AMP-activated protein kinase as regulator of P2Y6 receptor-induced insulin secretion in mouse pancreatic β-cells

5'-AMP-activated protein kinase (AMPK) and its pharmacological modulators have been targeted for treating type.2 diabetes. Extracellular uridine 5'-diphosphate (UDP) activates P2Y(6) receptors (P2Y(6)Rs) in pancreatic beta-cells to release insulin and reduce apoptosis, which would benefit diabetes. Here, we studied the role of P2Y(6)R in activation of AMPK in MING mouse pancreatic beta-cells and insulin secretion. Treatment with a potent P2Y(6)R dinucleotide agonist MRS2957 (500 nM) activated AMPK, which was blocked by P2Y(6)R-selective antagonist MRS2578. Also, MRS2957 induced phosphorylation of acetylcoenzyme A carboxylase (ACC), a marker of AMPK activity. Calcium chelator BAPTA-AM, calmodulin-dependent protein kinase kinase (CaMKK) inhibitor STO-069 and IP3 receptor antagonist 2-APB attenuated P2Y(6)R-mediated AMPK phosphorylation revealing involvement of intracellular Ca2+ pathways. P2Y(6)R agonist induced insulin secretion at high glucose, which was reduced by AMPK siRNA. Thus, P2Y(6)R has a crucial role in beta-cell function, suggesting its potential as a therapeutic target in diabetes. Published by Elsevier Inc.