Control of insulin secretion by GLP-1

Peptides. 2018 Feb:100:75-84. doi: 10.1016/j.peptides.2017.12.013.


Stimulation of insulin secretion by glucagon-like peptide-1 (GLP-1) and other gut-derived peptides is central to the incretin response to ingesting nutriments. Analogues of GLP-1, and inhibitors of its breakdown, have found widespread clinical use for the treatment of type 2 diabetes (T2D) and obesity. The release of these peptides underlies the improvements in glycaemic control and disease remission after bariatric surgery. Given therapeutically, GLP-1 analogues can lead to side effects including nausea, which limit dosage. Greater understanding of the interactions between the GLP-1 receptor (GLP-1R) and both the endogenous and artificial ligands therefore holds promise to provide more efficacious compounds. Here, we discuss recent findings concerning the signalling and trafficking of the GLP-1R in pancreatic beta cells. Leveraging "bias" at the receptor towards cAMP generation versus the recruitment of β-arrestins and extracellular signal-regulated kinases (ERK1/2) activation may allow the development of new analogues with significantly improved clinical efficacy. We describe how, unexpectedly, relatively low-affinity agonists, which prompt less receptor internalisation than the parent compound, provoke greater insulin secretion and consequent improvements in glycaemia.

Keywords: Beta cells; Endocytic trafficking; GLP-1; GLP-1 receptor; Insulin secretion; Receptor signalling.

Publication types

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

MeSH terms

  • Bariatric Surgery
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / surgery
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Glucagon-Like Peptide-1 Receptor / therapeutic use*
  • Humans
  • Incretins / metabolism
  • Insulin / chemistry
  • Insulin / metabolism*
  • Insulin Secretion / drug effects
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Ligands
  • MAP Kinase Signaling System / drug effects
  • Obesity / drug therapy*
  • Obesity / metabolism
  • Obesity / surgery
  • Peptides / chemistry
  • Peptides / therapeutic use


  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Incretins
  • Insulin
  • Ligands
  • Peptides
  • Glucagon-Like Peptide 1