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-HT2A, 5-HT2B, 5-HT2C, 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-HT2B agonist slightly increased insulin secretion, while a 5-HT2C 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-HT2B and 5-HT2C), 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-HT2B and 5-HT2C, and histamine H1 receptors.
Effects of electrical stimulation of the ventromedial hypothalamus (VMH) on gastric acid output and mucosal blood flow were examined in rats anesthetized with urethan. With stimulation of this area, a significant increase in acid output and mucosal blood flow occurred in 8 out of 16 animals. In these eight rats, the tip of the electrode had been placed mainly within the caudal portion of VMH. When the basal acid output was maintained at a relatively high level by pretreating the rats with 2-deoxy-D-glucose, electrical stimulation of the VMH significantly reduced the levels of these gastric parameters in 9 out of 12 animals. In the remaining three animals, the tip of the electrode had been placed in an area outside the VMH. These findings suggest that VMH is not a homogeneous neuron group, and both excitatory and inhibitory neurons probably play a role in regulating gastric functions.
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