β-adrenergic blockers increase cAMP and stimulate insulin secretion through a PKA/RYR2/TRPM5 pathway in pancreatic β-cells in vitro

β-adrenergic blockers (β-blockers) are extensively utilized in the treatment of various cardiovascular conditions. However, their direct effects on insulin secretion from pancreatic β-cells remain largely unexplored. This study investigates the impact of β-blockers on insulin secretion utilizing MIN6-K8 clonal β-cells and mouse islets in vitro. Various non-selective and β1-selective β-blockers were found to amplify glucose- and glimepiride-induced insulin secretion 1.5–2 fold. Surprisingly, β-blockers (propranolol and bisoprolol) were found to increase cAMP production 5–10 fold via adenylyl cyclase, the effects being dependent on α2-adrenoceptors, which suggests cross-reactivity of these β-blockers and their receptors. Propranolol-stimulated insulin secretion involves a novel signaling pathway mediated by protein kinase A (PKA), ryanodine receptor 2 (RYR2), and transient receptor potential cation channel subfamily M member 5 (TRPM5). Initially, cAMP activates PKA and triggers RYR2 phosphorylation and extracellular Ca ²⁺ influx, leading to Ca ²⁺ -induced Ca ²⁺ release (CICR). Subsequently, CICR activates TRPM5, resulting in augmented extracellular Ca ²⁺ influx through the L-type voltage-dependent Ca ²⁺ channel (VDCC). Remarkably, propranolol effectively increased cAMP levels and insulin secretion in diabetic NSY.B6- A ^y mouse islets, suggesting a potential strategy for restoring cAMP-stimulated insulin secretion in diabetic β-cells. Our findings provide insights into the fundamental pharmacology of adrenoceptors and the regulatory mechanisms of insulin secretion.