Endocrine Abstracts

Glucocorticoid (GC) excess is characterized by central obesity, insulin resistance and in some cases, type 2 diabetes mellitus. Whilst it is accepted that GCs cause insulin resistance, both insulin and GCs act synergistically to promote adipocyte differentiation. We have previously shown that acute treatment (24 h) with GCs enhances insulin signalling in human adipocytes. We hypothesise that the generation of cortisol from inactive cortisone by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may be an important regulator of insulin signalling, and that changes in 11β-HSD1 activity and expression across adipocyte differentiation are crucial in determining the response to glucocorticoids.

Human subcutaneous adipocytes (Chub-S7 cells) were grown to confluence and differentiated in chemically defined media. In differentiated adipocytes, both acute (24 h) and chronic (7 day) treatment with dexamethasone (Dex) increased insulin stimulated PKB/akt phosphorylation. 11β-HSD1 mRNA and protein levels increased across differentiation (1±0 vs 8.62±2.3 P<0.05). Furthermore, differentiated adipocytes, but not undifferentiated preadipocytes, were able to convert inactive cortisone to cortisol, in addition, activity was inhibited by glycyrrhetinic acid (GE) (ctrl 18.59%±3.1 vs GE 0%±0 P<0.05). In pre-adipocytes, consistent with lack of 11β-HSD1 expression and activity, cortisol but not cortisone increased insulin stimulated PKB/akt phosphorylation (ctrl 1±0 vs cortisol, 2.1±0.03 P<0.005; ctrl 1±0 vs cortisone 0.95±0.05, P=NS). In contrast, in differentiated adipocytes expressing 11β-HSD1, both cortisol and cortisone increased insulin stimulated PKB/akt phosphorylation in adipocytes (ctrl 1±0 vs cortisol, 2.5±0.49 P<0.05; ctrl 1±0 vs cortisone 1.69±0.09, P<0.05). This effect was abolished by co-incubation of cortisone with GE (cortisone, 1.69±0.09 vs cortisone+GE 1.14±0.14 P<0.05). Our data confirm that acute and chronic GC exposure enhance insulin signalling in human adipocytes and that 11β-HSD1 has a crucial regulatory role. These data highlight the importance of pre-receptor GC metabolism as a key mechanism in adipocyte differentiation and response to insulin stimulation.