title: Clozapine directly increases insulin and glucagon secretion from islets: implications for impairment of glucose tolerance.
abstract: Second generation antipsychotics cause derangements in glucose metabolism that are often interpreted as insulin resistance. In previous studies we have shown that this is not classical insulin resistance but the drugs were actually inducing a hyperglycaemic state associated with elevated hepatic glucose output (HGO) and increased levels of glucagon and insulin. However, it remains unclear whether these effects are directly elicited by drug actions in the liver and pancreas, or whether they are indirectly mediated. Here we investigated if clozapine is capable of inducing insulin resistance in the liver or enhancing insulin and glucagon secretion from the pancreas. It was observed that insulin signalling was elevated in livers from animals treated with clozapine indicating there was no insulin resistance in the early steps of insulin signalling. To explore whether the defects arise at later stages of insulin action we used an isolated perfused liver system. In this model, clozapine had no direct effect on insulin's counter regulatory effect on epinephrine-induced HGO. In isolated mouse islets clozapine significantly increased glucose-stimulated insulin secretion while simultaneously blocking glucose-induced reductions in glucagon secretion. We also show that the non-peptidic glucagon receptor like peptide-1 (GLP-1) receptor agonist Boc5 was able to overcome the inhibitory effects of clozapine on glucose metabolism. Taken together these results suggest that clozapine does not have any direct effect on glucose metabolism in the liver but it simultaneously stimulates insulin and glucagon secretion, a situation that would allow for the concurrent presence of high glucose and high insulin levels in treated animals.
authors.affiliation: Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand; Department of Pharmacology, University of New South Wales, NSW, Australia.
authors.forename: G C
authors.initials: GC
authors.lastname: Smith
authors.affiliation: The National Centre for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai, Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
authors.forename: T
authors.initials: T
authors.lastname: Mulvey
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore; Hubrecht Institute for Development Biology and Stem Cell Research, Utrecht, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Petersen
authors.affiliation: Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
authors.forename: S
authors.initials: S
authors.lastname: Lach
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan 250014, China.
authors.forename: P
authors.initials: P
authors.lastname: Xiu
authors.affiliation: School of Biological Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: A
authors.initials: A
authors.lastname: Phillips
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: W
authors.initials: W
authors.lastname: Han
authors.affiliation: The National Centre for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai, Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: wangmw@mail.shcnc.ac.cn.
authors.forename: M-W
authors.initials: MW
authors.lastname: Wang
authors.affiliation: Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand; The Maurice Wilkins Centre, Auckland, New Zealand. Electronic address: peter.shepherd@auckland.ac.nz.
authors.forename: P R
authors.initials: PR
authors.lastname: Shepherd
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D003503:Cyclobutanes / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D005934:Glucagon / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism; D013566:Sympathomimetics / Q000494:pharmacology; D046509:Tissue Culture Techniques
chemical_list: D014150:Antipsychotic Agents; C533559:Boc5 compound; D003503:Cyclobutanes; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D018027:Receptors, Glucagon; D013566:Sympathomimetics; D005934:Glucagon; D005947:Glucose; D003024:Clozapine; D004837:Epinephrine
keywords: Clozapine; Diabetes; Insulin signalling; Schizophrenia