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<p>Antipsychotic drugs exert their therapeutic effects through dopamine D<sub>2</sub>-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 D<sub>2</sub>-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, D<sub>2</sub>-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 D<sub>2</sub>-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; <i>P</i> &lt; 0.0001 &amp; g = −1.98; 95% CI − 2.88 to −1.09; p &lt; 0.0001 respectively), with greater GSIS suppression at higher glucose concentrations and dopamine doses. Though D<sub>2</sub>-like receptor antagonists alone had no significant effect (g = –0.25, 95% CI –0.68 to 0.18, <i>P</i> = 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 D<sub>2</sub>-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.</p>

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Dopaminergic modulation of pancreatic beta-cell insulin secretion and implications for antipsychotic-induced glucose dysregulation: a systematic review and meta-analysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Wiaam Al-Hasani,
  • Thomas Cheliotis-James,
  • Anthony S. Wierzbicki,
  • Zachary Freyberg,
  • Oliver Howes,
  • Toby Pillinger

摘要

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.