Dopamine D2 receptor signaling modulates pancreatic beta cell circadian rhythms.

Antipsychotic drugs disrupt dopamine-circadian interactions in pancreatic beta cells. Under physiological conditions, reciprocal connections link the circadian clock and the dopamine system in pancreatic beta cells. These connections facilitate the coordination of behavior and metabolism to maintain homeostasis (solid arrows). By blocking the negative feedback effects of dopamine on beta cells, antipsychotic drugs alter circadian rhythms and the temporal profile of long-term insulin secretion. In so doing, antipsychotic drugs perturb the influence of the circadian clock and dopamine on metabolism (dashed lines) predisposing subjects to weight gain, hyperinsulinemia and insulin resistance. Disruption of beta cell circadian rhythms may be one mechanism by which antipsychotic drugs induce metabolic side effects such as weight gain and hyperinsulinemia. • Key molecules involved in dopamine signaling are rhythmically expressed in beta cells. • Dopamine agonists reduce circadian rhythm amplitude in beta cells through D2 dopamine receptors. • The antipsychotic drug sulpiride alters the temporal profile of long-term insulin release in vitro. • Sulpiride causes greater weight gain and hyperinsulinemia when dosed in the dark vs. light phase. Antipsychotic drugs (APD) have clinically important, adverse effects on metabolism that limit their therapeutic utility. Pancreatic beta cells produce dopamine and express the D 2 dopamine receptor (D2R). As D2R antagonists, APDs alter glucose-stimulated insulin secretion, indicating that dopamine likely plays a role in APD-induced metabolic dysfunction. Insulin secretion from beta cells is also modulated by the circadian clock. Disturbed circadian rhythms cause metabolic disturbances similar to those observed in APD-treated subjects. Given the importance of dopamine and circadian rhythms for beta cells, we hypothesized that the beta cell dopamine system and circadian clock interact and dually regulate insulin secretion, and that circadian manipulations may alter the metabolic impact of APDs. We measured circadian rhythms, insulin release, and the impact of dopamine upon these processes in beta cells using bioluminescent reporters. We then assessed the impact of circadian timing on weight gain and metabolic outcomes in mice treated with the APD sulpiride at the onset of light or dark. We found that molecular components of the dopamine system were rhythmically expressed in beta cells. D2R stimulation by endogenous dopamine or the agonist bromocriptine reduced circadian rhythm amplitude, and altered the temporal profile of insulin secretion. Sulpiride caused greater weight gain and hyperinsulinemia in mice when given in the dark phase compared to the light phase. D2R-acting drugs affect circadian-dopamine interactions and modulate beta cell metabolic function. These findings identify circadian timing as a novel and important mechanism underlying APD-induced metabolic dysfunction, offering new possibilities for therapeutic interventions. [ABSTRACT FROM AUTHOR]