Treatment of Type 2 Diabetes by Free Fatty Acid Receptor Agonists

Abstract

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 glycemic 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 programs within industry and academia aimed at improving the safety and effectiveness of these potential treatments.

Distinct Phosphorylation Clusters Determine the Signaling Outcome of Free Fatty Acid Receptor 4/G Protein–Coupled Receptor 120

“…In this way, an mFFA4 ligand that can modulate the site-specific phosphorylation of residues within cluster 1 and 2 would have a highly refined signaling profile and, as a consequence, might activate a restricted number of physiologic responses compared with a ligand that activated nonselectively both phosphorylation-dependent and phosphorylation-independent signaling. This may be very important in the development of therapeutic compounds that target FFA4 (e.g., to regulate glycemia in type 2 diabetes) (Oh et al, 2014;Watterson et al, 2014;Milligan et al, 2015;Sekiguchi et al, 2015), in which it is desirable to activate those pathways that mediate therapeutically beneficial outcomes over pathways that lead to adverse/ toxic responses. Thus, the study presented here might provide the framework to develop mFFA4 biased ligands that specifically promote signaling with improved therapeutic potential.…”

“…Key contributions of such fatty acids to metabolic and inflammatory control, as well as to dysregulation of processes that are associated with obesity and metabolic syndrome (Oh et al, 2014;Watterson et al, 2014;Sekiguchi et al, 2015), are produced via specific interactions with G protein-coupled receptors (GPCRs) present at the surface of cells within tissues (including the gut, pancreas, and adipose tissue) that control metabolite distribution, flux, and storage (Oh et al, 2014;Watterson et al, 2014;Sekiguchi et al, 2015). Two GPCRs, free fatty acid receptor (FFA) 1 (also known as GPR40) and FFA4 (also known as GPR120), are known to respond selectively to longer-chain free fatty acids (Milligan et al, 2015).…”

Homology Modeling of Ffa2 Identifies Novel Agonists that Potentiate Insulin Secretion

“…Nutrient sensing G-protein coupled receptors (GPCRs) in pancreatic beta (β) cells are particularly tractable targets, as these receptors are well known to contribute to the regulation of insulin secretion and β cell mass in response to the nutritional status of the host (reviewed in ref 1). A new and seemingly important group of nutrient sensing GPCRs, free fatty acid receptors (FFAs) have drawn a great deal of interest recently as potential therapeutic targets (reviewed in ref 2). For example, the long-chain FFA, FFA1 (GPR40), has been shown to regulate glucose stimulated insulin secretion (GSIS), and several FFA1 agonists have shown promise in early stage clinical trials, though concerns over potential toxicity have slowed the progression of some of these agonists through trials 2…”

Long‐term safety and efficacy of fasiglifam (TAK‐875), a G‐protein‐coupled receptor 40 agonist, as monotherapy and combination therapy in Japanese patients with type 2 diabetes: a 52‐week open‐label phase III study

“…Long‐chain free fatty acids modulate glucose‐stimulated insulin secretion via an action mediated by G‐protein‐coupled receptor 40 (GPR40) . Fasiglifam is an orally available GPR40 agonist with a glucose‐dependent insulinotropic effect .…”