Blockade of multiple monoamines receptors reduce insulin secretion from pancreatic β-cells

Clinical use of olanzapine frequently causes severe hyperglycemia as an adverse effect. In this study, we elucidated mechanisms by which olanzapine reduced insulin secretion using the hamster pancreatic β-cell line HIT-T15. Reverse transcriptional-PCR analysis revealed expression of dopamine (D(2), D(3) and D(4)), serotonin (5-HT(2A), 5-HT(2B), 5-HT(2C), and 5-HT(6)), and histamine (H(1) and H(2)) receptors in HIT-T15 cells. Olanzapine decreased insulin secretion from HIT-T15 cells at clinically relevant concentrations (64–160 nM). A dopamine D(2) agonist, D(3) antagonist, and D(4) antagonist suppressed insulin secretion, whereas a D(2) antagonist and D(3) agonist increased it. A serotonin 5-HT(2B) agonist slightly increased insulin secretion, while a 5-HT(2C) antagonist slightly decreased it. Other agonists and antagonists for serotonin receptors did not affect insulin secretion. A histamine H(1) agonist increased insulin secretion, whereas an H(1) antagonist and H(2) agonist suppressed it. Our results suggest that dopamine (D(2), D(3) and D(4)), serotonin (5-HT(2B) and 5-HT(2C)), and histamine (H(1) and H(2)) receptors, which are expressed on pancreatic β-cells, directly modulate insulin secretion from pancreatic β-cells. Thus, olanzapine may induce hyperglycemia in clinical settings by suppressing insulin secretion from pancreatic β-cells through inhibition of dopamine D(3), serotonin 5-HT(2B) and 5-HT(2C), and histamine H(1) receptors.