| First Author | Zaborska KE | Year | 2022 |
| Journal | Diabetes Obes Metab | Volume | 24 |
| Issue | 9 | Pages | 1741-1752 |
| PubMed ID | 35546791 | Mgi Jnum | J:359610 |
| Mgi Id | MGI:7788560 | Doi | 10.1111/dom.14747 |
| Citation | Zaborska KE, et al. (2022) Liraglutide increases islet Ca(2+) oscillation frequency and insulin secretion by activating hyperpolarization-activated cyclic nucleotide-gated channels. Diabetes Obes Metab 24(9):1741-1752 |
| abstractText | 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(2+) handling and insulin secretion. METHODS: The impact of liraglutide (GLP-1 analogue) on islet Ca(2+) handling, HCN currents and insulin secretion was monitored with fluorescence microscopy, electrophysiology and enzyme immunoassays, respectively. Furthermore, liraglutide-mediated beta-to-delta-cell cross-communication was assessed following selective ablation of either mouse islet delta or beta cells. RESULTS: Liraglutide increased beta-cell Ca(2+) 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 beta-cell Ca(2+) oscillation frequency in islets from rodents exposed to a diabetogenic diet. Interestingly, liraglutide accelerated Ca(2+) oscillations in a majority of islet delta cells, which showed synchronized Ca(2+) oscillations equivalent to beta cells; therefore, we assessed if either cell type was driving this liraglutide-mediated islet Ca(2+) response. Although delta-cell loss did not impact liraglutide-mediated increase in beta-cell Ca(2+) oscillation frequency, beta-cell ablation attenuated liraglutide-facilitated acceleration of delta-cell Ca(2+) oscillations. CONCLUSION: The data presented here show that liraglutide-induced stimulation of islet HCN channels augments Ca(2+) oscillation frequency. As insulin secretion oscillates with beta-cell Ca(2+) , 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 delta-cell Ca(2+) oscillation frequency and somatostatin secretion kinetics in a beta-cell-dependent manner. |
