The A2b adenosine receptor (A2bAR) is a G-protein coupled receptor that, upon binding of adenosine, activates adenylyl cyclase and mediates downstream effects through secondary messengers, including cyclic 3’5’ AMP (cAMP) and Ca
++
. We have previously demonstrated that A2bAR knockout (KO) KO mice, post-high fat diet (HFD) develop a type 2 diabetic (T2D) phenotype, evidenced by elevated plasma insulin and glucose. Pancreatic islets from A2bAR KO mice demonstrated insulin hypersecretion post-4 weeks HFD, and high glucose challenge. To further understand the underlying mechanism, we focused on the contribution of the pancreatic A2bAR to this phenomnena. cAMP has been demonstrated to be a significant amplifier of glucose-stimulated insulin secretion. Through the use of A2bAR KO islets and diet-induced stress, we identified a new dual role for cAMP in mediating insulin secretion, dependent on cAMP level and duration. Short exposure to elevated cAMP indeed causes insulin hypersecretion. cAMP has, however, also a downregulating effect on the expression of GLUT2 mRNA and protein, which has the potential to inhibit insulin secretion. Thus, A2bAR short and long-term signaling in the pancreas play an important role in insulin homeostasis.