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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Inhibition of 5α-reductases impairs androgen and glucocorticoid metabolism and induces insulin resistance in humans and rodents. The contribution of hepatic glucocorticoids to these adverse metabolic changes was assessed utilizing a liver-selective glucocorticoid receptor (GR) antagonist, A-348441.Mice lacking 5α-reductase 1 (5αR1-KO) and their littermate controls were studied on a high fat diet, with or without A-348441(120 mg.kg-1.day-1). Male mice C57BL/6 (12 weeks) were also studied receiving dutasteride (1.8 mg.kg-1.day-1or vehicle) within a high fat diet, with or without A-348441.In 5αR1-KO mice, hepatic GR antagonism improved diet-induced insulin resistance, but notmore than controls. Liver steatosis was not affected by hepatic GR antagonism in either 5αR1-KO mice nor their littermate controls. In a second model of 5α-reductase inhibition using dutasteride, hepatic GR antagonism with A-348441 attenuated excess weight gain brought about by dutasteride administration (7.03±0.5vs.2.13±0.4g; dutasteride vs. dutasteride+A-348441; mean±SEM, p<0.05) and normalized the associated hyperinsulinemia after glucose challenge (AUC: 235.9±17vs.329.3±16vs.198.4±25*ng.mL-1min-1; high fat, high fat+dutasteride, high fat+dutasteride+A-348441, respectively; *p<0.05). However, A-348441 again did not reverse dutasteride-induced liver steatosis.Thus, overall hepatic GR antagonism improves insulin resistance but not steatosis induced by high fat diet. Moreover, it attenuates excessive insulin resistance caused by pharmacological inhibition of 5α-reductases, but not genetic disruption of 5αR1. Dutasteride might put patients at increased risk of type 2 diabetes mellitus and reduced exposure to glucocorticoids may be beneficial.
Author(s): Mak TCS, Livingstone DEW, Nixon M, Walker BR, Andrew R
Publication type: Article
Publication status: Published
Journal: Endocrinology
Year: 2019
Volume: 160
Issue: 9
Pages: 2061–2073
Print publication date: 30/09/2019
Online publication date: 14/06/2019
Acceptance date: 10/06/2019
Date deposited: 12/06/2019
ISSN (print): 0013-7227
ISSN (electronic): 1945-7170
Publisher: Oxford University Press
URL: https://doi.org/10.1210/en.2019-00236
DOI: 10.1210/en.2019-00236
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