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Noursadeghi Mousavi, Nilou

University of British Columbia

Glucocorticoid-induced diabetes mellitus is a significant metabolic complication arising from the therapeutic use of glucocorticoids such as dexamethasone (Dex). This study investigates the sex-specific metabolic and tissue effects of Dex in C57BL/6J mice to enhance our understanding of disease pathobiology and guide clinical mitigation strategies. A comprehensive literature review guided the choice of Dex dose and revealed a deficiency of studies that have modeled Dex action in both sexes. We analyzed metabolic responses after a single 50 mg/kg Dex administration and a 15-day 10 mg/kg Dex treatment regimen in female and male 19- to 20-week-old C57BL/6J mice. In the first experiment, a single 50 mg/kg Dex injection led to significant hyperinsulinemia, insulin resistance, glucose intolerance, and mortality in male mice, whereas female mice exhibited minimal effects. Conversely, in the pilot study, 15 days of 10 mg/kg Dex induced weight loss and improved glucose tolerance in male mice but had no significant impact on female mice. In the primary study, we examined tissue proteomes in the pancreas, liver, and gonadal fat. Fourteen days of 10 mg/kg Dex administration in the primary study highlighted significant variations in tissue-specific protein expression profiles between Dex-treated and control groups. Specifically, there was up-regulation of Glul, Hmgcs2, and Klk1b4 in the pancreas, down-regulation of Retnla in gonadal fat, and up-regulation of Fkbp5 in the liver. These changes suggest metabolic adaptations to Dex-induced stress. Our findings underscore the importance of considering biological sex and drug dose as variables in the use of glucocorticoids. Understanding these responses is crucial for optimizing Dex dosing and minimizing adverse metabolic effects, ultimately contributing to better management of conditions requiring glucocorticoid therapy.

Text

2024-08-15

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88949

Genome Science and Technology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/