Gut hormone polyagonists for the treatment of type 2 diabetes

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

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