Liraglutide increases islet Ca²⁺ oscillation frequency and insulin secretion by activating hyperpolarization-activated cyclic nucleotide-gated channels.

AIM: To determine whether hyperpolarization-activated cyclic nucleotide-gated (HCN) channels impact glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) modulation of islet Ca handling and insulin secretion. METHODS: The impact of liraglutide (GLP-1 analogue) on islet Ca handling, HCN currents and insulin secretion was monitored with fluorescence microscopy, electrophysiology and enzyme immunoassays, respectively. Furthermore, liraglutide-mediated β-to-δ-cell cross-communication was assessed following selective ablation of either mouse islet δ or β cells. RESULTS: Liraglutide increased β-cell Ca oscillation frequency in mouse and human islets under stimulatory glucose conditions. This was dependent in part on liraglutide activation of HCN channels, which also enhanced insulin secretion. Similarly, liraglutide activation of HCN channels also increased β-cell Ca oscillation frequency in islets from rodents exposed to a diabetogenic diet. Interestingly, liraglutide accelerated Ca oscillations in a majority of islet δ cells, which showed synchronized Ca oscillations equivalent to β cells; therefore, we assessed if either cell type was driving this liraglutide-mediated islet Ca response. Although δ-cell loss did not impact liraglutide-mediated increase in β-cell Ca oscillation frequency, β-cell ablation attenuated liraglutide-facilitated acceleration of δ-cell Ca oscillations. CONCLUSION: The data presented here show that liraglutide-induced stimulation of islet HCN channels augments Ca oscillation frequency. As insulin secretion oscillates with β-cell Ca , these findings have important implications for pulsatile insulin secretion that is probably enhanced by liraglutide activation of HCN channels and therapeutics that target GLP-1Rs for treating diabetes. Furthermore, these studies suggest that liraglutide as well as GLP-1-based therapies enhance δ-cell Ca oscillation frequency and somatostatin secretion kinetics in a β-cell-dependent manner.