The Role and Future of FFA1 as a Therapeutic Target.
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which were promising; however, the field suffered a significant setback when the lead compound TAK-875/fasiglifam was withdrawn from clinical development due to liver safety concerns.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.
Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada.|CRCHUM, University of Montreal, 900 rue St Denis, Montreal, QC, Canada, H2X 0A9.
Julien
J
Ghislain
Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada. vincent.poitout@umontreal.ca.|CRCHUM, University of Montreal, 900 rue St Denis, Montreal, QC, Canada, H2X 0A9. vincent.poitout@umontreal.ca.|Department of Medicine, University of Montreal, Montreal, QC, Canada. vincent.poitout@umontreal.ca.|Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, QC, Canada. vincent.poitout@umontreal.ca.
Vincent
V
Poitout
D000818:Animals; D001572:Benzofurans / Q000009:adverse effects / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology; D008659:Metabolic Diseases / Q000209:etiology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000502:physiology*; D015398:Signal Transduction; D013450:Sulfones / Q000009:adverse effects / Q000627:therapeutic use
D001572:Benzofurans; C473034:FFAR1 protein, human; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C557331:TAK-875
Allosteric agonist; Biased agonism; FFA1/Gpr40; Functional selectivity; Insulin secretion; Pancreatic islet; Type 2 diabetes; β cell