Inhibitory effects of antipsychotics on carbachol-enhanced insulin secretion from perifused rat islets: role of muscarinic antagonism in antipsychotic-induced diabetes and hyperglycemia.
Treatment with the atypical antipsychotics olanzapine and clozapine has been associated with an increased risk for deterioration of glucose homeostasis, leading to hyperglycemia, ketoacidosis, and diabetes, in some cases independent of weight gain. Because these events may be a consequence of their ability to directly alter insulin secretion from pancreatic beta-cells, we determined the effects of several antipsychotics on cholinergic- and glucose-stimulated insulin secretion from isolated rat islets. At concentrations encompassing therapeutically relevant levels, olanzapine and clozapine reduced insulin secretion stimulated by 10 micromol/l carbachol plus 7 mmol/l glucose. This inhibition of insulin secretion was paralleled by significant reductions in carbachol-potentiated inositol phosphate accumulation. In contrast, risperidone or ziprasidone had no adverse effect on cholinergic-induced insulin secretion or inositol phosphate accumulation. None of the compounds tested impaired the islet secretory responses to 8 mmol/l glucose alone. Finally, in vitro binding and functional data show that olanzapine and clozapine (unlike risperidone, ziprasidone, and haloperidol) are potent muscarinic M3 antagonists. These findings demonstrate that low concentrations of olanzapine and clozapine can markedly and selectively impair cholinergic-stimulated insulin secretion by blocking muscarinic M3 receptors, which could be one of the contributing factors to their higher risk for producing hyperglycemia and diabetes in humans.
Johnson
David E
DE
Pfizer Global Research and Development, Department of Neuroscience, Groton Laboratories, MS 8220-4159, Eastern Point Road, Groton, CT 06340, USA.
Yamazaki
Hanae
H
Ward
Karen M
KM
Schmidt
Anne W
AW
Lebel
Wesley S
WS
Treadway
Judith L
JL
Gibbs
E Michael
EM
Zawalich
Walter S
WS
Rollema
Hans
H
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D000077152:Olanzapine; D051381:Rats; D017207:Rats, Sprague-Dawley
D014150:Antipsychotic Agents; D007328:Insulin; D018727:Muscarinic Antagonists; D001569:Benzodiazepines; D002217:Carbachol; D003024:Clozapine; D000077152:Olanzapine