists have been efficacious for the treatment of type 2 diabetes due to their ability to reduce weight and attenuate hyperglycemia. However, the activity of GLP-1R-directed strategies is sub-maximal, and the only potent, sustainable treatment for metabolic dysfunction is bariatric surgery, necessitating the development of novel therapeutics. GLP-1 is structurally related to glucagon and glucose-dependent insulinotropic peptide (GIP), allowing for the development of intermixed, unimolecular peptides with activity at each of their respective receptors...
June 13, 2018: Endocrine Reviews
Alberto Oddo, Sofia Mortensen, Henning Thøgersen, Leonardo De Maria, Stephanie Hennen, James McGuire, Jacob Kofoed, Lars Linderoth, Steffen Reedtz-Runge
Peptide agonists acting on the glucagon-like peptide 1 receptor (GLP-1R) promote glucose-dependent insulin release and therefore represent important therapeutic agents for Type 2 diabetes (T2D). Previous data indicated that an N-terminal type II beta-turn motif might be an important feature for agonists acting on GLP-1R. In contrast, recent publications reporting the structure of full-length GLP-1R have shown the N-terminus of receptor-bound agonists in an alpha-helical conformation. In order to reconcile these conflicting results we prepared N-terminally constrained analogs of glucagon-like peptide 1 (GLP-1) and exendin-4 and evaluated their receptor affinity and functionality in vitro; we then examined their crystal structures in complex with the ECD of GLP-1R and used molecular modeling and molecular dynamics simulations for further investigations...
June 7, 2018: Biochemistry
Andrej Babic, Laurent Vinet, Vineetha Chellakudam, Karolina Janikowska, Eric Allemann, Norbert Lange
Novel drug delivery systems targeting native, transplanted or cancerous beta-cells are of utmost importance. Herein, we present new exendin-4 derivatives with modified unnatural amino acids at strategic positions within the polypeptide sequence. The modified peptides allowed modular orthogonal chemical modifications to attach imaging agents and amphiphilic squalene-PEG groups. The resulting conjugates, SQ-PEG-ExC1-Cy5 and SQ-PEG-ExC40-Cy5 fluorescence probes display low nM affinity to GLP-1R in fluorescence-based binding assays with EC50 at 1...
June 5, 2018: Bioconjugate Chemistry
Rania G Abdel-Latif, Gehan H Heeba, Ashraf Taye, Mohamed M A Khalifa
Ischemic stroke is a major cause of neurological damage and brain dysfunction with consequent strong cerebral oxidative imbalance, inflammatory and apoptotic responses. Lixisenatide is a new potent glucagon-like peptide -1 (GLP-1) analogue that has been used clinically in the treatment of type II diabetes. Recent studies suggested the beneficial central effects of GLP-1-based therapies on different neurodegenerative diseases. This study aimed to investigate the ameliorative effect of lixisenatide in global cerebral ischemia-reperfusion (I/R) rat model and elaborate the underline mechanisms that could mediate the proposed activity...
June 1, 2018: European Journal of Pharmacology
Panagiotis Anagnostis, Pavlos Siolos, Konstantinos Christou, Nifon K Gkekas, Nikoletta Kosmidou, Vasilios G Athyros, Asterios Karagiannis
Both type 1 and type 2 diabetes are associated with increased risk for cardiovascular disease (CVD) events. This risk seems to be reduced by achievement of euglycemia. However, after the withdrawal of rosiglitazone from the market, the question arose as to whether this risk concerns simply a matter of euglycemia or the distinct role played by each antidiabetic drug with respect to its effect on CVD risk. To address this issue, many studies have been published during the last decade involving old and new antidiabetic agents, which however yielded contradictory results...
March 2018: Hormones: International Journal of Endocrinology and Metabolism
Jean-Philippe Krieger, Ellen Paula Santos da Conceição, Graciela Sanchez-Watts, Myrtha Arnold, Klaus G Pettersen, Mazher Mohammed, Salvatore Modica, Pius Lossel, Shaun F Morrison, Christopher J Madden, Alan G Watts, Wolfgang Langhans, Shin J Lee
Endogenous intestinal glucagon-like peptide-1 (GLP-1) controls satiation and glucose metabolism via vagal afferent neurons (VAN). Recently, VAN have received increasing attention for their role in brown adipose tissue (BAT) thermogenesis. It is however unclear whether VAN GLP-1 receptor (GLP-1R) signaling affects BAT thermogenesis and energy expenditure (EE), and whether this VAN mechanism contributes to energy balance. First, we tested the effect of the GLP-1R agonist Exendin-4 (Ex4, 0.3 μg/kg IP) on EE and BAT thermogenesis, and whether these effects require VAN GLP-1R signaling, using a rat model with a selective Glp1r knockdown (kd) in VAN...
May 30, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Uma Anand, Yiangos Yiangou, Ayesha Akbar, Tom Quick, Anthony MacQuillan, Mike Fox, Marco Sinisi, Yuri E Korchev, Ben Jones, Steve R Bloom, Praveen Anand
INTRODUCTION: Glucagon like-peptide 1 receptor (GLP-1R) agonists diminish appetite and may contribute to the weight loss in inflammatory bowel disease (IBD). OBJECTIVES: The aim of this study was to determine, for the first time, the expression of GLP-1R by colon nerve fibres in patients with IBD, and functional effects of its agonists in cultured rat and human sensory neurons. METHODS: GLP-1R and other nerve markers were studied by immunohistochemistry in colon biopsies from patients with IBD (n = 16) and controls (n = 8), human dorsal root ganglia (DRG) tissue, and in GLP-1R transfected HEK293 cells...
2018: PloS One
David C Hornigold, Emma Roth, Victor Howard, Sarah Will, Stephanie Oldham, Matthew P Coghlan, Clemence Blouet, James L Trevaskis
Combination approaches for the treatment of metabolic diseases such as obesity and diabetes are becoming increasingly relevant. Co-administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist with a cholecystokinin receptor-1 (CCKR1) agonist exert synergistic effects on weight loss in obese rodents. Here, we report on the effects of a novel fusion peptide (C2816) comprised of a stabilized GLP-1R agonist, AC3174, and a CCKR1-selective agonist, AC170222. C2816 was constructed such that AC3174 was linked to the N-terminus of AC170222, thus preserving the C-terminal amide of the CCK moiety...
May 18, 2018: Appetite
Jessica M Adams, Hongjuan Pei, Darleen A Sandoval, Randy J Seeley, Rui B Chang, Stephen D Liberles, David P Olson
Glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved weight loss drugs. Despite their widespread use, the sites of action through which GLP-1R agonists (GLP1RAs) impact appetite and body weight are still not fully understood. Here, we determined whether GLP-1Rs in either GABAergic or glutamatergic neurons are necessary for the acute and chronic effects of the GLP1RA liraglutide on food intake, visceral illness, body weight and neural network activation. We found that mice lacking GLP-1Rs in vGAT -expressing GABAergic neurons responded identically to controls in all parameters measured, whereas deletion of GLP-1Rs in vGlut2 -expressing glutamatergic neurons eliminated liraglutide-induced weight loss and visceral illness and severely attenuated its effects on feeding...
May 18, 2018: Diabetes
Yoshio Fujitani
The incidence of type 2 diabetes increases with age. The age-dependent decline in functional β-cell mass contributes to the increased risk of onset of diabetes, reflecting the central role of pancreatic β cells in glucose homeostasis. Indeed, the replication rate of human and rodent β cells is known to decline sharply with age, and such a characteristic of β cells may explain the increased onset of type 2 diabetes in the older population. The molecular mechanism involved in the age-dependent decline of β-cell proliferation has been extensively studied, mainly using rodents and in vitro culture systems, but its molecular basis is still largely unknown...
May 16, 2018: Journal of Diabetes Investigation
Olusola Olalekan Elekofehinti, Esther Opeyemi Ariyo, Moses Orimoloye Akinjiyan, Olanrewaju Sam Olayeriju, Akeem Olalekan Lawal, Isaac Gbadura Adanlawo, Joao Batista Teixeira Rocha
Momordica charantia (bitter lemon) belongs to the cucurbitaceae family which has been extensively used in traditional medicines for the cure of various ailments such as cancer and diabetes. The underlying mechanism of M. charantia to maintain glycemic control was investigated. GLP-1 and DPP-4 gene modulation by M. charantia (5-20% inclusion in rats diet) was investigated in vivo by RT-PCR and possible compounds responsible for diabetic action predicted through in silico approach. Phytochemicalss previously characterized from M...
May 12, 2018: Pathophysiology: the Official Journal of the International Society for Pathophysiology
Jonathan D Douros, Alfor G Lewis, Eric P Smith, JingJing Niu, Megan Capozzi, April Wittmann, Jonathan Campbell, Jenny Tong, Constance Wagner, Parinaz Mahbod, Randy Seeley, David A D'Alessio
Bariatric surgeries, including vertical sleeve gastrectomy (VSG), resolve diabetes in 40-50% of patients. Studies examining the molecular mechanisms underlying this effect have centered on the role of the insulinotropic glucagon-like peptide 1 (GLP-1), in great part because of the ∼10-fold rise in its circulating levels after surgery. However, there is currently debate over the role of direct β-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. In order to assess the importance of β-cell GLP-1 receptor (GLP-1R) for improving glucose control after VSG, a mouse model of this procedure was developed and combined with a genetically modified mouse line allowing an inducible, β-cell specific Glp1r knockdown ( Glp1r β-cell-ko )...
May 14, 2018: Diabetes
Saifei Lei, Lachlan Clydesdale, Antao Dai, Xiaoqing Cai, Yang Feng, Dehua Yang, Yi-Lynn Liang, Cassandra Koole, Peishen Zhao, Thomas Coudrat, Arthur Christopoulos, Ming-Wei Wang, Denise Wootten, Patrick M Sexton
G protein-coupled receptors (GPCRs) can be differentially activated by ligands to generate multiple and distinct, downstream signaling profiles, a phenomenon termed biased agonism. The glucagon-like peptide-1 receptor (GLP-1R) is a class B GPCR and a key drug target for managing metabolic disorders; however, its peptide agonists display biased signaling that affect their relative efficacies. In this study, we combined mutagenesis experiments and mapping of surface mutations onto recently described GLP-1R structures, which revealed two major domains in the GLP-1/GLP-1R/Gs protein active structure that are differentially important for both receptor quiescence, and ligand-specific initiation and propagation of biased agonism...
May 1, 2018: Journal of Biological Chemistry
Josephine B Hebsgaard, Charles Pyke, Emre Yildirim, Lotte B Knudsen, Steffen Heegaard, Peter H Kvist
Semaglutide is a human glucagon-like peptide-1 (GLP-1) analog that is in development for the treatment of type 2 diabetes. In the pre-approval cardiovascular outcomes trial SUSTAIN 6, semaglutide was associated with a significant increase in the risk of diabetic retinopathy complications versus placebo. GLP-1 receptor (GLP-1R) expression has previously been demonstrated in the retina in animals and humans. However, antibodies used to detect expression have been documented to be non-specific and fail to detect the GLP-1R using immunohistochemistry (IHC), a problem common for many G-protein coupled receptors...
April 29, 2018: Diabetes, Obesity & Metabolism
Darline Garibay, Jon Lou, Seon A Lee, Karolina E Zaborska, Margot H Weissman, Erica Sloma, Leanne Donahue, Andrew D Miller, Andrew C White, M Dodson Michael, Kyle W Sloop, Bethany P Cummings
Bariatric surgery, such as vertical sleeve gastrectomy (VSG), causes high rates of type 2 diabetes remission and remarkable increases in postprandial glucagon-like peptide-1 (GLP-1) secretion. GLP-1 plays a critical role in islet function by potentiating glucose-stimulated insulin secretion; however, the mechanisms remain incompletely defined. Therefore, we applied a murine VSG model to an inducible β cell-specific GLP-1 receptor (GLP-1R) knockout mouse model to investigate the role of the β cell GLP-1R in islet function...
April 24, 2018: Cell Reports
Ben Jones, Teresa Buenaventura, Nisha Kanda, Pauline Chabosseau, Bryn M Owen, Rebecca Scott, Robert Goldin, Napat Angkathunyakul, Ivan R Corrêa, Domenico Bosco, Paul R Johnson, Lorenzo Piemonti, Piero Marchetti, A M James Shapiro, Blake J Cochran, Aylin C Hanyaloglu, Asuka Inoue, Tricia Tan, Guy A Rutter, Alejandra Tomas, Stephen R Bloom
Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but the functional and therapeutic consequences of modulating GLP-1R endocytic trafficking have not been clearly defined. Here, we investigate a series of biased GLP-1R agonists with variable propensities for GLP-1R internalization and recycling...
April 23, 2018: Nature Communications
Bassant Orabi, Rasha Kaddoura, Amr S Omar, Cornelia Carr, Abdulaziz Alkhulaifi
Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors produce some beneficial and deleterious effects in diabetic patients not mediated by their glycemic lowering effects, and there is a need for better understanding of the molecular basis of these effects. They possess antioxidant and anti-inflammatory effects with some direct vasodilatory action (animal and human trial data) that may indirectly influence heart failure (HF). Unlike GLP-1R agonists, signaling for HF adverse effects was observed with two DPP-4 inhibitors, saxagliptin and alogliptin...
May 2018: Heart Failure Reviews
Melissa H Bloodworth, Mark Rusznak, Connor C Pfister, Jian Zhang, Lisa Bastarache, Sandra Alvarez Calvillo, James D Chappell, Kelli L Boyd, Shinji Toki, Dawn C Newcomb, Matthew T Stier, Weisong Zhou, Kasia Goleniewska, Martin L Moore, Tina V Hartert, Kevin D Niswender, R Stokes Peebles
No abstract text is available yet for this article.
April 17, 2018: Journal of Allergy and Clinical Immunology
Xingguang Cai, Lidan Sun, Yuxuan Dai, Yosefa Avraham, Chunxia Liu, Jing Han, Yuan Liu, Dazhi Feng, Wenlong Huang, Hai Qian
Glucagon-like peptide-1 is a potent hypoglycemic hormone with beneficial properties for the treatment of diabetes. However, its half-life is short because the rapid metabolic degradation. This study aims to prolong the half-life of glucagon-like peptide-1 through conjugation with the fatty acid side chain which helps the conjugates to interact with the albumin. Firstly, we chose two optimized polypeptide chains which have tremendous hypoglycemic effect named Cys17 -Gly8 -GLP-1(7-36)-NH2 and Cys37 -Gly8 -GLP-1(7-37)-NH2 , and various fatty acid chains were modified...
May 15, 2018: Bioorganic & Medicinal Chemistry
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