Format

Send to

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

The Role and Future of FFA1 as a Therapeutic Target.

Ghislain J1,2, Poitout V3,4,5,6.

Author information

1
Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada.
2
CRCHUM, University of Montreal, 900 rue St Denis, Montreal, QC, Canada, H2X 0A9.
3
Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada. vincent.poitout@umontreal.ca.
4
CRCHUM, University of Montreal, 900 rue St Denis, Montreal, QC, Canada, H2X 0A9. vincent.poitout@umontreal.ca.
5
Department of Medicine, University of Montreal, Montreal, QC, Canada. vincent.poitout@umontreal.ca.
6
Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, QC, Canada. vincent.poitout@umontreal.ca.

Abstract

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which were promising; however, the field suffered a significant setback when the lead compound TAK-875/fasiglifam was withdrawn from clinical development due to liver safety concerns.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

PMID:
27807697
DOI:
10.1007/164_2016_51
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center