Therapeutic Potential of EP3 Receptor Antagonists for Treatment of Noninsulin Dependent Diabetes Mellitus across Multiple Preclinical Models

The EP3 receptor (EP3r) is a member of the EP receptor subfamily, which facilitate a broad range of physiological and pathological prostaglandin E2 (PGE2) actions. Multiple reports have demonstrated that infusion of PGE2 blunts glucose-stimulated insulin secretion (GSIS) in healthy subjects and that inhibition of PGE2 production in noninsulin dependent diabetes mellitus (NIDDM) patients can partially restore impaired GSIS. The suppression of GSIS by PGE2 has been attributed to EP3r, resulting in the suggestion that EP3r antagonism may be an attractive strategy for treatment of NIDDM. We sought to investigate the therapeutic potential of EP3r antagonists in preclinical models. EP3r-mediated suppression of GSIS was validated in vivo using a dose-range (3-30 µg/kg/minutes) of the EP3r-specific agonist sulprostone in conscious rat ivGTTs. Using this model, we defined the EP3r antagonist plasma exposure required to oppose maximal EP3r-mediated GSIS suppression. Efficacy of an EP3r-specific antagonist was then evaluated in the GK, ZDF, and DIO/streptozotocin diabetic rat models. Despite achieving plasma concentrations at least 2-fold higher than the efficacious exposure predicted by the ivGTT model, an EP3r antagonist did not impact GSIS nor glucose homeostasis in these models. We further interrogated the ability of EP3r to suppress GSIS in conscious non-human primates (NHPs) using infusions of both sulprostone and an EP3r-specific antagonist during ivGTT. In NHPs sulprostone resulted in a significant reduction in both the fasting insulin and acute insulin response compared to vehicle. Surprisingly, EP3r agonism also significantly suppressed fasting plasma glucagon. Given the combined effect on islet hormone secretion in NHPs, and the lack of EP3r antagonist efficacy across multiple diabetic rodent models, these results call into question the therapeutic potential of EP3r antagonists for NIDDM patients.