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The Activation of the Glucagon-Like Peptide-1 (GLP-1) Receptor by Peptide and Non-Peptide Ligands
The Activation of the Glucagon-Like Peptide-1 (GLP-1) Receptor by Peptide and Non-Peptide Ligands Clare Louise Wishart Submitted in accordance with the requirements for the degree of Doctor of Philosophy of Science University of Leeds School of Biomedical Sciences Faculty of Biological Sciences September 2013 I Intellectual Property and Publication Statements The candidate confirms that the work submitted is her own and that appropriate credit has been given where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. The right of Clare Louise Wishart to be identified as Author of this work has been asserted by her in accordance with the Copyright, Designs and Patents Act 1988. © 2013 The University of Leeds and Clare Louise Wishart. II Acknowledgments Firstly I would like to offer my sincerest thanks and gratitude to my supervisor, Dr. Dan Donnelly, who has been nothing but encouraging and engaging from day one. I have thoroughly enjoyed every moment of working alongside him and learning from his guidance and wisdom. My thanks go to my academic assessor Professor Paul Milner whom I have known for several years, and during my time at the University of Leeds he has offered me invaluable advice and inspiration. Additionally I would like to thank my academic project advisor Dr. Michael Harrison for his friendship, help and advice. I would like to thank Dr. Rosalind Mann and Dr. Elsayed Nasr for welcoming me into the lab as a new PhD student and sharing their experimental techniques with me, these techniques have helped me no end in my time as a research student. -
Neuroendocrine and Sympathetic Responses to an Orexin Receptor Antagonist, SB-649868, and Alprazolam Following Insulin-Induced Hypoglycemia in Humans
Psychopharmacology (2014) 231:3817–3828 DOI 10.1007/s00213-014-3520-7 ORIGINAL INVESTIGATION Neuroendocrine and sympathetic responses to an orexin receptor antagonist, SB-649868, and Alprazolam following insulin-induced hypoglycemia in humans Ameera X. Patel & Sam R. Miller & Pradeep J. Nathan & Ponmani Kanakaraj & Antonella Napolitano & Philip Lawrence & Annelize Koch & Edward T. Bullmore Received: 8 October 2013 /Accepted: 24 February 2014 /Published online: 26 April 2014 # The Author(s) 2014. This article is published with open access at Springerlink.com Abstract it has previously been validated using the insulin tolerance test Rationale The orexin-hypocretin system is important for (ITT) model in humans. translating peripheral metabolic signals and central neuronal Results Of the primary endpoints, ITT induced defined in- inputs to a diverse range of behaviors, from feeding, motiva- creases in pulse rate, plasma cortisol, and adrenocorticotropic tion and arousal, to sleep and wakefulness. Orexin signaling is hormone in the placebo condition, but these responses were thus an exciting potential therapeutic target for disorders of not significantly impacted by alprazolam or SB-649868 pre- sleep, feeding, addiction, and stress. treatment. Of the secondary endpoints, ITT induced a defined Objectives/methods Here, we investigated the low dose phar- increase in plasma concentrations of adrenaline, noradrena- macology of orexin receptor antagonist, SB-649868, on neu- line, growth hormone (GH), and prolactin in the placebo roendocrine, sympathetic nervous system, and behavioral re- condition. Alprazolam pre-treatment significantly reduced sponses to insulin-induced hypoglycemic stress, in 24 healthy the GH response to ITT (p<0.003), the peak electromyogra- male subjects (aged 18–45 years; BMI 19.0–25.9 kg/m2), phy (p<0.0001) and galvanic skin response (GSR, p=0.04)to using a randomized, double-blind, placebo-controlled, acoustic startle, the resting GSR (p=0.01), and increased within-subject crossover design. -
Orexin Receptor Antagonists As Therapeutic Agents for Insomnia
REVIEW ARTICLE published: 25 December 2013 doi: 10.3389/fphar.2013.00163 Orexin receptor antagonists as therapeutic agents for insomnia Ana C. Equihua 1, Alberto K. De La Herrán-Arita 2 and Rene Drucker-Colin 1* 1 Neuropatología Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, México 2 Center for Sleep Sciences and Medicine, Stanford University, Palo Alto, CA, USA Edited by: Insomnia is a common clinical condition characterized by difficulty initiating or maintaining Christopher J. Winrow, Merck, USA sleep, or non-restorative sleep with impairment of daytime functioning. Currently, Reviewed by: treatment for insomnia involves a combination of cognitive behavioral therapy (CBTi) Matthew R. Ebben, Weill Medical and pharmacological therapy. Among pharmacological interventions, the most evidence College of Cornell University, USA Gabriella Gobbi, McGill University, exists for benzodiazepine (BZD) receptor agonist drugs (GABAA receptor), although Canada concerns persist regarding their safety and their limited efficacy. The use of these Matt Carter, University of hypnotic medications must be carefully monitored for adverse effects. Orexin (hypocretin) Washington, USA neuropeptides have been shown to regulate transitions between wakefulness and Michihiro Mieda, Kanazawa University, Japan sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the *Correspondence: development of a new class of pharmacological agents that antagonize the physiological Rene Drucker-Colin, Departamento effects of orexin. The development of these agents may lead to novel therapies for de Neurociencias, Instituto de insomnia without the side effect profile of hypnotics (e.g., impaired cognition, disturbed Fisiología Celular, Universidad arousal, and motor balance difficulties). However, antagonizing a system that regulates Nacional Autónoma de México, Circuito exterior S/N, Apdo. -
(Pram) and Insulin A21G Improves Post-Prandial Glucose Vs Novolog
ADO09, A Co-Formulation Of Pramlintide (Pram) and Insulin A21G improves Post-Prandial Glucose Vs Novolog® in Type 1 Diabetes (T1DM) G.Meiffren¹, G.Andersen², R.Eloy¹, C.Seroussi¹, C.Mégret¹, S.Famulla², Y.-P Chan¹, M.Gaudier¹, O.Soula¹, J.H. DeVries²,T.Heise² (1 Adocia, Lyon, France ; 2 Profil, Neuss, Germany) Introduction & Background Overall safety Outpatient period results - CGM metrics o ADO09 (M1Pram) is a co-formulation of pramlintide and insulin A21G o Both treatments were well tolerated without any treatment-related serious adverse events o Most of the CGM metrics (TiR [70-180], TiR [80-140], mean blood glucose per day), were significantly improved developed to leverage the beneficial effects of pramlintide on post-prandial (Table 2). As expected M1Pram had numerically more, mostly gastrointestinal adverse events with M1Pram (Table 4). Postprandial and mean 24-hour glucose profiles were improved with M1Pram (Fig. 3) glucose without additional injections than insulin aspart Table 4: CGM metrics, all days. Significant differences are marked in bold Objective and design o No severe hypoglycemia were seen, slightly more hypoglycemic events occurred with M1Pram Ratio of LSMean* o To compare the effect of M1Pram and insulin aspart (Novolog®, Novo than with aspart (Table 3) Difference Parameter Treatment LS Mean M1Pram / Aspart P-value Nordisk) on post-prandial glucose control, glycemic control assessed by Table 2: Incidence of adverse events throughout the trial (M1Pram-Aspart) (95% CI) CGM and safety/tolerability M1Pram Aspart M1Pram -
Searching for Novel Peptide Hormones in the Human Genome Olivier Mirabeau
Searching for novel peptide hormones in the human genome Olivier Mirabeau To cite this version: Olivier Mirabeau. Searching for novel peptide hormones in the human genome. Life Sciences [q-bio]. Université Montpellier II - Sciences et Techniques du Languedoc, 2008. English. tel-00340710 HAL Id: tel-00340710 https://tel.archives-ouvertes.fr/tel-00340710 Submitted on 21 Nov 2008 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITE MONTPELLIER II SCIENCES ET TECHNIQUES DU LANGUEDOC THESE pour obtenir le grade de DOCTEUR DE L'UNIVERSITE MONTPELLIER II Discipline : Biologie Informatique Ecole Doctorale : Sciences chimiques et biologiques pour la santé Formation doctorale : Biologie-Santé Recherche de nouvelles hormones peptidiques codées par le génome humain par Olivier Mirabeau présentée et soutenue publiquement le 30 janvier 2008 JURY M. Hubert Vaudry Rapporteur M. Jean-Philippe Vert Rapporteur Mme Nadia Rosenthal Examinatrice M. Jean Martinez Président M. Olivier Gascuel Directeur M. Cornelius Gross Examinateur Résumé Résumé Cette thèse porte sur la découverte de gènes humains non caractérisés codant pour des précurseurs à hormones peptidiques. Les hormones peptidiques (PH) ont un rôle important dans la plupart des processus physiologiques du corps humain. -
Effects of Dietary Macronutrients on Appetite-Related Hormones in Blood on Body Composition of Lean and Obese Rats
Animal Industry Report Animal Industry Report AS 652 ASL R2081 2006 Effects of Dietary Macronutrients on Appetite-Related Hormones in Blood on Body Composition of Lean and Obese Rats Michelle Bohan Iowa State University Lloyd L. Anderson Iowa State University Allen H. Trenkle Iowa State University Donald C. Beitz Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/ans_air Part of the Agriculture Commons, and the Animal Sciences Commons Recommended Citation Bohan, Michelle; Anderson, Lloyd L.; Trenkle, Allen H.; and Beitz, Donald C. (2006) "Effects of Dietary Macronutrients on Appetite-Related Hormones in Blood on Body Composition of Lean and Obese Rats ," Animal Industry Report: AS 652, ASL R2081. DOI: https://doi.org/10.31274/ans_air-180814-908 Available at: https://lib.dr.iastate.edu/ans_air/vol652/iss1/22 This Companion Animal is brought to you for free and open access by the Animal Science Research Reports at Iowa State University Digital Repository. It has been accepted for inclusion in Animal Industry Report by an authorized editor of Iowa State University Digital Repository. For more information, please contact [email protected]. Iowa State University Animal Industry Report 2006 Effects of Dietary Macronutrients on Appetite-Related Hormones in Blood on Body Composition of Lean and Obese Rats A.S. Leaflet R2081 ghrelin. Ghrelin is an antagonist of leptin by acting upon the neuropeptide Y/Y1 receptor pathway. Leptin causes Michelle Bohan, graduate student of biochemistry; satiety, whereas ghrelin stimulates nutrient intake. Leptin Lloyd Anderson, distinguished professor of animal science; and ghrelin thereby regulate the action of each other. -
A Plant-Based Meal Increases Gastrointestinal Hormones
nutrients Article A Plant-Based Meal Increases Gastrointestinal Hormones and Satiety More Than an Energy- and Macronutrient-Matched Processed-Meat Meal in T2D, Obese, and Healthy Men: A Three-Group Randomized Crossover Study Marta Klementova 1, Lenka Thieme 1 , Martin Haluzik 1, Renata Pavlovicova 1, Martin Hill 2, Terezie Pelikanova 1 and Hana Kahleova 1,3,* 1 Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic; [email protected] (M.K.); [email protected] (L.T.); [email protected] (M.H.); [email protected] (R.P.); [email protected] (T.P.) 2 Institute of Endocrinology, 113 94 Prague, Czech Republic; [email protected] 3 Physicians Committee for Responsible Medicine, Washington, DC 20016, USA * Correspondence: [email protected]; Tel.: +1-202-527-7379 Received: 6 December 2018; Accepted: 9 January 2019; Published: 12 January 2019 Abstract: Gastrointestinal hormones are involved in regulation of glucose metabolism and satiety. We tested the acute effect of meal composition on these hormones in three population groups. A randomized crossover design was used to examine the effects of two energy- and macronutrient-matched meals: a processed-meat and cheese (M-meal) and a vegan meal with tofu (V-meal) on gastrointestinal hormones, and satiety in men with type 2 diabetes (T2D, n = 20), obese men (O, n = 20), and healthy men (H, n = 20). Plasma concentrations of glucagon-like peptide -1 (GLP-1), amylin, and peptide YY (PYY) were determined at 0, 30, 60, 120 and 180 min. Visual analogue scale was used to assess satiety. We used repeated-measures Analysis of variance (ANOVA) for statistical analysis. -
OREXIN ANTAGONISTS BELSOMRA (Suvorexant), DAYVIGO (Lemborexant)
OREXIN ANTAGONISTS BELSOMRA (suvorexant), DAYVIGO (lemborexant) RATIONALE FOR INCLUSION IN PA PROGRAM Background Belsomra (suvorexant) and Dayvigo (lemborexant) are orexin receptor antagonists used to treat difficulty in falling and staying asleep (insomnia). Orexins are chemicals that are involved in regulating the sleep-wake cycle and play a role in keeping people awake (1-2). Regulatory Status FDA-approved indication: Orexin receptor antagonists are indicated for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance (1-2). Orexin Antagonists are contraindicated in patients with narcolepsy (1-2). Orexin Antagonists are central nervous system (CNS) depressants that can impair daytime wakefulness even when used as prescribed. Medications that treat insomnia can cause next-day drowsiness and impair driving and other activities that require alertness. Orexin Antagonists can impair driving skills and may increase the risk of falling asleep while driving. People can be impaired even when they feel fully awake. Patients should also be made aware of the potential for next-day driving impairment, because there is individual variation in sensitivity to the drug (1-2). The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or mental illness that should be evaluated (1-2). Warnings and precautions that should be discussed with the patient on Orexin Antagonist therapy include adverse reactions on abnormal thinking and behavioral changes (such as amnesia, anxiety, hallucinations and other neuropsychiatric symptoms), complex behaviors (such as sleep- driving, preparing and eating food, or making phone calls), dose-dependent increase in suicidal ideation, and sleep paralysis which is the inability to move or speak for up to several minutes during sleep-wake transitions (1-2). -
Glucagon-Like Peptide 1 Secretion by the L-Cell the View from Within Gareth E
Glucagon-Like Peptide 1 Secretion by the L-Cell The View From Within Gareth E. Lim1 and Patricia L. Brubaker1,2 Glucagon-like peptide 1 (GLP-1) is a gut-derived peptide GLP-1 receptor antagonists as well as GLP-1 receptor null secreted from intestinal L-cells after a meal. GLP-1 has mice have demonstrated that GLP-1 makes an essential numerous physiological actions, including potentiation of contribution to the “incretin” effect after a meal (3,4). glucose-stimulated insulin secretion, enhancement of However, GLP-1 secretion is reduced in patients with type -cell growth and survival, and inhibition of glucagon 2 diabetes (5–7), and this may contribute in part to the release, gastric emptying, and food intake. These antidia- reduced incretin effect and the hyperglycemia that is betic effects of GLP-1 have led to intense interest in the use observed in these individuals (8). Thus, interest has now of this peptide for the treatment of patients with type 2 focused on the factors that regulate the release of this diabetes. Oral nutrients such as glucose and fat are potent physiological regulators of GLP-1 secretion, but non-nutri- peptide after nutrient ingestion. Many different GLP-1 ent stimulators of GLP-1 release have also been identified, secretagogues have been described in the literature over including the neuromodulators acetylcholine and gastrin- the past few decades, including nutrients, neurotransmit- releasing peptide. Peripheral hormones that participate in ters, neuropeptides, and peripheral hormones (rev. in energy homeostasis, such as leptin, have also been impli- 9,10). However, the specific receptors, ion channels, and cated in the regulation of GLP-1 release. -
Diabetes Recommendations and Tier Coverage Chart
DIABETES RECOMMENDATIONS AND TIER COVERAGE CHART The American Diabetes Association guidelines for 2020, recommend metformin as the preferred initial treatment for type 2 diabetes (T2DM) along with weight management and physical activity. In patients who have established ASVD or at high risk, CKD, or HF, a SGLT2i or GLP-1 receptor with proven efficacy is recommended independent of A1C. • ASCVD dominates: o GLP-1RA with proven CVD benefit (dulaglutide, liraglutide, injectable semaglutide) OR o SGLT2i with proven CVD benefit (canagliflozin, empagliflozin) if adequate eGFR • HF or CKD dominates: o SGLT2i with evidence of reducing HF and/or CKD progression (empagliflozin, canagliflozin, dapagliflozin) if adequate eGFR OR o If SGLT2i intolerant/contraindicated or eGFR is inadequate, then GLP-1RA with proven CVD benefit In individuals without established cardiovascular disease, pharmacological treatment should be patient-centered taking into account side-effects, cost, impact on weight, risk of hypoglycemia, and other patient preferences. For more detailed information regarding ADA recommendations for pharmacological agents to treat T2DM click here. The following chart is a list of oral and injectable diabetes medications listed by class with their respective A1C reduction and insurance coverage and/or coverage requirements for BCBS, HPHC, Tufts, TMP, and MassHealth. Tufts Medicare Medications BCBSMA HPHC Tufts Preferred MassHealth Biguanides A1C reduction: 1-1.5% metformin Tier 1 Tier 1;2 Tier 1 Tier 1 Covered Glucoghage (metformin) NC NC NC;Tier -
Amylin: Pharmacology, Physiology, and Clinical Potential
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2015 Amylin: Pharmacology, Physiology, and Clinical Potential Hay, Debbie L ; Chen, Steve ; Lutz, Thomas A ; Parkes, David G ; Roth, Jonathan D Abstract: Amylin is a pancreatic -cell hormone that produces effects in several different organ systems. Here, we review the literature in rodents and in humans on amylin research since its discovery as a hormone about 25 years ago. Amylin is a 37-amino-acid peptide that activates its specific receptors, which are multisubunit G protein-coupled receptors resulting from the coexpression of a core receptor protein with receptor activity-modifying proteins, resulting in multiple receptor subtypes. Amylin’s major role is as a glucoregulatory hormone, and it is an important regulator of energy metabolism in health and disease. Other amylin actions have also been reported, such as on the cardiovascular system or on bone. Amylin acts principally in the circumventricular organs of the central nervous system and functionally interacts with other metabolically active hormones such as cholecystokinin, leptin, and estradiol. The amylin-based peptide, pramlintide, is used clinically to treat type 1 and type 2 diabetes. Clinical studies in obesity have shown that amylin agonists could also be useful for weight loss, especially in combination with other agents. DOI: https://doi.org/10.1124/pr.115.010629 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-112571 Journal Article Published Version Originally published at: Hay, Debbie L; Chen, Steve; Lutz, Thomas A; Parkes, David G; Roth, Jonathan D (2015). -
Multi-Functionality of Proteins Involved in GPCR and G Protein Signaling: Making Sense of Structure–Function Continuum with In
Cellular and Molecular Life Sciences (2019) 76:4461–4492 https://doi.org/10.1007/s00018-019-03276-1 Cellular andMolecular Life Sciences REVIEW Multi‑functionality of proteins involved in GPCR and G protein signaling: making sense of structure–function continuum with intrinsic disorder‑based proteoforms Alexander V. Fonin1 · April L. Darling2 · Irina M. Kuznetsova1 · Konstantin K. Turoverov1,3 · Vladimir N. Uversky2,4 Received: 5 August 2019 / Revised: 5 August 2019 / Accepted: 12 August 2019 / Published online: 19 August 2019 © Springer Nature Switzerland AG 2019 Abstract GPCR–G protein signaling system recognizes a multitude of extracellular ligands and triggers a variety of intracellular signal- ing cascades in response. In humans, this system includes more than 800 various GPCRs and a large set of heterotrimeric G proteins. Complexity of this system goes far beyond a multitude of pair-wise ligand–GPCR and GPCR–G protein interactions. In fact, one GPCR can recognize more than one extracellular signal and interact with more than one G protein. Furthermore, one ligand can activate more than one GPCR, and multiple GPCRs can couple to the same G protein. This defnes an intricate multifunctionality of this important signaling system. Here, we show that the multifunctionality of GPCR–G protein system represents an illustrative example of the protein structure–function continuum, where structures of the involved proteins represent a complex mosaic of diferently folded regions (foldons, non-foldons, unfoldons, semi-foldons, and inducible foldons). The functionality of resulting highly dynamic conformational ensembles is fne-tuned by various post-translational modifcations and alternative splicing, and such ensembles can undergo dramatic changes at interaction with their specifc partners.