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

Abstract

Aim 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. Methods 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 β‐to‐δ‐cell cross‐communication was assessed following selective ablation of either mouse islet δ or β cells. Results Liraglutide increased β‐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 β‐cell Ca2+ oscillation frequency in islets from rodents exposed to a diabetogenic diet. Interestingly, liraglutide accelerated Ca2+ oscillations in a majority of islet δ cells, which showed synchronized Ca2+ oscillations equivalent to β cells; therefore, we assessed if either cell type was driving this liraglutide‐mediated islet Ca2+ response. Although δ‐cell loss did not impact liraglutide‐mediated increase in β‐cell Ca2+ oscillation frequency, β‐cell ablation attenuated liraglutide‐facilitated acceleration of δ‐cell Ca2+ oscillations. Conclusion The data presented here show that liraglutide‐induced stimulation of islet HCN channels augments Ca2+ oscillation frequency. As insulin secretion oscillates with β‐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 δ‐cell Ca2+ oscillation frequency and somatostatin secretion kinetics in a β‐cell‐dependent manner.

Exendin-4 affects calcium signalling predominantly during activation and activity of beta cell networks in acute mouse pancreas tissue slices

“…High doses of theophylline on the other hand decreased both the length of the burst and intervals between them, increasing fraction of the plateau phase only through the increased frequency ( 62 ). A recent study of a different GLP-1RA, liraglutide, also showed an increase in [Ca 2+ ] IC oscillatory frequency ( 123 ), as did most experiments with forskolin, where the beta cell active time was elevated by a prominent increase in the frequency of [Ca 2+ ] IC oscillations ( 61 , 70 ), even when their duration decreased ( 70 ). Quantitatively, the effect on beta cell active time in previous studies is also comparable to our results, but is heterogeneous and ranges from 24-100% with GLP-1 ( 79 , 124 ), 30-80% with different doses of theophylline ( 62 ), 30-100% with forskolin ( 61 , 70 , 110 ) to approximately 40% with Ex-4 ( 102 ), and 100% with dbcAMP ( 62 , 110 ) on the background of comparable glucose levels (9-12 mM).…”

“…However, among the different possible mechanisms promoting beta cell function during activation and activity in the presence of GLP-1RAs, a plausible contribution to the enhanced [Ca 2+ ] IC dynamics observed in the present study likely stems from potentiating effects on L-type voltage-dependent Ca 2+ channels ( 45 , 52 , 116 , 124 ), together with activation of Ca 2+ induced Ca 2+ release from intracellular stores ( 51 , 52 , 125 – 127 ). However, evidence also exists that activation of hyperpolarization-activated cyclic nucleotide-gated channels by GLP-1RAs plays a role in augmenting beta cell [Ca 2+ ] oscillations ( 2 , 123 ). Additionally, cAMP mediated inhibition in Na + /K + ATPase activity could support beta cell depolarization, joining efforts with K ATP channels ( 128 ).…”

The MODY-associatedKCNK16L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

“…For example, Adcy5 has been shown to amplify glucose-stimulated cAMP production, which enhances glucose-stimulated insulin secretion. As cAMP is also a critical signal for β-cell Ca 2+ entry (31, 32), the impact of cAMP on Kcnk16 L114P islet Ca 2+ handling was examined. Elevation of cAMP through activation of the GLP-1 receptor (with 200 nM liraglutide) only increased glucose-stimulated [Ca 2+ ] c oscillation frequency in WT islets and did not impact the loss of glucose-stimulated [Ca 2+ ] c entry in Kcnk16 L114P islet (Supplemental figure 10).…”

Network representation of multicellular activity in pancreatic islets: Technical considerations for functional connectivity analysis

“…They are primarily situated in the mantle of pancreatic islets in mice, and this outer region is particularly susceptible to damage during the islet isolation process, potentially resulting in the loss of alpha cells during islet preparation. Given that both glucagon and GLP-1 have been shown to elevate the frequency of oscillations in beta cells, the diminished intra-islet alpha cell signalling could be a contributing factor to the observed decrease in beta cell oscillatory frequency in isolated islets [ 71 , 91 , 118 , 119 ]. Further, there may be a run-down of certain ion channels and changes in the expression [ 120 , 121 ] with time, which obviously impact the identity and physiology of beta cells in the cultured isolated islets more than in the immediately used islets in slices [ 122 , 123 ].…”