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AMPK β1 activation suppresses antipsychotic-induced hyperglycemia in mice
Shamshoum, Hesham Medak, Kyle D. Townsend, Logan K. Ashworth, Kristen E. Bush, Natasha D. Halm, Margaret K. Kemp, Bruce E. Wright, David C.
Shamshoum, Hesham
Medak, Kyle D.
Townsend, Logan K.
Ashworth, Kristen E.
Bush, Natasha D.
Halm, Margaret K.
Kemp, Bruce E.
Wright, David C.
Abstract
Olanzapine (OLZ) is a second-generation antipsychotic that is used to treat schizophrenia but also causes acute hyperglycemia. This study aimed to determine if the ablation of AMPK β1-containing complexes potentiates acute OLZ-induced metabolic dysfunction and if the activation of AMPK β1 suppresses these effects. Female AMPK β1-/- or wild-type (WT) control mice were treated with OLZ, and changes in bloodglucose, serum and liver metabolites, whole-body fuel oxidation, and pyruvate-induced increases in blood glucose were measured. Additionally, WT mice were cotreated with OLZ and A769662, a specific AMPK β1 activator, and we determined if cotreatment protected against acute, OLZ-induced metabolic dysfunction. OLZ-induced increases in blood glucose were exacerbated in AMPK β1-/- mice compared with WT mice, and this was paralleled by greater OLZ-induced increases in markers of liver glucose production, such as pyruvate tolerance, serum glucagon, and glucagon responsiveness. Cotreatment with A769662 attenuated OLZ-induced increases in blood glucose, serum nonesterified fatty acid, and glycerol. Furthermore, this effect was absent in AMPK β1-/- mice, consistent with A769662's specificity for the AMPK β1 subunit. Reductions in AMPK activity potentiate the effects of acute OLZ treatment on blood glucose, whereas specifically targeting AMPK β1-containing complexes is sufficient to protect against OLZ-induced hyperglycemia.—Shamshoum, H., Medak, K. D., Townsend, L. K., Ashworth, K. E., Bush, N. D., Hahn, M. K., Kemp, B. E., Wright, D. C. AMPK β1 activation suppresses antipsychotic-induced hyperglycemia in mice.
Keywords
olanzapine, A769662, liver, glucose, lipids
Date
2019
Type
Journal article
Journal
The FASEB Journal
Book
Volume
33
Issue
12
Page Range
14010-14021
Article Number
ACU Department
Faculty of Health Sciences
Collections
Relation URI
Source URL
Event URL
Open Access Status
License
All rights reserved
File Access
Controlled