Endocrine Abstracts

Management of adrenal insufficiency primarily involves hydrocortisone (cortisol) replacement, yet dosing challenges and the increased risk of adverse cardiovascular complications persist. Preliminary evidence suggests another endogenous glucocorticoid, corticosterone, does not induce the same adverse cardiometabolic effects as cortisol. We hypothesised this protection results from selective export of corticosterone, but not cortisol, from metabolic tissues by the transmembrane transporter ABCC1 (ATP-binding cassette Subfamily C Member 1). We used a murine model to i) compare the metabolic effects of corticosterone and cortisol treatment; ii) to assess the effect of Abcc1 deletion; and iii) to identify potential sexually-dimorphic responses. Adult (8-12 weeks) male and female mice lacking Abcc1 (ABCC1-KO) or wild-type (WT) littermates were adrenalectomised and administered either corticosterone or cortisol in drinking water (25μg/ml) for 5 weeks. Body composition (TD-NMR) was measured between 3-4 weeks and metabolic parameters (insulin tolerance, HOMA-IR) between 4-5 weeks. In male mice, corticosterone but not cortisol treatment revealed significant genotype effects on body composition, with KO mice displaying reduced fat-mass and increased lean-mass compared to WT mice. In contrast, female mice displayed reduced weight gain in response to cortisol compared to corticosterone, independent of genotype. Steroid treatment or genotype had no effect on body composition. In male mice, metabolic measures including HOMA-IR and insulin tolerance were exacerbated in cortisol- compared to corticosterone-treated mice, but no genotype effects were observed. Similarly, in female mice, cortisol induced greater insulin intolerance than corticosterone, independent of genotype effects. However, HOMA-IR was not different in female mice between glucocorticoid treatments. This study demonstrates that in both male and female mice, chronic glucocorticoid treatment with cortisol induces greater whole-body insulin resistance than corticosterone, an effect independent of changes in body weight or composition. Contrary to our hypothesis, ABCC1 does not confer protection from corticosterone-induced metabolic dysregulation, but exerts steroid sex-specific effects on adiposity.