GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity.

GPR119 is a G protein-coupled receptor expressed predominantly in the pancreas (beta-cells) and gastrointestinal tract (enteroendocrine cells) in humans. De-orphanization of GPR119 has revealed two classes of possible endogenous ligands, viz., phospholipids and fatty acid amides. Of these, oleoylethanolamide (OEA) is one of the most active ligands tested so far. This fatty acid ethanolamide is of particular interest because of its known effects of reducing food intake and body weight gain when administered to rodents. Agonists at the GPR119 receptor cause an increase in intracellular cAMP levels via G(alphas) coupling to adenylate cyclase. In vitro studies have indicated a role for GPR119 in the modulation of insulin release by pancreatic beta-cells and of GLP-1 secretion by gut enteroendocrine cells. The effects of GPR119 agonists in animal models of diabetes and obesity are reviewed, and the potential value of such compounds in future therapies for these conditions is discussed.

Glucokinase activator PSN-GK1 displays enhanced antihyperglycaemic and insulinotropic actions.

AIMS/HYPOTHESIS: We evaluated the insulinotropic and antihyperglycaemic actions of glucokinase activators (GKAs), especially through acute and subchronic studies in rodent diabetes models with (2R)-2-(4-cyclopropanesulphonylphenyl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a novel and potent GKA. MATERIALS AND METHODS: The action of PSN-GK1 on or in the following were investigated: (1) on human liver glucokinase, insulin secretion from MIN6 cells and 2-deoxy-D: -[(3)H]glucose (2-DG) uptake into rat hepatocytes; and (2) in Zucker diabetic fatty rats and in non-diabetic C57Bl/6, diabetic db/db and ob/ob mice. RESULTS: At 5 mmol/l glucose, PSN-GK1 activated glucokinase (4.3-fold, median effective concentration [EC(50)] 130 nmol/l), increased MIN6 insulin secretion (26-fold, EC(50) 267 nmol/l) and 2-DG hepatocytic uptake (threefold, EC(50) 1 micromol/l); at higher glucose concentrations, EC(50)s and fold-effectiveness were both lower. In C57Bl/6 mice, PSN-GK1 reduced blood glucose at 1 and 10 mg/kg (by mouth), but insulin was increased significantly at only the higher dose. In hyperinsulinaemic 10-mmol/l glucose clamps, PSN-GK1 increased 2-DG incorporation into liver glycogen sixfold, directly demonstrating liver effects. PSN-GK1 improved glycaemic profiles in db/db mice and Zucker diabetic fatty rats, diabetic animal models in which GKA efficacy has not previously been described, without causing hypoglycaemia. In ob/ob mice, it dose-dependently reduced excursions in OGTTs. Moreover, after subchronic administration, no tachyphylaxis was evident and glycaemia was improved without alterations to lipid levels, liver weight, glycogen content or body weight. CONCLUSIONS/INTERPRETATION: PSN-GK1 was potently antihyperglycaemic through its effects on insulin release and hepatic glucose metabolism. It is one of the most potent GKAs described in the literature and is active in diabetic animal models where GKAs have not been reported to show efficacy to date. Ongoing human trials are investigating the potential of this novel therapeutic approach.