AMP‐ACTIVATED PROTEIN KINASE AS REGULATOR OF P2Y6 RECEPTOR‐INDUCED INSULIN SECRETION IN MOUSE PANCREATIC BETA CELLS

Abstract

5′‐AMP‐activated protein kinase (AMPK) and its pharmacological modulators have been targeted for treating type 2 diabetes. Extracellular UDP activates P2Y6 receptors (P2Y6Rs) in pancreatic β cells to release insulin and reduce apoptosis, which would benefit diabetes. Here, we studied the role of P2Y6R in activation of AMPK and insulin secretion in MIN6 mouse pancreatic beta cells. Treatment with a potent P2Y6R dinucleotide agonist MRS2957 activated AMPK, which was blocked by P2Y6R‐selective antagonist. Also, MRS2957 induced phosphorylation of acetyl‐coenzyme 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 P2Y6R‐mediated AMPK phosphorylation revealing involvement of intracellular calcium signaling pathways. P2Y6R agonist induced insulin secretion only at high glucose, which was reduced by AMPK gene silencing suggesting an involvement of AMPK in P2Y6 receptor‐mediated insulin secretion. Thus, P2Y6R has a crucial role in β cell function, suggesting its potential as a therapeutic target in diabetes.