Discovery, Characterization, and Clinical Development of the Glucagon-Like Peptides
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Hemodynamic and Renal Effects of Atrial Natriurectic Peptide in Normal
European Journal of Clinical Investigation The Journal of the European Society for Clinical Investigation Editors-in-Chief R. Arnold, M. Brandis, M. Kern Editorial Board 0. L. M. Bijvoet, A. B. Boneu, G. B. Bolli, J. Brodehl, P. van Brummelen, U. Fölsch, E. Harms, R. D. Hesch, D. R. Higgs, K. Hierholzer, U. Keller, G. Klöppel, K. Kühn, S. Lamberts, H. Löffler, S. Matern, F. R. Matthias, K. H. Meyer z. Büschenfelde, S. Moncada, K. J. Netter, C. Nissen, G. Paumgartner, B. A. Peskar, L. B. A. van de Putte, M. J. Rennie, C. Reiger, E. O. Riecken, H. -D. Roher, H. H. Ropers, P. Schauder, G. Schernthaner, H. Scholz, K. Schrör, V. Schusdziarra, M. Sheppard, K. Sikora, M. V. Singer, E. Steiness, B. E. Strauer, K. Unsicker, G. Utermann, P. Verroust, P. v. Wiehert, R. Ziegler, R. Zinkernagel Volume 18,1988 Published for the European Society for Clinical Investigation by Blackwell Scientific Publications, Oxford London Edinburgh Boston Palo Alto Melbourne Published by Blackwell Scientific Publications Ltd, Osney Mead, Oxford OX2 OEL, U.K. © 1988 Blackwell Scientific Publications Ltd. Authorization of photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Blackwell Scientific Publications Ltd for libraries and other users registered with the Copyright Clearance Center (CCC) Transactional Reporting Service, provided that the base fee of $3-00 per copy is paid directly to CCC, 27 Congress Street, Salem, MA 01970, U.S.A. Special requests should be addressed to the Editor. 0014-2972/88 $3 00. The use of registered names, trade marks, etc., in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulation and therefore free for general use. -
Β Cell Tone Is Defined by Proglucagon Peptides Through Camp Signaling
β Cell tone is defined by proglucagon peptides through cAMP signaling Megan E. Capozzi, … , David A. D’Alessio, Jonathan E. Campbell JCI Insight. 2019;4(5):e126742. https://doi.org/10.1172/jci.insight.126742. Research Article Endocrinology Metabolism Paracrine interactions between pancreatic islet cells have been proposed as a mechanism to regulate hormone secretion and glucose homeostasis. Here, we demonstrate the importance of proglucagon-derived peptides (PGDPs) for α to β cell communication and control of insulin secretion. Signaling through this system occurs through both the glucagon-like peptide receptor (Glp1r) and glucagon receptor (Gcgr). Loss of PGDPs, or blockade of their receptors, decreases insulin secretion in response to both metabolic and nonmetabolic stimulation of mouse and human islets. This effect is due to reduced β cell cAMP and affects the quantity but not dynamics of insulin release, indicating that PGDPs dictate the magnitude of insulin output in an isolated islet. In healthy mice, additional factors that stimulate cAMP can compensate for loss of PGDP signaling; however, input from α cells is essential to maintain glucose tolerance during the metabolic stress induced by high-fat feeding. These findings demonstrate an essential role for α cell regulation of β cells, raising the possibility that abnormal paracrine signaling contributes to impaired insulin secretion in diabetes. Moreover, these findings support reconsideration of the role for α cells in postprandial glucose control. Find the latest version: https://jci.me/126742/pdf RESEARCH ARTICLE β Cell tone is defined by proglucagon peptides through cAMP signaling Megan E. Capozzi,1 Berit Svendsen,1 Sara E. -
2016 IES Annual Meeting Final Programme
ROYAL ACADEMY OF MEDICINE IN IRELAND IRISH JOURNAL OF MEDICAL SCIENCE Irish Endocrine Society 40th Annual Meeting 14th and 15th October 2016 Stormont Hotel, Belfast Local Organiser: Doctor Hamish Courtney, REVISEDRoyal Victoria Hospital, PROOF Belfast Irish Journal of Medical Science Volume XXX Supplement X DOI 10.1007/s11845-016-1482-y 123 123 Journal : Large 11845 Dispatch : 17-8-2016 Pages : 57 Article No. : 1482 h LE h TYPESET MS Code : 1482 h44CP h DISK Ir J Med Sci Disclosure statement This supplement is paid for by the Irish Endocrine Society. However the meeting costs are supported by the following commercial sponsors: Abbott Amgen Astra Zeneca Besins Healthcare BMS Boehringer Ingleheim Consilient Ipsen Janssen-Cilag Kyowa Kirin Lilly Menarini Merck Serono MSD Novartis Novo Nordisk Pfizer Sanofi REVISED PROOF 123 Journal : Large 11845 Dispatch : 17-8-2016 Pages : 57 Article No. : 1482 h LE h TYPESET MS Code : 1482 h44CP h DISK Ir J Med Sci Novo Lecture Nordisk Lecture 1976 D.K. O’Donovan 1977 S. Bloom 1978 J.H.S. Robertson 1979 A.G. Cudworth 1980 D.A.D. Montgomery 1981 Peter Watkins 1982 G. Joplin 1983 D.R. London 1984 A.X. Bertagna 1985 Malcolm Nattrass Laurence Kennedy 1986 Brian Frier JB Ferriss 1987 Maurice Scanlon TJ McKenna 1988 D.A. Heath AB Atkinson 1989 J. Ward GH Tomkin 1990 R. Volpe KD Buchanan 1991 Michael Besser PPA Smyth 1992 R.V. Ragontte DH Hadden 1993 Bruce Weintraub David Powell 1994 Oscar Croffard Patrick Bell 1995 Robert Lindsay Brian Sheridan 1996 C.R.W. Edwards Rosemary Freaney 1997 Stephanie Amiel David McCance 1998 Robert Turner Randle Hayes 1999 Ian Hay Sean K Cunningham 2000 Stephen O’Rahilly Michael Cullen 2001 Andre Lacroix Daphne Owens 2002 J. -
Development and Characterization of GLP-1 Total and Active V-PLEX
T1530-12-77 Development and Characterization of GLP-1 Total and Active V-PLEX® Assays Priscilla Krai, Jennifer Morgan, Lalitha Janaki, Jon Buhrman, Laure Moller, Colleen Kenten, Vivek Chitnis, Seth B. Harkins, David Stewart, and Jacob N. Wohlstadter Meso Scale Discovery, Rockville, Maryland, USA CONTACT INFORMATION: [email protected] PURPOSE CALIBRATION CURVES AND SPECIFICITY ACCURACY AND PRECISION Glucagon like peptide-1 (GLP-1), an incretin hormone, is a major target of interest for researchers studying metabolic, To assess the specificity of each assay, both V-PLEX GLP-1 Total and GLP-1 Active Kits were tested for Quality control samples were prepared by spiking calibrator into non-human serum matrix at three levels (high, neurologic, and cardiovascular disorders. After post-translational processing of proglucagon, the GLP-1 peptide is LIMITS OF DETECTION nonspecific binding to the following GLP-1 metabolites and other general metabolic targets. mid, and low) within the quantitative linear range of the assay. The controls were measured using a minimum of secreted in its bioactive form, which binds a specific receptor (GLP-1R) to stimulate insulin release. Once in circulation, Cross-reactivity at or below 0.02% is reported as not detected (ND). three replicates tested over multiple days and multiple operators for a total of at least 36 runs. The accuracy of The figure below demonstrates typical calibration curves for the analytes in the V-PLEX GLP-1 Total and however, the peptide is rapidly cleaved by proteases (e.g. DPP-IV), yielding several other metabolites that account for *Although weakly cross-reactive, Liraglutide and GLP-1 have nearly identical sequences and have the control determinations fell within 20% of the expected concentration with precision of less than 20% CV in the GLP-1 Active Kits. -
Lessons from Single and Double Incretin Receptor Knockout Mice
Regulatory Peptides 128 (2005) 125–134 www.elsevier.com/locate/regpep Review GIP and GLP-1 as incretin hormones: Lessons from single and double incretin receptor knockout mice Tanya Hansotia, Daniel J. Drucker* Department of Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, and the University of Toronto, 200 Elizabeth Street MBRW4R-402, Toronto, Ontario, Canada M5G 2C4 Received 6 July 2004; received in revised form 8 July 2004; accepted 15 July 2004 Available online 25 August 2004 Abstract Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut-derived incretins secreted in response to nutrient ingestion. Both incretins potentiate glucose-dependent insulin secretion and enhance h-cell mass through regulation of h-cell proliferation, neogenesis and apoptosis. In contrast, GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. Furthermore, human subjects with Type 2 diabetes exhibit relative resistance to the actions of GIP, but not GLP-1R agonists. The physiological importance of both incretins has been investigated through generation and analysis of incretin receptor knockout mice. Elimination of incretin receptor action in GIPRÀ/À or GLP-1RÀ/À mice produces only modest impairment in glucose homeostasis. Similarly, double incretin receptor knockout (DIRKO) mice exhibit normal body weight and normal levels of plasma glucagon and hypoglycemic responses to exogenous insulin. However, glucose-stimulated insulin secretion is significantly decreased following oral but not intraperitoneal glucose challenge in DIRKO mice and the glucose lowering actions of dipeptidyl peptidase-IV (DPP-IV) inhibitors are extinguished in DIRKO mice. Hence, incretin receptor signaling exerts physiologically relevant actions critical for glucose homeostasis, and represents a pharmacologically attractive target for development of agents for the treatment of Type 2 diabetes. -
1 to the Stomach Inhibits Gut-Brain Signalling by the Satiety Hormone Cholecystokinin (CCK)
Targeted Expression of Plasminogen Activator Inhibitor (PAI)-1 to the Stomach Inhibits Gut-Brain Signalling by the Satiety Hormone Cholecystokinin (CCK) Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor in Philosophy By Joanne Gamble October 2013 I For Lily, you are the sunshine in my life…. II Table of Contents Figures and tables VII Acknowledgements XI Publications XIII Abstract XIV Chapter 1 ................................................................................................................................ 1 1.1 Overview ........................................................................................................................... 2 1.2 The Gastrointestinal Tract and Digestive Function ...................................................... 4 1.2.1 Distribution, Structure and Biology of Enteroendocrine (EEC) Cells ........................ 5 1.2.2 Luminal Sensing ......................................................................................................... 6 1.3 Energy Homeostasis ......................................................................................................... 7 1.3.1 Gut Hormones ........................................................................................................... 10 1.3.1.1 The Gastrin Family ............................................................................................ 11 1.3.2 PP-fold Family ......................................................................................................... -
Defects in Α-Cell Function in Patients with Diabetes Due to Chronic
Diabetes Care 1 Lena Mumme,1 Thomas G.K. Breuer,1 Defects in -Cell Function in CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL a Stephan Rohrer,1 Nina Schenker,1 Patients With Diabetes Due to Bjorn¨ A. Menge,1 Jens J. Holst,2 Michael A. Nauck,1 and Juris J. Meier1 Chronic Pancreatitis Compared With Patients With Type 2 Diabetes and Healthy Individuals https://doi.org/10.2337/dc17-0792 OBJECTIVE Diabetes frequently develops in patients with chronic pancreatitis. We examined the alterations in the glucagon response to hypoglycemia and to oral glucose adminis- tration in patients with diabetes due to chronic pancreatitis. RESEARCH DESIGN AND METHODS Ten patients with diabetes secondary to chronic pancreatitis were compared with 13 patients with type 2 diabetes and 10 healthy control subjects. A stepwise hypo- glycemic clamp and an oral glucose tolerance test (OGTT) were performed. RESULTS Glucose levels during the OGTT were higher in patients with diabetes and chronic pancreatitis and lower in control subjects (P < 0.0001). Insulin and C-peptide levels were reduced, and the glucose-induced suppression of glucagon was impaired in both groups with diabetes (all P < 0.0001 vs. control subjects). During hypoglycemia, glucagon concentrations were reduced in patients with chronic pancreatitis and with type 2 diabetes (P < 0.05). The increase in glucagon during the clamp was inversely related to the glucose-induced glucagon suppression and positively related to b-cell function. Growth hormone responses to hypoglycemia were lower in patients with type 2 diabetes (P = 0.0002) but not in patients with chronic pancreatitis. 1Diabetes Division, Department of Medicine I, CONCLUSIONS St. -
Hormonal Control of Glucose Homoeostasis in Ruminants
PYOC.Nutr. SOC.(1983), 42, 149 '49 Hormonal control of glucose homoeostasis in ruminants By G. H. MCDOWELL,Dairy Research Unit, Department of Animal Husbandry, University of Syndey, Camden, NSW, 2570, Australia Little, if any, glucose is absorbed from the alimentary tract of the grazing ruminant and it appears that significant absorption of glucose only occurs in ruminants consuming relatively large amounts of grain (Bergman, 1973; Lindsay, 1978). In spite of this, ruminants have an absolute requirement for glucose which is similar to that of nonruminants. Certainly glucose is an essential metabolite for the brain as there is no oxidation of ketones in the brain of the ruminant (Lindsay, 1980). Moreover, glucose is required for turnover and synthesis of fat, as a precursor of muscle glycogen and in pregnant and lactating ruminants, glucose is an essential metabolite. Indeed the glucose requirements of late-pregnant and lactating ruminants increase dramatically beyond that required for maintenance (Bergman, 1973, see also Table 2, p. 164). It is not surprising that volatile fatty acids derived from rumen fermentation of carbohydrate provide some 70% of the energy requirements of the ruminant (Bergman, 1973). Even so, gluconeogenesis and the maintenance of glucose homoeostasis are critical processes in view of the absolute requirements for glucose. Unlike the situation in monogastric species, gluconeogenesis is maximal after feed ingestion and decreases during food restriction. The major factor influencing the rate of gluconeogenesis is the availability of substrates (Lindsay, 1978). In fed ruminants the principal precursors are propionate and amino acids, with lactate and glycerol making minor contributions to glucose production. -
Gut Hormones
259 PROCEEDINGS OF THE NUTRITION SOCIETY The Three Hundred and Eighteenth Scktajk Meeting was held in the Medical and Biological Sciences Building, University of Southampton, on 20 and 21 July I978 SYMPOSIUM ON ‘HORMONES AND FOOD UTILIZATION’ Gut hormones By S. R. BLOOM, Department of Medicine and J. M. POLAK,Department of Pathology, The Royal Postgraduate Medical School, Hamwsmith Hospital, Du Cane Road, London W12 oHS History At the end of the last century Pavlov proposed that the control of alimentary function was by nervous reflex. His explanation was intellectually satisfying and a great advance on previous extremely woolly theories. Histologically fine nerve fibres which could be seen running in the gut w& and sectioning the main nerve trunks undoubtedly affected gastrointestinal function. Meanwhile, however, Brown Sequard, attempting to rejuvenate his ageing body, was able to show that extracts of testes greatly increased his prowess in several directions. His findings, published in 1889, caught the public imagination and by the end of the century extracts of numerous organs were available for the purpose of treating real and imagined ailments. Thus when Bayliss & Starling were investigating the influence of the duodenum on the exocrine pancreas, the idea of making duodenal extracts came readily. They were astonished to find that such an extract had all the effects on the exocrine pancreas that had been previously attributed to Pavlov’s nervous reflexes. They proposed that there must be a chemical messenger released from the duodenum which acted via the circulation and proposed the term hormone. Nature of the gut endocrine system Although the first substance to be named hormone, secretin, was from the alimentary tract, progress in the understanding of gut endocrinology was very slow. -
Glucose-Dependent Insulinotropic Polypeptide (GIP): from Prohormone to Actions in Endocrine Pancreas and Adipose Tissue
PHD THESIS DANISH MEDICAL BULLETIN Glucose-dependent Insulinotropic Polypeptide (GIP): From prohormone to actions in endocrine pancreas and adipose tissue Randi Ugleholdt The two incretins, glucagon-like peptide 1 (GLP-1) and glu- This review has been accepted as a thesis with two original papers by University of cose dependent insulinotropic polypeptide (gastric inhibitory Copenhagen 14th of December 2009 and defended on 28th of January 2010 peptide, GIP) have long been recognized as important gut hor- mones, essential for normal glucose homeostasis. Plasma levels Tutor: Jens Juul Holst of GLP-1 and GIP rise within minutes of food intake and stimulate Official opponents: Jens Frederik Rehfeld, Baptist Gallwitz & Thure Krarup pancreatic β-cells to release insulin in a glucose-dependent man- ner. This entero-insular interaction is called the incretin effect and Correspondence: Department of Biomedical Sciences, Cellular and Metabolic Re- search Section, University of Copenhagen, Faculty of Health Sciences, Blegdamsvej accounts for up to 70% of the meal induced insulin release in man 3B build. 12.2, 2200 Copenhagen N, Denmark and via this incretin effect, the gut hormones facilitate the uptake of glucose in muscle, liver and adipose tissue (2). Although the E-mail: [email protected] pancreatic effects of these two gut hormones have been the target of extensive investigation both hormones also have nu- merous extrapancreatic effects. Thus, GLP-1 decreases gastric Dan Med Bull 2011;58:(12)B4368 emptying and acid secretion and affects appetite by increasing fullness and satiety thereby decreasing food intake and, if main- THE TWO ORIGINAL PAPERS ARE tained at supraphysiologic levels, eventually body weight (3). -
Hedonic Interruption of the Physiological Controls of Eating: Sites and Mechanisms
Dissertation der Graduate School of Systemic Neurosciences der Ludwig-Maximillians-Universität München Hedonic interruption of the physiological controls of eating: sites and mechanisms ESTE LEIDMAA PhD Thesis 5th of Febuary 2016 Thesis Advisory Committee Professor Osborne Almeida (Supervisor) Professor Christophe Magnan (2nd reviewer) Professor Heidrun Potschka Dr. Susanne E La Fleur (External reviewer) Prof. Harald Luksch (Reviewer from GSN) Date of the thesis defence: 22.06.2016 Pühendusega minu perele Table of Contents Table of Contents ........................................................................................................................... List of Abbreviations ...................................................................................................................... i Abstract ............................................................................................................................................ 5 Chapter 1. General Introduction ...................................................................................................... 7 1.1. Feeding – an essential behaviour .................................................................................... 8 1.1.1. Meeting the energy demands of brain and body ....................................................... 8 1.1.2. Overeating and obesity ............................................................................................. 10 1.1.3. Pathological consequences of obesity ..................................................................... -
Purification and Sequence of Rat Oxyntomodulin (Enteroglucagon/Peptide/Intestine/Proglucagon/Radlolmmunoassay) NATHAN L
Proc. Nati. Acad. Sci. USA Vol. 91, pp. 9362-9366, September 1994 Biochemistry Purification and sequence of rat oxyntomodulin (enteroglucagon/peptide/intestine/proglucagon/radlolmmunoassay) NATHAN L. COLLIE*t, JOHN H. WALSHO, HELEN C. WONG*, JOHN E. SHIVELY§, MIKE T. DAVIS§, TERRY D. LEE§, AND JOSEPH R. REEVE, JR.t *Department of Physiology, School of Medicine, University of California, Los Angeles, CA 90024; *Center for Ulcer Research and Education, Gastroenteric Biology Center, Department of Medicine, Veterans Administration Wadsworth Center, School of Medicine, University of California, Los Angeles, CA 90073; and §Division of Immunology, Beckman Institute of City of Hope Research Institute, Duarte, CA 91010 Communicated by Jared M. Diamond, May 26, 1994 ABSTRACT Structural information about rat enteroglu- glucagon plus two glucagon-like sequences (GLP-1 and -2) cagon, intestinal peptides containing the pancreatic glucagon arranged in tandem. The present study concerns the enter- sequence, has been based previously on cDNA, immunologic, oglucagon portion of proglucagon (i.e., the N-terminal 69 and chromatographic data. Our interests in testing the phys- residues and its potential cleavage fragments). iological actions of synthetic enteroglucagon peptides in rats Our use of the term "enteroglucagon" refers to intestinal required that we identify precisely the forms present in vivo. peptides containing the pancreatic glucagon sequence. Fig. 1 From knowledge of the proglucagon gene sequence, we syn- shows two proposed enteroglucagon forms, proglucagon-(1- thesized an enteroglucagon C-terminal octapeptide common to 69) (glicentin) and proglucagon-(33-69) (OXN; see Fig. 1). both proposed enteroglucagon forms, glicentin and oxynto- The primary structures based on amino acid sequence data of modulin, but sharing no sequence overlap with glucagon.