• Abstract and Figures
• Public Full-text

Dear author, Please note that changes made in the online proofing system will be added to the article before publication but are not reflected in this PDF. We also ask that this file not be used for submitting corrections. MOLMET885_proof ■ 2 October 2019 ■ 1/59 Review 61 62 1 63 2 64 3 Q8 Glucagon-like peptide 1 (GLP-1) 65 4 66 5 67 6 1,2,3,* 4 5 6 7 8 2,9,10 68 7 Q7 T.D. Müller , B. Finan , S.R. Bloom ,D.D’Alessio , D.J. Drucker , P.R. Flatt , A. Fritsche , 11 12 13 14 15 16 17 69 8 F. Gribble , H.J. Grill , J.F. Habener , J.J. Holst , W. Langhans , J.J. Meier , M.A. Nauck , 18 19 11 20 21,22 20 70 9 D. Perez-Tilve , A. Pocai , F. Reimann , D.A. Sandoval , T.W. Schwartz , R.J. Seeley , 1,2 23 24 4,25 1,2,26 71 10 K. Stemmer , M. Tang-Christensen , S.C. Woods , R.D. DiMarchi , M.H. Tschöp 72 11 73 12 Q4 ABSTRACT 74 13 75 14 Background: The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous 76 15 metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, 77 16 b increase of natriuresis and diuresis, and modulation of rodent -cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases 78 17 fl fi in ammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modi ed for 79 18 enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several 80 19 GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity. 81 20 Scope of review: In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its 82 21 therapeutic implications on various diseases. 83 22 Major conclusions: Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond 84 23 fi fi its classical identi cation as an incretin hormone. The numerous bene cial effects of GLP-1 render this hormone an interesting candidate for the 85 24 development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders 86 25 Ó 2019 Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 87 26 88 27 89 28 1. FROM THE DISCOVERY OF INSULIN TO THE DISCOVERY OF blood glucose transformed juvenile-onset (type-1) diabetes from a fatal 90 29 Q5 GLP-1 to a manageable disease. However, early on, it was noted that insulin 91 30 derived from pancreatic extracts [1] or as crude insulin preparations [2] fi 92 31 Maintenance of adequate glucose metabolism is a prerequisite for sometimes rst elevated blood glucose and then later decreased blood 93 32 human health, and pathological failure to buffer against prolonged glucose levels. The increase in blood glucose, which peaked around 94 33 episodes of hypo- and/or hyperglycemia can result in severe micro- 20 min after the administration, was believed to be caused by a toxic fi 95 34 vascular disease, metabolic damage, coma, and death. Unsurprisingly, fraction resulting from suboptimal insulin puri cation [2]. The same ’ 96 35 before the discovery and commercialization of insulin in the 1920 s, toxic fraction was thought to be responsible for local skin irritations and 97 36 juvenile-onset diabetes, with its paucity of endogenous insulin, was a abscesses that were sometimes observed in patients treated with ’ 98 37 disease with only a few years between a patient s diagnosis and these formulations [2]. These observations spurred efforts to optimize fi 99 38 premature demise. The discovery of insulin and its ability to lower the isolation and puri cation of insulin from tissue homogenates. 100 39 1 101 40 Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, 2 3 102 41 Q1 Germany German Center for Diabetes Research (DZD), Neuherberg, Germany Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany 4Novo Nordisk Research Center Indianapolis, Indianapolis, IN, 103 42 5 6 USA Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK Division of Endocrinology, Duke University Medical Center, Durham, NC, 104 43 7 8 Q2 USA The Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, M5G1X5, Canada SAAD Centre for Pharmacy 105 44 & Diabetes, Ulster University, Coleraine, Northern Ireland, UK 9Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of 10 106 45 Tübingen, Tübingen, Germany Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany 11Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council, 107 46 12 Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK Institute of Diabetes, Obesity and Metabolism, Department of 108 47 13 Psychology, University of Pennsylvania, Philadelphia, PA, 19104, USA Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard University, Boston, 109 48 MA, USA 14Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, 15 16 110 49 Denmark Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland Diabetes Division, St Josef Hospital, Ruhr-University Bochum, Bochum, 17 18 111 50 Germany Diabetes Center Bochum-Hattingen, St Josef Hospital (Ruhr-Universität Bochum), Bochum, Germany Department of Internal Medicine, University of Cincinnati- College of Medicine, Cincinnati, OH, USA 19Cardiovascular & ImmunoMetabolism, Janssen Research & Development, Welsh and McKean Roads, Spring House, PA, 19477, 112 51 20 21 USA Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA Novo Nordisk Foundation Center for Basic Metabolic Research, University of 113 52 22 23 Copenhagen, DL-2200, Copenhagen, Denmark Department of Biomedical Sciences, University of Copenhagen, DK-2200, Copenhagen, Denmark Obesity Research, 114 53 Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark 24Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, 25 26 115 54 Q3 USA Department of Chemistry, Indiana University, Bloomington, IN, USA Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany 116 55 117 56 *Corresponding author. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health 118 57 (GmbH), Neuherberg, Germany. E-mail: [email protected] (T.D. Müller). 119 58 Received July 17, 2019 Revision received September 10, 2019 Accepted September 22, 2019 Available online xxx 120 59 121 60 https://doi.org/10.1016/j.molmet.2019.09.010 122 MOLECULAR METABOLISM xxx (xxxx) xxx Ó 2019 Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1 www.molecularmetabolism.com MOLMET885_proof ■ 2 October 2019 ■ 2/59 Review 1 Aiming to develop a fast and inexpensive method for commercial in- was subsequently detected in the pancreas of dogs [31] as well as in 63 2 sulin purification, in 1923, Charles Kimball and John Murlin precipi- islets isolated from birds [32] and guinea pigs [33]. Collectively, these 64 3 tated a pancreatic fraction that, after evaporation and reconstitution in studies suggested that glucagon might originate from a larger pre- 65 4 water, had a robust hyperglycemic effect when injected into rabbits cursor molecule that is post-translationally cleaved into several frac- 66 5 and dogs [3]. Because the fraction was incapable of decreasing blood tions of distinct size and with different functions. Immunoprecipitation 67 6 glucose, Kimball and Murlin hypothesized that the hyperglycemic ef- analysis of rat pancreatic islets identified this precursor as an 18,000 68 7 fect resulted from a secreted factor, one that antagonizes insulin’s molecular weight (MW) protein, now classified as proglucagon [34]. In 69 8 hypoglycemic effect. The factor was named ‘the glucose agonist’,or the pancreas, proglucagon was found to be cleaved to produce two 70 9 “glucagon” [3]. Over the subsequent decades, substantial research fragments, mature glucagon and a 10,000-MW second protein. This 71 10 efforts were directed toward unravelling the molecular underpinnings latter protein lacked the glucagon sequence and was named major 72 11 of glucose regulation by the two opposing pancreatic hormones (as proglucagon fragment (MPGF) [34,35](Figure 1). 73 12 reviewed in [4,5]). Among the numerous major discoveries made in In the early 1980s, it was established that the major form of the in- 74 13 this regard was the finding that the hyperglycemic effect of glucagon testinal glucagon-immunoreactive material, a peptide designated gli- 75 14 resides in its ability to act in the liver to stimulate glycogenolysis and centin, contained the full glucagon sequence [36e40], and glicentin 76 15 gluconeogenesis [6e12] despite its seemingly paradoxical ability to was proposed to represent at least a fragment of proglucagon, 77 16 stimulate insulin secretion in humans reported by Ellis Samols in 1965 because it was also identified in the pancreas [41]. Although glicentin 78 17 [13]. In the early 1950’s, Earl Sutherland and Christian de Duve was initially thought to comprise w100 amino acids, its purification 79 18 demonstrated that pancreatic glucagon production was abolished from porcine intestine established glicentin as a 69-amino acid peptide 80 19 when the function of islet a-cells was compromised by treatment with [39].

Load more

  60

Copy Link