Acute Peripheral but Not Central Administration of Olanzapine Induces Hyperglycemia Associated with Hepatic and Extra-Hepatic Insulin Resistance 英文参考文献.docVIP
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Acute Peripheral but Not Central Administration of Olanzapine Induces Hyperglycemia Associated with Hepatic and Extra-Hepatic Insulin Resistance 英文参考文献
AcutePeripheralbutNotCentralAdministrationof
OlanzapineInducesHyperglycemiaAssociatedwith
HepaticandExtra-HepaticInsulinResistance
ElodieM.Girault1*,AnnekeAlkemade2,EwoutFoppen1,2,Marie¨tteT.Ackermans3,EricFliers2,
AndriesKalsbeek1,2
1HypothalamicIntegrationMechanisms,NetherlandsInstitute forNeuroscience,anInstituteoftheRoyalNetherlandsAcademyofArtsandScience,Amsterdam,The
Netherlands,2DepartmentofEndocrinologyandMetabolism,AcademicMedicalCenter(AMC),UniversityofAmsterdam,Amsterdam,TheNetherlands,3Laboratoryof
Endocrinology,DepartmentofClinicalChemistry,AcademicMedicalCenter(AMC),UniversityofAmsterdam,Amsterdam,TheNetherlands
Abstract
Atypical antipsychotic drugs such as Olanzapine induce weight gain and metabolic changes associated with the
developmentoftype2diabetes.Themechanismsunderlyingthemetabolicside-effectsofthesecentrallyactingdrugsare
still unknown to a large extent. We compared the effects of peripheral (intragastric; 3mg/kg/h) versus central
(intracerebroventricular;30mg/kg/h)administrationofOlanzapineonglucosemetabolismusingthestableisotopedilution
technique(Experiment1)incombinationwithlowandhighhyperinsulinemic-euglycemicclamps(Experiments2and3),in
order to evaluate hepatic and extra-hepatic insulin sensitivity, in adult male Wistar rats. Blood glucose, plasma
corticosterone and insulin levels were measured alongside endogenous glucose production and glucose disappearance.
Livers were harvested to determine glycogen content. Under basal conditions peripheral administration of Olanzapine
inducedpronouncedhyperglycemiawithoutasignificantincreaseinhepaticglucoseproduction(Experiment1).Theclamp
experimentsrevealedaclearinsulinresistancebothathepatic(Experiment2)andextra-hepaticlevels(Experiment3).The
inductionofinsulinresistanceinExperiments2and3wassupportedbydecreasedhepaticglycogenstoresinOlanzapine-
treated rats. Central administration of Olanzapine, however, did not result in any significant changes in blood glucose,
plasmainsulinorcorticostero
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