GPR119 agonists as potential new oral agents for the treatment of type 2 diabetes and obesity

Abstract

Background: GPR119 is a G_αs-protein-coupled receptor expressed predominantly in pancreatic islets and gastrointestinal tract in humans. Objective/methods: To review the available literature on GPR119 agonists. Results: GPR119 de-orphanisation indicates two classes of possible endogenous agonists, phospholipids and fatty acid amides, with oleoylethanolamide and N-oleoyldopamine being the most potent. GPR119 agonists increase intracellular cAMP leading to increased glucose-dependent insulin secretion from pancreatic β-cells and incretin secretion from gut enteroendocrine cells. In various animal models of type 2 diabetes and obesity, orally available, potent, selective, synthetic GPR119 agonists: i) lower blood glucose without hypoglycaemia; ii) slow diabetes progression; and iii) reduce food intake and body weight. Conclusions: Oral GPR119 agonists may have the potential to achieve blood glucose control together with body weight loss in type 2 diabetics, an outcome only achievable currently with injectable glucagon-like peptide 1 receptor agonists.

Keywords::

• antidiabetic agents
• antiobesity agents
• GLP-1
• GPR119

Acknowledgements

The authors express their gratitude to their many colleagues at (OSI) Prosidion and OSI Pharmaceuticals, Inc., who have contributed to the GPR119 agonists project.

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