The Role and Future of FFA1 as a Therapeutic Target

Handb Exp Pharmacol. 2017;236:159-180. doi: 10.1007/164_2016_51.


Of the 415 million people suffering from diabetes worldwide, 90% have type 2 diabetes. Type 2 diabetes is characterized by hyperglycemia and occurs in obese individuals as a result of insulin resistance and inadequate insulin levels. Accordingly, diabetes drugs are tailored to enhance glucose disposal or target the pancreatic islet β cell to increase insulin secretion. The majority of the present-day insulin secretagogues, however, increase the risk of iatrogenic hypoglycemia, and hence alternatives are actively sought. The long-chain fatty acid, G protein-coupled receptor FFA1/Gpr40, is expressed in β cells, and its activation potentiates insulin secretion in a glucose-dependent manner. Preclinical data indicate that FFA1 agonism is an effective treatment to restore glucose homeostasis in rodent models of diabetes. This initial success prompted clinical trials in type 2 diabetes patients, the results of which were promising; however, the field suffered a significant setback when the lead compound TAK-875/fasiglifam was withdrawn from clinical development due to liver safety concerns. Nevertheless, recent developments have brought to light a surprising complexity of FFA1 agonist action, signaling diversity, and biological outcomes, raising hopes that with a greater understanding of the mechanisms at play the second round will be more successful.

Keywords: Allosteric agonist; Biased agonism; FFA1/Gpr40; Functional selectivity; Insulin secretion; Pancreatic islet; Type 2 diabetes; β cell.

Publication types

  • Review

MeSH terms

  • Animals
  • Benzofurans / adverse effects
  • Benzofurans / therapeutic use
  • Diabetes Mellitus, Type 2 / drug therapy
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / physiology
  • Metabolic Diseases / etiology
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / physiology*
  • Signal Transduction
  • Sulfones / adverse effects
  • Sulfones / therapeutic use


  • Benzofurans
  • FFAR1 protein, human
  • Insulin
  • Receptors, G-Protein-Coupled
  • Sulfones
  • TAK-875