227-LB: GLP-1 Activation of HCN Channels Increases Glucose-Stimulated β- and δ- Cell Ca2+ Oscillation Frequency

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control human β-cell insulin secretion. Here, we examined if HCN channels impact glucagon-like-peptide 1 (GLP-1) receptor modulation of islet Ca²⁺ handling. We found that Liraglutide (100nM LIRA), a GLP-1 analog, increased mouse β-cell Ca²⁺ oscillation frequency and cAMP levels in high (11 mM) but not low glucose. Similarly, a subset of human β-cells (65%) show LIRA-induced elevations in Ca²⁺ oscillation frequency (by 70%, P<0.001) under stimulatory glucose (7 mM) conditions. While mouse islet HCN inhibition (20 μM ivabradine) did not alter glucose-stimulated (9 mM) Ca²⁺ oscillation frequency, it prevented LIRA-induced changes of islet Ca²⁺ fluctuations. As LIRA is used to treat type-2-diabetes, we examined and demonstrated that islets from high fat diet-fed, glucose intolerant mice also responded to LIRA with increased Ca²⁺ oscillation frequency (by 93%, P<0.01). These changes in β-cell Ca²⁺ handling may contribute to LIRA-mediated increased insulin secretion, which could also play a role in LIRA inhibition of glucagon secretion. However, as somatostatin also inhibits glucagon secretion, we next investigated the influence of LIRA on &#120575;;-cells. Interestingly, LIRA increased Ca²⁺ oscillation frequency equivalently in β- and &#120575;;-cells (by 85%, P<0.0001), which showed synchronized Ca²⁺ fluctuations. To establish the origin of synchronization cues, we ablated either β- or δ-cells and determined the LIRA-mediated effect on Ca²⁺ handling in remaining δ- or β-cells, respectively. Although δ-cell ablation did not affect the LIRA-mediated elevations in β-cell Ca²⁺ oscillation frequency, β-cell ablation interfered with glucose- and LIRA-mediated δ-cell Ca²⁺ fluctuations. As the kinetics of pulsatile insulin secretion dictate insulin sensitivity, the data presented here suggests that GLP-1 stimulation of islet HCN channels may improve peripheral insulin sensitivity in diabetics treated with LIRA.