Glucagon receptor knockout mice are protected against acute olanzapine-induced hyperglycemia

Journal article


Castellani, Laura N., Peppler, Willem T., Sutton, Charles D., Whitfield, Jamie, Charron, Maureen J. and Wright, David C.. (2017) Glucagon receptor knockout mice are protected against acute olanzapine-induced hyperglycemia. Psychoneuroendocrinology. 82, pp. 38 - 45. https://doi.org/10.1016/j.psyneuen.2017.05.005
AuthorsCastellani, Laura N., Peppler, Willem T., Sutton, Charles D., Whitfield, Jamie, Charron, Maureen J. and Wright, David C.
Abstract

Objectives: To determine if glucagon is involved in mediating the increase in blood glucose levels caused by the second-generation antipsychotic drug olanzapine. Materials and methods: Whole body glucagon receptor deficient mice (Gcgr−/−) or WT littermate controls were injected with olanzapine (5 mg/kg BW IP) and changes in blood glucose measured over the following 120 min. Separate cohorts of mice were treated with olanzapine and changes in pyruvate tolerance, insulin tolerance and whole body substrate oxidation were determined. Results: Olanzapine treatment increased serum glucagon and lead to rapid increases in blood glucose concentrations in WT mice. Gcgr−/− mice were protected against olanzapine-induced increases in blood glucose but this was not explained by differences in terminal serum insulin concentrations, enhanced AKT phosphorylation in skeletal muscle, adipose tissue or liver or differences in RER. In both genotypes olanzapine induced an equivalent degree of insulin resistance as measured using an insulin tolerance test. Olanzapine treatment led to an exaggerated glucose response to a pyruvate challenge in WT but not Gcgr−/− mice and this was paralleled by reductions in the protein content of PEPCK and G6Pase in livers from Gcgr−/− mice. Conclusions: Gcgr−/− mice are protected against olanzapine-induced increases in blood glucose. This is likely a result of reductions in liver glucose output, perhaps secondary to decreases in PEPCK and G6Pase protein content. Our findings highlight the central role of the liver in mediating olanzapine-induced disturbances in glucose homeostasis.

Keywordsmice; olanzapine; glucagon; glucose; liver; insulin
Year2017
JournalPsychoneuroendocrinology
Journal citation82, pp. 38 - 45
PublisherPergamon Press
ISSN0306-4530
Digital Object Identifier (DOI)https://doi.org/10.1016/j.psyneuen.2017.05.005
Scopus EID2-s2.0-85019127499
Page range38 - 45
Research GroupMary MacKillop Institute for Health Research
Publisher's version
File Access Level
Controlled
Place of publicationUnited Kingdom
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