Clozapine and quetiapine acutely reduce glucagon-like peptide-1 production and increase glucagon release in obese rats: implications for glucose metabolism and food choice behaviour.
OBJECTIVE
Second generation antipsychotic drug (SGA) treatment is associated with detrimental effects on glucose metabolism which is often attributed to the development of obesity and insulin resistance. However, we have recently demonstrated that clozapine and quetiapine also have direct effects of glucose metabolism in animals. This study compares clozapine and quetiapine and investigates the effects of these on the development of obesity and the direct effects of these drugs on glucose metabolism compared with those caused by the obesity per se.


METHODS
Three groups of male Sprague-Dawley rats were fed a high fat/high sugar diet to induce obesity while another three groups were fed a chow diet. One group on each diet was injected daily with vehicle, clozapine or quetiapine and effects on glucose metabolism were monitored.


RESULTS
Clozapine and quetiapine treatment did not directly cause obesity or potentiate diet induced obesity but did induce a preference for the high fat/high sugar diet. Neither drug caused a impairment in insulin tolerance over that caused by obesity but both drugs acutely induced impairments in glucose tolerance that were additive with the effects induced by the diet induced obesity. Both drugs caused increases in glucagon levels and a suppression of GLP-1. We investigated two strategies for restoring GLP-1 signalling. The DPP-IV inhibitor sitagliptin only partially restored GLP-1 levels and did not overcome the deleterious effects on glucose tolerance whereas the GLP-1 receptor agonist exendin-4 normalised both glucagon levels and glucose metabolism.


CONCLUSIONS
Our findings indicate that the clozapine and quetiapine induced impairments in glucose tolerance in rats are independent of insulin resistance caused by obesity and that these defects are linked with a suppression of GLP-1 levels. These studies suggest the need to perform follow up studies in humans to determine whether clozapine and quetiapine induce acute derangements in glucose metabolism and whether GLP-1 replacement therapy might be the most appropriate therapeutic strategy for treating derangements in glucose metabolism in subjects taking these drugs.
Smith
Greg C
GC
Department of Molecular Medicine and Pathology and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
Vickers
Mark H
MH
Cognard
Emmanuelle
E
Shepherd
Peter R
PR
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology*; D003987:Dibenzothiazepines / Q000494:pharmacology*; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D000077270:Exenatide; D005518:Food Preferences / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005934:Glucagon / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test / Q000379:methods; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D000069348:Quetiapine Fumarate; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology
D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D010455:Peptides; D011719:Pyrazines; D014230:Triazoles; D014688:Venoms; D000069348:Quetiapine Fumarate; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide; D005947:Glucose; D003024:Clozapine; D000068900:Sitagliptin Phosphate