Endocrine Abstracts

Adrenal insufficiency, characterised by inadequate cortisol production, significantly impacts quality of life and overall health. Current treatment primarily involves hydrocortisone replacement. However, dosing challenges and risk of adverse cardiovascular complications persist with this therapy. Consequently, there is a pressing need for safer glucocorticoid replacement options to mitigate the cardiometabolic toxicity, while effectively managing adrenal insufficiency. Preliminary evidence suggests another endogenous glucocorticoid, corticosterone, does not induce the same metabolic effects in adipose tissue as cortisol, and so may be a viable option as a safer, alternative replacement therapy. While animal models of glucocorticoid excess suggest high-dose corticosterone induces cardiometabolic dysregulation, its effect at lower doses, especially in adrenal insufficiency, remains unclear. Therefore, the aim of this study was to investigate the dose-dependent effects of corticosterone in a mouse model of adrenal insufficiency. Adult male C57Bl/6J mice (8 weeks old) were adrenalectomised and administered corticosterone in drinking water (25, 50, or 100 µg/mL) or vehicle (1% v/v ethanol) for 4 weeks (n=7-10 per group). Energy expenditure was assessed by indirect calorimetry using the Promethion Core (Sable Systems) after 3 weeks. Body composition was measured by TD-NMR (Bruker MiniSpec) between 3-4 weeks of treatment. At week 4, insulin sensitivity was assessed by an insulin tolerance test. Mice were fasted for 6 hours (0800-1400) before insulin bolus (0.75U/kg; IP) and quantification of glucose levels over 2h. Fasting blood was used to quantify insulin levels (ELISA, Millipore). Mice were culled by decapitation, and blood and tissues harvested for downstream analysis. Circulating and tissue corticosterone levels were quantified by liquid chromatography- tandem mass spectrometry. While corticosterone did not induce changes in body weight, body composition was significantly altered, with corticosterone increasing fat-mass and decreasing lean-mass in a dose-dependent manner. This increase in adiposity occurred independently of changes in energy expenditure, food intake, or physical activity. Corticosterone impaired insulin tolerance in a dose-dependent manner, in parallel with reducing the glucose disposal rate (K_ITT). Moreover, corticosterone dose-dependently increased fasting insulin levels, and increased the HOMA-IR index of insulin resistance. Circulating and adipose corticosterone levels were only significantly increased with the highest dose (100µg/ml vs Vehicle). However, Pearson correlation analysis identified significant correlation between adipose corticosterone and indices of metabolic regulation. This study demonstrates that even relatively low-dose corticosterone can induce metabolic dysfunction in adrenal insufficiency. Further work is needed to determine the relative ‘risk’ by comparing corticosterone and cortisol, and to identify the underlying mechanisms behind potential differences.