title: Inhibitory effects of antipsychotics on carbachol-enhanced insulin secretion from perifused rat islets: role of muscarinic antagonism in antipsychotic-induced diabetes and hyperglycemia.
abstract: 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.
authors.affiliation: Pfizer Global Research and Development, Department of Neuroscience, Groton Laboratories, MS 8220-4159, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Johnson
authors.forename: Hanae
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ward
authors.forename: Anne W
authors.initials: AW
authors.lastname: Schmidt
authors.forename: Wesley S
authors.initials: WS
authors.lastname: Lebel
authors.forename: Judith L
authors.initials: JL
authors.lastname: Treadway
authors.forename: E Michael
authors.initials: EM
authors.lastname: Gibbs
authors.forename: Walter S
authors.initials: WS
authors.lastname: Zawalich
authors.forename: Hans
authors.initials: H
authors.lastname: Rollema
mesh_terms: 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
chemical_list: D014150:Antipsychotic Agents; D007328:Insulin; D018727:Muscarinic Antagonists; D001569:Benzodiazepines; D002217:Carbachol; D003024:Clozapine; D000077152:Olanzapine