title: Effects of intracerebroventricular (ICV) olanzapine on insulin sensitivity and secretion in vivo: an animal model.
abstract: The atypical antipsychotics (AAPs) have been associated with an increased risk of type 2 diabetes. While weight gain associated with AAPs is a risk factor for diabetes, preclinical work suggests that among these medications, olanzapine, when given peripherally in a single dose, causes pronounced effects on insulin sensitivity and secretion. Given a critical role of the hypothalamus in control of glucose metabolism, we examined the effect of central administration of olanzapine. Sprague-Dawley rats were treated with a single 75 μg intracerebroventricular (ICV) dose of olanzapine and tested using separate hyperinsulinemic-euglycemic and hyperglycemic clamps. Dosing of olanzapine was established based on inhibition of amphetamine-induced locomotion. In contrast to the single dosing peripheral paradigm, there was no effect of central olanzapine on insulin sensitivity, either with respect to hepatic glucose production or peripheral glucose uptake. Analogous to the peripheral model, a single ICV dose of olanzapine followed by the hyperglycemic clamp decreased insulin (p=0.0041) and C-peptide response (p=0.0039) to glucose challenge as compared to vehicle, mirrored also by a decrease in the steady state glucose infusion rate required to maintain hyperglycemia (p=0.002). In conclusion, we demonstrate novel findings that at least part of the effect of olanzapine on beta-cell function in vivo is central.
authors.affiliation: Center for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8; Institute of Medical Sciences, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8. Electronic address: maggie.hahn@utoronto.ca.
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Hahn
authors.affiliation: Center for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8; Institute of Medical Sciences, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Araba
authors.initials: A
authors.lastname: Chintoh
authors.affiliation: Center for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8; Institute of Medical Sciences, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8; Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8.
authors.forename: Gary
authors.initials: G
authors.lastname: Remington
authors.affiliation: Center for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8.
authors.forename: Celine
authors.initials: C
authors.lastname: Teo
authors.affiliation: Center for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8; Institute of Medical Sciences, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Steve
authors.initials: S
authors.lastname: Mann
authors.affiliation: Center for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8.
authors.forename: Tamara
authors.initials: T
authors.lastname: Arenovich
authors.affiliation: Center for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8; Department of Psychology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Paul
authors.initials: P
authors.lastname: Fletcher
authors.affiliation: Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Loretta
authors.initials: L
authors.lastname: Lam
authors.affiliation: Center for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8; Department of Pharmacology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Jose
authors.initials: J
authors.lastname: Nobrega
authors.affiliation: Center for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8; Institute of Medical Sciences, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Melanie
authors.initials: M
authors.lastname: Guenette
authors.affiliation: Center for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8; Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8; Department of Nutritional Sciences, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Tony
authors.initials: T
authors.lastname: Cohn
authors.affiliation: Institute of Medical Sciences, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8; Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000494:pharmacology; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D057967:Infusions, Intraventricular; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008099:Liver / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D000077152:Olanzapine; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D014150:Antipsychotic Agents; D001786:Blood Glucose; D002096:C-Peptide; D000697:Central Nervous System Stimulants; D007328:Insulin; D001569:Benzodiazepines; D000661:Amphetamine; D005947:Glucose; D000077152:Olanzapine
keywords: Antipsychotics; Central effects; Glucose metabolism; Insulin secretion; Insulin sensitivity; Intracerebroventricular; Olanzapine