Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1

Cell Metab. 2018 Apr 3;27(4):740-756. doi: 10.1016/j.cmet.2018.03.001.


Glucagon-like peptide-1 (GLP-1) released from gut enteroendocrine cells controls meal-related glycemic excursions through augmentation of insulin and inhibition of glucagon secretion. GLP-1 also inhibits gastric emptying and food intake, actions maximizing nutrient absorption while limiting weight gain. Here I review the circuits engaged by endogenous versus pharmacological GLP-1 action, highlighting key GLP-1 receptor (GLP-1R)-positive cell types and pathways transducing metabolic and non-glycemic GLP-1 signals. The role(s) of GLP-1 in the benefits and side effects associated with bariatric surgery are discussed and actions of GLP-1 controlling islet function, appetite, inflammation, and cardiovascular pathophysiology are highlighted. Refinement of the risk-versus-benefit profile of GLP-1-based therapies for the treatment of diabetes and obesity has stimulated development of orally bioavailable agonists, allosteric modulators, and unimolecular multi-agonists, all targeting the GLP-1R. This review highlights established and emerging concepts, unanswered questions, and future challenges for development and optimization of GLP-1R agonists in the treatment of metabolic disease.

Keywords: G protein-coupled receptor; body weight; cardiovascular disease; diabetes; drug; hypertension; incretin; inflammation; metabolism; obesity.

Publication types

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

MeSH terms

  • Animals
  • Blood Glucose / drug effects
  • Diabetes Mellitus, Type 1 / therapy*
  • Diabetes Mellitus, Type 2 / therapy*
  • Eating / drug effects
  • Glucagon-Like Peptide 1 / adverse effects
  • Glucagon-Like Peptide 1 / pharmacology*
  • Glucagon-Like Peptide 1 / therapeutic use
  • Glucagon-Like Peptide-1 Receptor / agonists
  • Glucagon-Like Peptide-1 Receptor / physiology
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Insulin / metabolism
  • Mice
  • Obesity / therapy*
  • Rats
  • Weight Gain / drug effects


  • Blood Glucose
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Insulin
  • Glucagon-Like Peptide 1

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