EP3 Signaling is Decoupled from the Regulation of Glucose-stimulated Insulin Secretion in β-cells Compensating for Obesity and Insulin Resistance

Of the β-cell signaling pathways altered by obesity and insulin resistance, some are adaptive while others contribute to β-cell failure. Two critical second messengers are Ca and cAMP, which control the timing and amplitude of insulin secretion. Previous work has shown the importance of the cAMP-inhibitory Prostaglandin EP3 receptor (EP3) in mediating the β-cell dysfunction of type 2 diabetes (T2D). Here, we used three groups of C57BL/6J mice as a model of the progression from metabolic health to T2D: wildtype, normoglycemic (NGOB), and hyperglycemic (HGOB). Robust increases in β-cell cAMP and insulin secretion were observed in NGOB islets as compared to wildtype controls; an effect lost in HGOB islets, which exhibited reduced β-cell cAMP and insulin secretion despite increased glucose-dependent Ca influx. An EP3 antagonist had no effect on β-cell cAMP or Ca oscillations, demonstrating agonist-independent EP3 signaling. Finally, using sulprostone to hyperactivate EP3 signaling, we found EP3-dependent suppression of β-cell cAMP and Ca duty cycle effectively reduces insulin secretion in HGOB islets, while having no impact insulin secretion on NGOB islets, despite similar and robust effects on cAMP levels and Ca duty cycle. Finally, increased cAMP levels in NGOB islets are consistent with increased recruitment of the small G protein, Rap1GAP, to the plasma membrane, sequestering the EP3 effector, Gɑ, from inhibition of adenylyl cyclase. Taken together, these results suggest that rewiring of EP3 receptor-dependent cAMP signaling contributes to the progressive changes in β cell function observed in the model of diabetes.