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

Area of Science:

• Endocrinology
• Pharmacology
• Cell Biology

Background:

• Olanzapine, an antipsychotic, is known to cause hyperglycemia.
• The precise mechanisms underlying olanzapine-induced hyperglycemia are not fully understood.
• Pancreatic beta cells play a crucial role in insulin secretion and glucose homeostasis.

Purpose of the Study:

• To investigate the mechanisms by which olanzapine affects insulin secretion.
• To identify specific receptors on pancreatic beta cells that mediate olanzapine's effects.
• To elucidate the role of dopamine, serotonin, and histamine receptors in olanzapine-induced insulin suppression.

Main Methods:

• Utilized the hamster pancreatic beta-cell line HIT-T15.
• Performed reverse transcriptional-PCR to identify receptor expression.
• Assessed the effects of olanzapine and various receptor agonists/antagonists on insulin secretion.

Main Results:

• HIT-T15 cells express dopamine (D2, D3, D4), serotonin (5-HT2A, 5-HT2B, 5-HT2C, 5-HT6), and histamine (H1, H2) receptors.
• Olanzapine significantly decreased insulin secretion at clinically relevant concentrations.
• Specific dopamine, serotonin, and histamine receptor modulators differentially affected insulin secretion, implicating D3, 5-HT2B, 5-HT2C, and H1 receptors.

Conclusions:

• Dopamine, serotonin, and histamine receptors are expressed on pancreatic beta cells and modulate insulin secretion.
• Olanzapine likely suppresses insulin secretion by inhibiting dopamine D3, serotonin 5-HT2B/5-HT2C, and histamine H1 receptors.
• These findings provide a cellular mechanism for olanzapine-induced hyperglycemia.