Gut hormone polyagonists for the treatment of type 2 diabetes

Sara J Brandt; Anna Götz; Matthias H Tschöp; Timo D Müller

doi:10.1016/j.peptides.2017.12.021

Gut hormone polyagonists for the treatment of type 2 diabetes

Peptides. 2018 Feb:100:190-201. doi: 10.1016/j.peptides.2017.12.021.

Authors

Sara J Brandt¹, Anna Götz², Matthias H Tschöp³, Timo D Müller⁴

Affiliations

¹ Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Business Campus Garching, Parkring 13, 85748 Garching, Germany.
² Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Business Campus Garching, Parkring 13, 85748 Garching, Germany; Department of Internal Medicine I, University Hospital RWTH Aachen, Aachen, Germany; Institute for Diabetes und Regeneration, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Business Campus Garching, Parkring 13, 85748, Garching, Germany.
³ Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Business Campus Garching, Parkring 13, 85748 Garching, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
⁴ Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Business Campus Garching, Parkring 13, 85748 Garching, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany. Electronic address: timo.mueller@helmholtz-muenchen.de.

Abstract

Chemical derivatives of the gut-derived peptide hormone glucagon-like peptide 1 (GLP-1) are among the best-in-class pharmacotherapies to treat obesity and type 2 diabetes. However, GLP-1 analogs have modest weight lowering capacity, in the range of 5-10%, and the therapeutic window is hampered by dose-dependent side effects. Over the last few years, a new concept has emerged: combining the beneficial effects of several key metabolic hormones into a single molecular entity. Several unimolecular GLP-1-based polyagonists have shown superior metabolic action compared to GLP-1 monotherapies. In this review article, we highlight the history of polyagonists targeting the receptors for GLP-1, GIP and glucagon, and discuss recent progress in expanding of this concept to now allow targeted delivery of nuclear hormones via GLP-1 and other gut hormones, as a novel approach towards more personalized pharmacotherapies.

Keywords: GLP-1/Glucagon Co-agonism; Gip; Polypharmacology; Type 2 diabetes.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Diabetes Mellitus, Type 2 / drug therapy*
Diabetes Mellitus, Type 2 / metabolism
Diabetes Mellitus, Type 2 / pathology
Gastric Inhibitory Polypeptide / antagonists & inhibitors
Gastric Inhibitory Polypeptide / therapeutic use*
Gastrointestinal Hormones / antagonists & inhibitors
Gastrointestinal Hormones / genetics
Gastrointestinal Hormones / therapeutic use
Glucagon-Like Peptide 1 / analogs & derivatives
Glucagon-Like Peptide 1 / antagonists & inhibitors
Glucagon-Like Peptide 1 / therapeutic use*
Glucagon-Like Peptide-1 Receptor / antagonists & inhibitors
Glucagon-Like Peptide-1 Receptor / genetics
Humans
Incretins / metabolism
Insulin / genetics
Insulin / metabolism
Obesity / drug therapy*
Obesity / metabolism
Obesity / pathology
Receptors, Gastrointestinal Hormone / antagonists & inhibitors
Receptors, Gastrointestinal Hormone / genetics
Receptors, Glucagon / antagonists & inhibitors
Receptors, Glucagon / genetics

Substances

GLP1R protein, human
Gastrointestinal Hormones
Glucagon-Like Peptide-1 Receptor
Incretins
Insulin
Receptors, Gastrointestinal Hormone
Receptors, Glucagon
Gastric Inhibitory Polypeptide
Glucagon-Like Peptide 1
gastric inhibitory polypeptide receptor