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Inhibitory Effects of Antipsychotics on Carbachol-Enhanced Insulin Secretion From Perifused Rat Islets

Role of Muscarinic Antagonism in Antipsychotic-Induced Diabetes and Hyperglycemia

¹ Department of Neuroscience, Pfizer Global Research and Development, Groton, Connecticut
² Yale School of Nursing, Yale University, New Haven, Connecticut
³ Department of General Pharmacology, Pfizer Global Research and Development, Groton, Connecticut
⁴ Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, Connecticut

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 ß-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 µmol/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.

Abbreviations: KPSS, Krebs-Henseleit physiological salt solution; KRBB, Krebs-Ringer bicarbonate buffer; SGA, second-generation antipsychotic

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