Dopamine D 2 receptor signaling modulates pancreatic beta cell circadian rhythms

• Published in: Psychoneuroendocrinology Vol. 113; p. 104551
• Main Authors: Wei, Heather, Zapata, Rizaldy C, Lopez-Valencia, Mariela, Aslanoglou, Despoina, Farino, Zachary J, Benner, Valerie, Osborn, Olivia, Freyberg, Zachary, McCarthy, Michael J
• Format: Journal Article
• Language: English
• Published: England 01-03-2020
• Subjects: Animals; Blood Glucose - metabolism; Bromocriptine - pharmacology; Circadian Rhythm - drug effects; Circadian Rhythm - physiology; Diabetes Mellitus, Type 2 - metabolism; Dopamine - metabolism; Dopamine Agonists - pharmacology; Female; Glucose - metabolism; Insulin - metabolism; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - physiology; Levodopa - pharmacology; Mice; Mice, Inbred C57BL; Obesity - metabolism; Receptors, Dopamine D2 - metabolism; Receptors, Dopamine D2 - physiology; Sulpiride - pharmacology; Weight Gain; Obesity; Antipsychotic; Dopamine; Circadian rhythm; Diabetes; Insulin
• ISSN: 1873-3360
• DOI: 10.1016/j.psyneuen.2019.104551

Antipsychotic drugs (APD) have clinically important, adverse effects on metabolism that limit their therapeutic utility. Pancreatic beta cells produce dopamine and express the D
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.