Enhancement of insulin secretion is a major therapeutic approach for type 2 diabetes (T2D). Activation of P2Y purinergic receptor (P2YR) causes potentiation of insulin secretion in a glucose-dependent manner, making it a promising therapeutic target for T2D. Here we show that activation of P2YR to potentiate insulin secretion is mediated by adenylyl cyclase/cyclic AMP (cAMP) and the downstream effector, exchange protein directly activated by cAMP (Epac), leading to inhibition of voltage-dependent potassium (Kv) channels. P2YR-mediated Kv channel inhibition results in prolongation of action potential duration, and in turn elevates intracellular Ca2+ level and insulin secretion. Taken together, the data indicate that cAMP/Epac/Kv channel pathway mediates P2YR-regulated insulin secretion, which may have important therapeutic implications for T2D. (C) 2015 Elsevier Inc. All rights reserved.