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

Abstract

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 (D₂, D₃ and D₄), serotonin (5-HT_2A, 5-HT_2B, 5-HT_2C, and 5-HT₆), and histamine (H₁ and H₂) receptors in HIT-T15 cells. Olanzapine decreased insulin secretion from HIT-T15 cells at clinically relevant concentrations (64–160 nM). A dopamine D₂ agonist, D₃ antagonist, and D₄ antagonist suppressed insulin secretion, whereas a D₂ antagonist and D₃ 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 H₁ agonist increased insulin secretion, whereas an H₁ antagonist and H₂ agonist suppressed it. Our results suggest that dopamine (D₂, D₃ and D₄), serotonin (5-HT_2B and 5-HT_2C), and histamine (H₁ and H₂) 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 D₃, serotonin 5-HT_2B and 5-HT_2C, and histamine H₁ receptors.