GPR119 agonists for type 2 diabetes: past failures and future hopes for preclinical and early phase candidates

ABSTRACT

Introduction

Type 2 diabetes (T2D) is metabolic disorder associated with a decrease in insulin activity and/or secretion from the β-cells of the pancreas, leading to elevated circulating glucose. Current management practices for T2D are complex with varying long-term effectiveness. Agonism of the G protein-coupled receptor GPR119 has received a lot of recent interest as a potential T2D therapeutic.

Areas covered

This article reviews studies focused on GPR119 agonism in animal models of T2D and in patients with T2D.

Expert opinion

GPR119 agonists in vitro and in vivo can potentially regulate incretin hormone release from the gut, then pancreatic insulin release which regulates blood glucose concentrations. However, the success in controlling glucose homeostasis in rodent models of T2D and obesity, failed to translate to early-stage clinical trials in patients with T2D. However, in more recent studies, acute and chronic dosing with the GPR119 agonist DS-8500a had increased efficacy, although this compound was discontinued for further development. New trials on GPR119 agonists are needed, however it may be that the future of GPR119 agonists lie in the development of combination therapy with other T2D therapeutics.

KEYWORDS:

• GPR119
• T2D
• agonist
• glucose
• insulin
• rodent models
• clinical studies
• incretin hormones

Article highlights

• Glucose homeostasis is an important target for the treatment of adverse outcomes associated with T2D and obesity.

• GPR119 expression is highest in the enteroendocrine cells of the digestive tract and in the β-cells of the pancreas, and agonism increases cAMP in vitro in heterologous expression systems.

• Agonism of GPR119 stimulates incretin hormone release in the gastrointestinal tract and insulin release from the pancreas, which all contribute to circulating glucose concentrations.

• Advances in GPR119 agonist development have led to the identification of therapeutics that show promising effects in the control of glucose homeostasis in rodent models of T2D and obesity.

• Challenges remain for successful clinical application of GPR119 agonists for the treatment of T2D.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.