1472-P: Dual Pancreatic Adrenergic and Dopaminergic Signaling as a Therapeutic Mechanism for Treatment of Dysglycemia by Bromocriptine

Dopaminergic agonism effectively treats dysglycemia, with dopaminergic agonist bromocriptine approved as a type 2 diabetes therapy. Though bromocriptine’s actions have been mainly attributed to stimulation of dopamine D₂ receptors (D2R) in the brain, we previously showed that bromocriptine also targets metabolically-relevant peripheral tissues including the endocrine pancreas. Here, we employ bromocriptine as a tool to elucidate roles of dopaminergic and adrenergic signaling in regulation of pancreatic hormone secretion. Using bromocriptine, we demonstrate a new mechanism for metabolic actions in pancreatic α-cells and β-cells via D2R and adrenergic α_2A receptor (α_2A-AR) signaling. In β-cells, bromocriptine acts jointly on D2R and α_2A-AR to reduce glucose-stimulated insulin secretion (GSIS) , while in α-cells, bromocriptine acts via D2R to reduce glucagon secretion. Bromocriptine reduces cAMP in β-cells via concurrent actions on D2R and α_2A-AR, further emphasizing shared roles of adrenergic and dopaminergic receptor agonism in GSIS regulation. At the receptor level, α_2A-AR activation by bromocriptine leads to receptor recruitment of an ensemble of G proteins driven mainly via G protein signaling with no β-arrestin2 recruitment. In contrast, D2R recruits both G proteins and β-arrestin2 upon bromocriptine stimulation, demonstrating signaling unique to each receptor. Docking studies also reveal that bromocriptine binding to α_2A-AR is distinct from bromocriptine-bound D2R, providing a structural basis for bromocriptine’s dual actions on β-cell α_2A-AR and D2R. Together, joint dopaminergic and adrenergic receptor actions on α-cell and β-cell hormone release provide a new therapeutic mechanism to improve dysglycemia in diabetes.