Endocrine Abstracts

Glucocorticoid excess, Cushing's syndrome, is a recognised cause of insulin resistance and in some cases diabetes mellitus. In addition, patients develop reversible central obesity. However, the exact mechanisms that underpin the development of glucocorticoid mediated insulin resistance and central obesity are not known. We have hypothesized that at a cellular level, the tissue specific generation of cortisol from inactive cortisone through the action of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) may be an important regulator of proteins involved in the insulin signalling cascade.

Paired subcutaneous (sc) and omental (om) biopsies were obtained from women undergoing elective abdominal surgery. Preadipocytes were isolated by collagenase digestion and cultured to confluence. Cells were treated with or without cortisol (100nM) and gene expression profiling performed using an Affymetrix microarray technique (n=3). The data were subsequently validated using real-time PCR (n=8-16).

11beta-HSD1 was more highly expressed in om preadipocytes and expression increased with cortisol treatment in both sc and om depots (sc: 3.8 fold, p<0.0005; om: 3.5 fold, p<0.0005). IRS1 (3.5 fold, p<0.001) and PKBbeta/C-akt2 (3.6 fold, p<0.001) were more highly expressed in sc preadipocytes. Conversely, IRS2 was more highly expressed in om cells (1.8 fold, p<0.05). However, in sc cells only, cortisol increased IRS1 (1.4 fold, p<0.01) and IRS2 expression (2.4 fold, p<0.05).

We have demonstrated transcriptional regulation of key components of the insulin signalling cascade in human adipose tissue by cortisol. In addition, we have highlighted differences in expression and glucocorticoid regulation between sc and om depots. These observations may not only help to explain depot specific differences in adipocyte differentiation, but also the insulin resistance associated with central obesity. Furthermore, inhibition of the intracellular generation of glucocorticoids to enhance insulin signalling remains a novel strategy for insulin sensitisation.