Treatment of type 2 diabetes by free fatty acid receptor agonists

• Main Authors: Kenneth R Watterson, Brian D Hudson, Trond eUlven, Graeme eMilligan
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2014-08-01
• Series: Frontiers in Endocrinology
• Subjects: Inflammation; Insulin; diabetes; Incretin; FFA receptor
• Online Access: http://journal.frontiersin.org/Journal/10.3389/fendo.2014.00137/full

Dietary free fatty acids (FFAs), such as ω-3 fatty acids, regulate metabolic and anti-inflammatory processes, with many of these effects attributed to FFAs interacting with a family of G protein-coupled receptors. Selective synthetic ligands for Free Fatty Acid receptors (FFA1-4) have consequently been developed as potential treatments for type 2 diabetes (T2D). In particular, clinical studies show that Fasiglifam, an agonist of the long chain FFA receptor, FFA1, improved glycaemic control and reduced HbA1c levels in T2D patients, with a reduced risk of hypoglycemia. However, this ligand was removed from clinical trials due to potential liver toxicity and determining if this is a target or a ligand-specific feature is now of major importance. Pre-clinical studies also show that FFA4 agonism increases insulin sensitivity, induces weight loss and reduces inflammation and the metabolic and anti-inflammatory effects of short chain fatty acids (SCFAs) are linked with FFA2 and FFA3 activation. In this review, we therefore show that FFA receptor agonism is a potential clinical target for T2D treatment and discuss ongoing drug development programmes within industry and academia aimed at improving the safety and effectiveness of these potential treatments.