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Abstract
Background: Diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. Hyperglycemia, or raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious damage to many of the body's systems, especially nerves and blood vessels. Diabetes causes about 5% of all deaths globally each year and is likely to increase by > 50% in the next 10 years without urgent action. In light of these alarming statistics, the pharmaceutical industry has been on a quest to characterize more promising molecular targets to satisfy stringent new criteria for anti-hyperglycemic agents introduced by the American Diabetes Association. On to this stage, G-protein-coupled receptor 119 (GPR119) has emerged as arguably one of the most exciting targets for the treatment of type 2 diabetes mellitus in the new millennium. Objective: In this review, we outline the current clinical trial landscape and paint a detailed illustration of the key structural information realized from GPR119 agonist campaigns that have recently emerged in the Patent Cooperation Treaty literature. Conclusion: GPR119 agonists mediate a unique nutrient-dependent dual elevation of both insulin and glucagon like peptide 1/glucose-dependant insulinotropic peptide levels in vivo. As a stand-alone therapy or in tandem with approved DPP-IV inhibitors, they could herald a brand new treatment paradigm for type 2 diabetes mellitus. With the passage of the first GPR119 agonist clinical candidates into Phase I trials (Arena/Ortho McNeil APD597; Metabolex MBX-2982; Prosidion/OSI PSN821) and confirmatory reports of clinical proof of concept with respect to glycemic control and incretin release, the spotlight has been set for this new class of therapeutic.
