Activation of dopamine D2 receptor damages islet beta cell function by the AKT pathway

Dopamine (DA), a catecholamine neurotransmitter, acts through five G protein-coupled receptors categorized into D1-like (D1, D5) and D2-like (D2, D3, D4) subfamilies. Emerging evidence suggests dopamine receptors influence pancreatic islet function and glucose homeostasis, yet the specific role of dopamine D2 receptors (D2Rs) in type 1 diabetes mellitus (T1DM) pathogenesis remains unclear. This study investigated D2R’s impact on T1DM progression and its underlying signaling mechanisms using both in vitro and in vivo approaches. MIN6 pancreatic beta cells were treated with D2R agonist quinpirole (50 μM), antagonist haloperidol (10 μM), or their combination, followed by 24-h streptozotocin (STZ) exposure. Cell viability was assessed using CCK-8 assays, apoptosis was evaluated through TUNEL staining and caspase-3/9 expression analysis, insulin secretion was measured by ELISA, and AKT pathway activation was examined via Western blot. Additionally, DRD2 knockout (DRD2-/-) mice were subjected to STZ-induced T1DM to validate in vitro findings. Results demonstrated that quinpirole significantly reduced MIN6 cell viability, enhanced apoptosis markers (cleaved caspase-3/9), decreased insulin secretion, and suppressed phosphorylated AKT (p-AKT) expression in STZ-treated cells. These detrimental effects were partially mitigated by haloperidol co-treatment. Importantly, DRD2-/-mice showed significantly higher insulin levels in both peripheral blood and pancreatic tissue compared to wild-type T1DM mice, suggesting D2R deficiency confers protection against STZ-induced beta-cell dysfunction. These findings collectively indicate that D2R activation negatively regulates pancreatic beta-cell survival and insulin secretion through AKT pathway suppression, positioning D2R as a potential therapeutic target for T1DM intervention.