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Glucagon-Like Peptide 1 (GLP-1) Review Glucagon-like peptide 1 (GLP-1) T.D. Müller 1,2,3,*, B. Finan 4, S.R. Bloom 5,D.D’Alessio 6, D.J. Drucker 7, P.R. Flatt 8, A. Fritsche 2,9,10, F. Gribble 11, H.J. Grill 12, J.F. Habener 13, J.J. Holst 14, W. Langhans 15, J.J. Meier 16, M.A. Nauck 17, D. Perez-Tilve 18, A. Pocai 19, F. Reimann 11, D.A. Sandoval 20, T.W. Schwartz 21,22, R.J. Seeley 20, K. Stemmer 1,2, M. Tang-Christensen 23, S.C. Woods 24, R.D. DiMarchi 4,25, M.H. Tschöp 2,26,27 ABSTRACT Background: The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent b-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity. Scope of review: In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases. Major conclusions: Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders Ó 2019 The Authors. 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/). Keywords GLP-1; Insulin; Glucagon; Diabetes; Obesity; Incretin 1. FROM THE DISCOVERY OF INSULIN TO THE DISCOVERY OF disease with only a few years between a patient’s diagnosis and GLP-1 premature demise. The discovery of insulin and its ability to lower blood glucose transformed juvenile-onset (type-1) diabetes from a fatal Maintenance of adequate glucose metabolism is a prerequisite for to a manageable disease. However, early on, it was noted that insulin human health, and pathological failure to buffer against prolonged derived from pancreatic extracts [1] or as crude insulin preparations [2] episodes of hypo- and/or hyperglycemia can result in severe micro- sometimes first elevated blood glucose and then later decreased blood vascular disease, metabolic damage, coma, and death. Unsurprisingly, glucose levels. The increase in blood glucose, which peaked around before the discovery and commercialization of insulin in the 1920’s, 20 min after the administration, was believed to be caused by a toxic juvenile-onset diabetes, with its paucity of endogenous insulin, was a fraction resulting from suboptimal insulin purification [2]. The same 1Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany 2German Center for Diabetes Research (DZD), Neuherberg, Germany 3Department 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, USA 5Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK 6Division of Endocrinology, Duke University Medical Center, Durham, NC, USA 7The Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, M5G1X5, Canada 8SAAD Centre for Pharmacy & Diabetes, Ulster University, Coleraine, Northern Ireland, UK 9Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany 10Division 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, Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK 12Institute of Diabetes, Obesity and Metabolism, Department of Psychology, University of Pennsylvania, Philadelphia, PA, 19104, USA 13Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard University, Boston, MA, USA 14Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark 15Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland 16Diabetes Division, St Josef Hospital, Ruhr-University Bochum, Bochum, Germany 17Diabetes Center Bochum-Hattingen, St Josef Hospital (Ruhr-Universität Bochum), Bochum, Germany 18Department 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, USA 20Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA 21Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DL-2200, Copenhagen, Denmark 22Department of Biomedical Sciences, University of Copenhagen, DK-2200, Copenhagen, Denmark 23Obesity Research, Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark 24Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA 25Department of Chemistry, Indiana University, Bloomington, IN, USA 26Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany 27Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany *Corresponding author. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany. E-mail: [email protected] (T.D. Müller). Received July 17, 2019 Revision received September 10, 2019 Accepted September 22, 2019 Available online 30 September 2019 https://doi.org/10.1016/j.molmet.2019.09.010 72 MOLECULAR METABOLISM 30 (2019) 72e130 Ó 2019 The Authors. 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/). www.molecularmetabolism.com toxic fraction was thought to be responsible for local skin irritations and glucagon-producing a-cells in terms of their morphology and ultra- abscesses that were sometimes observed in patients treated with structure [29], classifying these intestinal cells as “L-cells” [30]. these formulations [2]. These observations spurred efforts to optimize Glucagon-like immunoreactive material of larger size than of glucagon the isolation and purification of insulin from tissue homogenates. was subsequently detected in the pancreas of dogs [31] as well as in Aiming to develop a fast and inexpensive method for commercial insulin islets isolated from birds [32] and guinea pigs [33]. Collectively, these purification, in 1923, Charles Kimball and John Murlin precipitated a studies suggested that glucagon might originate from a larger pre- pancreatic fraction that, after evaporation and reconstitution in water, cursor molecule that is post-translationally cleaved into several frac- had a robust hyperglycemic effect when injected into rabbits and dogs tions of distinct size and with different functions. Immunoprecipitation [3]. Because the fraction was incapable of decreasing blood glucose, analysis of rat pancreatic islets identified this precursor as an 18,000 Kimball and Murlin hypothesized that the hyperglycemic effect resulted molecular weight (MW) protein, now classified as proglucagon [34]. In from a secreted factor, one that antagonizes insulin’s hypoglycemic the pancreas, proglucagon was found to be cleaved to produce two effect. The factor was named ‘the glucose agonist’,or“glucagon” [3]. fragments, mature glucagon and a 10,000-MW second protein. This Over the subsequent decades, substantial research efforts were latter protein lacked the glucagon sequence and was named major directed toward unravelling the molecular underpinnings of glucose proglucagon fragment (MPGF) [34,35](Figure 1). regulation by the two opposing pancreatic hormones (as reviewed in In the early 1980s, it was established that the major form of the in- [4,5]). Among the numerous major discoveries made in this regard was testinal glucagon-immunoreactive material, a peptide designated gli- the finding that the hyperglycemic effect of glucagon resides in its centin, contained the full glucagon sequence [36e40], and glicentin ability to act in the liver to stimulate glycogenolysis and gluconeo- was proposed to represent at least a fragment of proglucagon, genesis [6e12] despite its seemingly paradoxical ability to stimulate because it was also identified in the pancreas [41]. Although glicentin insulin secretion in humans reported by Ellis Samols in 1965 [13]. In the was initially thought to comprise w100 amino acids, its purification early 1950’s, Earl Sutherland and Christian de Duve demonstrated
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