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Liraglutide increases islet Ca2+ oscillation frequency and insulin secretion by
activating hyperpolarization-activated cyclic nucleotide-gated channels.
Authors Zaborska KE, Jordan KL, Thorson AS, Dadi PK, Schaub CM, Nakhe AY, Dickerson MT,
Lynch JC, Weiss AJ, Dobson JR, Jacobson DA
Submitted By Submitted Externally on 6/21/2022
Status Published
Journal Diabetes, obesity & metabolism, REFERENCES
Year 2022
Date Published 5/1/2022
Volume : Pages Not Specified : Not Specified
PubMed Reference 35546791
Abstract To determine whether hyperpolarization-activated cyclic nucleotide-gated (HCN)
channels impact glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) modulation of
islet Ca2+ handling and insulin secretion., The impact of liraglutide (GLP-1
analogue) on islet Ca2+ handling, HCN currents and insulin secretion was
monitored with fluorescence microscopy, electrophysiology and enzyme
immunoassays, respectively. Furthermore, liraglutide-mediated ß-to-d-cell
cross-communication was assessed following selective ablation of either mouse
islet d or ß cells., Liraglutide increased ß-cell Ca2+ 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
ß-cell Ca2+ oscillation frequency in islets from rodents exposed to a
diabetogenic diet. Interestingly, liraglutide accelerated Ca2+ oscillations in a
majority of islet d cells, which showed synchronized Ca2+ oscillations
equivalent to ß cells; therefore, we assessed if either cell type was driving
this liraglutide-mediated islet Ca2+ response. Although d-cell loss did not
impact liraglutide-mediated increase in ß-cell Ca2+ oscillation frequency,
ß-cell ablation attenuated liraglutide-facilitated acceleration of d-cell Ca2+
oscillations., The data presented here show that liraglutide-induced stimulation
of islet HCN channels augments Ca2+ oscillation frequency. As insulin secretion
oscillates with ß-cell Ca2+ , 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 d-cell Ca2+ oscillation frequency and somatostatin secretion
kinetics in a ß-cell-dependent manner.


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