Deciphering the involvement of norepinephrine and β-adrenergic receptor subtypes in glucose induced insulin secretion: an integrated in silico and in vitro exploration using isolated pancreatic islets of C57BL/6J mice.

Abstract

Regulating insulin production by pancreatic beta cells is crucial for maintaining metabolic balance. Previous studies observed elevated neurotransmitter levels, like norepinephrine (NE), in metabolic syndrome mice with impaired insulin secretion. Given the therapeutic potential of β-adrenergic receptors (β-ARs) for diabetes and obesity, and the lack of structural data on murine β-ARs, we aimed to construct and validate 3D models to investigate their roles in insulin secretion regulation. We constructed high-quality 3D models for murine β1-AR, β2-AR, and β3-AR using Phyre2 and Ramachandran plot analysis. Molecular docking revealed NE's strong binding affinity for all three β-AR subtypes through favorable docking scores and hydrogen bond formations. We evaluated the physiological impact of NE on glucose-induced insulin secretion via β-ARs under physiological and elevated glucose conditions using pancreatic islets from C57BL/6J mice. At physiological glucose levels, NE did not significantly increase insulin secretion. However, higher NE concentrations suppressed insulin release at elevated glucose. The β3-AR agonist CL316243 significantly increased (p < 0.01), insulin secretion under normal and hyperglycemic conditions, while the β3-AR antagonist L748337 substantially decreased (p < 0.01)insulin release under normal glucose, confirming their interactions through docking studies. The nonselective β-AR antagonist propranolol significantly decreased (p < 0.01)insulin secretion, suggesting alternative interactions with β1-AR and β2-AR despite lacking hydrogen bonds. Our study enhances the understanding of NE's role in modulating insulin secretion and underscores the significance of β-ARs, especially β3-AR, in its regulation, providing valuable insights for potential therapeutic interventions targeting these receptors in metabolic disorders.