Glucagon-like peptide 1 (GLP-1)

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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 β-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

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Most cited references 835

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The molecular biology of memory storage: a dialogue between genes and synapses.

E R Kandel (2001)

One of the most remarkable aspects of an animal's behavior is the ability to modify that behavior by learning, an ability that reaches its highest form in human beings. For me, learning and memory have proven to be endlessly fascinating mental processes because they address one of the fundamental features of human activity: our ability to acquire new ideas from experience and to retain these ideas over time in memory. Moreover, unlike other mental processes such as thought, language, and consciousness, learning seemed from the outset to be readily accessible to cellular and molecular analysis. I, therefore, have been curious to know: What changes in the brain when we learn? And, once something is learned, how is that information retained in the brain? I have tried to address these questions through a reductionist approach that would allow me to investigate elementary forms of learning and memory at a cellular molecular level-as specific molecular activities within identified nerve cells.

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The biology of incretin hormones.

Daniel Drucker (2006)

Gut peptides, exemplified by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted in a nutrient-dependent manner and stimulate glucose-dependent insulin secretion. Both GIP and GLP-1 also promote beta cell proliferation and inhibit apoptosis, leading to expansion of beta cell mass. GLP-1, but not GIP, controls glycemia via additional actions on glucose sensors, inhibition of gastric emptying, food intake and glucagon secretion. Furthermore, GLP-1, unlike GIP, potently stimulates insulin secretion and reduces blood glucose in human subjects with type 2 diabetes. This article summarizes current concepts of incretin action and highlights the potential therapeutic utility of GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes.

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Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus.

M. Nauck, M. M. Heimesaat, C Orskov … (1993)

In type-2 diabetes, the overall incretin effect is reduced. The present investigation was designed to compare insulinotropic actions of exogenous incretin hormones (gastric inhibitory peptide [GIP] and glucagon-like peptide 1 [GLP-1] [7-36 amide]) in nine type-2 diabetic patients (fasting plasma glucose 7.8 mmol/liter; hemoglobin A1c 6.3 +/- 0.6%) and in nine age- and weight-matched normal subjects. Synthetic human GIP (0.8 and 2.4 pmol/kg.min over 1 h each), GLP-1 [7-36 amide] (0.4 and 1.2 pmol/kg.min over 1 h each), and placebo were administered under hyperglycemic clamp conditions (8.75 mmol/liter) in separate experiments. Plasma GIP and GLP-1 [7-36 amide] concentrations (radioimmunoassay) were comparable to those after oral glucose with the low, and clearly supraphysiological with the high infusion rates. Both GIP and GLP-1 [7-36 amide] dose-dependently augmented insulin secretion (insulin, C-peptide) in both groups (P < 0.05). With GIP, the maximum effect in type-2 diabetic patients was significantly lower (by 54%; P < 0.05) than in normal subjects. With GLP-1 [7-36 amide] type-2 diabetic patients reached 71% of the increments in C-peptide of normal subjects (difference not significant). Glucagon was lowered during hyperglycemic clamps in normal subjects, but not in type-2 diabetic patients, and further by GLP-1 [7-36 amide] in both groups (P < 0.05), but not by GIP. In conclusion, in mild type-2 diabetes, GLP-1 [7-36 amide], in contrast to GIP, retains much of its insulinotropic activity. It also lowers glucagon concentrations.

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Author and article information

Contributors

T.D. Müller

Journal

Journal ID (nlm-ta): Mol Metab

Journal ID (iso-abbrev): Mol Metab

Title: Molecular Metabolism

Publisher: Elsevier

ISSN (Electronic): 2212-8778

Publication date PMC-release: 30 September 2019

Publication date Collection: December 2019

Publication date (Electronic): 30 September 2019

Volume: 30

Pages: 72-130

Affiliations

[1 ]Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany

[2 ]German Center for Diabetes Research (DZD), Neuherberg, Germany

[3 ]Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany

[4 ]Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA

[5 ]Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK

[6 ]Division of Endocrinology, Duke University Medical Center, Durham, NC, USA

[7 ]The Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, M5G1X5, Canada

[8 ]SAAD Centre for Pharmacy & Diabetes, Ulster University, Coleraine, Northern Ireland, UK

[9 ]Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany

[10 ]Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany

[11 ]Metabolic 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

[12 ]Institute of Diabetes, Obesity and Metabolism, Department of Psychology, University of Pennsylvania, Philadelphia, PA, 19104, USA

[13 ]Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard University, Boston, MA, USA

[14 ]Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

[15 ]Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland

[16 ]Diabetes Division, St Josef Hospital, Ruhr-University Bochum, Bochum, Germany

[17 ]Diabetes Center Bochum-Hattingen, St Josef Hospital (Ruhr-Universität Bochum), Bochum, Germany

[18 ]Department of Internal Medicine, University of Cincinnati-College of Medicine, Cincinnati, OH, USA

[19 ]Cardiovascular & ImmunoMetabolism, Janssen Research & Development, Welsh and McKean Roads, Spring House, PA, 19477, USA

[20 ]Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA

[21 ]Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DL-2200, Copenhagen, Denmark

[22 ]Department of Biomedical Sciences, University of Copenhagen, DK-2200, Copenhagen, Denmark

[23 ]Obesity Research, Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark

[24 ]Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA

[25 ]Department of Chemistry, Indiana University, Bloomington, IN, USA

[26 ]Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany

[27 ]Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany

Author notes

[∗ ]Corresponding author. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany. timo.mueller@ 123456helmholtz-muenchen.de

Article

Publisher ID: S2212-8778(19)30913-5

DOI: 10.1016/j.molmet.2019.09.010

PMC ID: 6812410

PubMed ID: 31767182

SO-VID: a2250c3b-6765-4e8f-8e6d-e327292d3719

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 17 July 2019

Date revision received : 10 September 2019

Date accepted : 22 September 2019

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Glucagon-like peptide 1 (GLP-1)

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Abstract

Background

Scope of review

Major conclusions

Related collections

Karger: Nutrition and Dietetics

Most cited references 835

The molecular biology of memory storage: a dialogue between genes and synapses.

The biology of incretin hormones.

Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus.

Author and article information

Contributors

Journal

Affiliations

Author notes

Article

History

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Comments

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Similar content 359

Cited by 445

Most referenced authors 9,610