Here we describe a mathematical model for the regulation of cAMP dynamics in pancreatic -cells. Incretin hormones such as glucagon-like peptide 1 (GLP-1) increase cAMP and augment insulin secretion in pancreatic -cells. Imaging experiments performed in MIN6 insulinoma cells expressing a genetically encoded cAMP biosensor and loaded with Fura-2, a calcium indicator, showed that cAMP oscillations are differentially regulated by periodic changes in membrane potential and GLP-1. We modeled the interplay of intracellular calcium, its interaction with calmodulin, G-protein coupled receptor activation, adenylyl cyclases (AC) and phosphodiesterases (PDE). Simulations with the model demonstrate that cAMP oscillations are coupled to cytoplasmic Ca²⁺ oscillations in the -cell. Slow Ca²⁺ oscillations (< 1/min) produce low-frequency cAMP oscillations, and faster Ca²⁺ oscillations (> 3-4/min) entrain high frequency, low amplitude cAMP oscillations. The model predicts that GLP-1 receptor agonists induce cAMP oscillations in phase with cytoplasmic Ca²⁺ oscillations. In contrast, observed antiphasic Ca²⁺ and cAMP oscillations can be simulated following combined glucose and tetraethylammonium-induced changes in membrane potential. The model provides additional evidence for a pivotal role for Ca²⁺-dependent AC and PDE activation in coupling of Ca²⁺ and cAMP signals. Our results reveal important differences in the effects of glucose/TEA and GLP-1 on cAMP dynamics in MIN6 -cells.