Dopaminergic modulation of pancreatic beta-cell insulin secretion and implications for antipsychotic-induced glucose...

Antipsychotic drugs exert their therapeutic effects through dopamine D₂-like receptor blockade but are also associated with clinically significant dysglycaemia. Whether these metabolic effects reflect consistent actions on peripheral dopaminergic targets, including pancreatic β-cell D₂-like receptors, remains uncertain. We conducted a systematic review and meta-analysis of preclinical in vitro and ex vivo studies examining the effects of dopamine, D₂-like receptor agonists and antagonists on insulin secretion in isolated pancreatic islets or β-cell lines. PubMed, Embase, and PsycINFO were searched from inception to Sept 22, 2025. Two reviewers independently screened studies, extracted data, and performed random-effects meta-analyses with subgroup and meta-regression analyses assessing glucose concentration, compound type, and dose. 39 studies met inclusion criteria, with 37 included in the metanalysis. Dopamine and D₂-like receptor agonists showed no significant effect under low-glucose conditions but robustly inhibited glucose-stimulated insulin secretion (GSIS) in rodent and rabbit models (g = -2.36; 95% CI: -2.77 to -1.96; P < 0.0001 & g = -1.98; 95% CI - 2.88 to -1.09; p < 0.0001 respectively), with greater GSIS suppression at higher glucose concentrations and dopamine doses. Though D₂-like receptor antagonists alone had no significant effect (g = -0.25, 95% CI -0.68 to 0.18, P = 0.25), these drugs blocked GSIS inhibiton by co-administered dopamine (g = 1.59 [0.76 to 2.42]; p = 0.0002). These findings demonstrate that D₂-like receptor activation inhibits pancreatic β-cell insulin secretion in a glucose- and dose-dependent manner, whereas receptor blockade reverses this effect, identifying a peripheral dopaminergic mechanism that may contribute to antipsychotic drug-associated dysglycaemia independent of weight gain. Together, these findings highlight the need for metabolic monitoring beyond weight alone in response to treatment with antipsychotic medications.