Context: Glucocorticoid (GC) excess is characterized by central obesity, insulin resistance and in some cases, type 2 diabetes. However, the impact of GC upon insulin signaling in human adipose tissue has not been fully explored.

Objective: We have examined the effect of GC upon insulin signaling in both human subcutaneous primary pre-adipocyte cultures and a novel human immortalized subcutaneous adipocyte cell line (Chub-S7) and contrasted this with observations in primary cultures of human skeletal muscle

Design and Setting: An in vitro study characterizing the impact of GC upon insulin signalling in human tissues.

Patients: Biopsy specimens were from healthy volunteers who gave their full and informed written consent.

Interventions: Combinations of treatments including GC, RU38486 and wortmannin were used.

Main outcome measures: Insulin signaling cascade gene and protein expression and insulin stimulated glucose uptake.

Results: In human adipocytes, pre-treatment with GC induced a dose (1.0 [control]; 1.2±0.1 [50nM]; 2.2±0.2 [250nM], p<0.01 vs. control; 3.4±0.2 [1000nM], p<0.001 vs. control) and time (1.0 [1hr]; 3.2±2.0 [6hr]; 9.1±5.9 [24hr], p<0.05 vs. 1hr; 4.5±2.2 [48hr]) dependent increase in insulin stimulated PKB/akt phosphorylation. In addition, whilst IRS1 protein expression did not change, IRS1 tyrosine phosphorylation increased. Furthermore, GC induced IRS2 mRNA expression (2.8-fold, p<0.05) and increased insulin stimulated glucose uptake (1.0 [control] 1.8±0.1 [insulin] vs. 2.8±0.2 [insulin+GC], p<0.05). In contrast, in primary cultures of human muscle, GC decreased insulin stimulated glucose uptake (1.0 [control] 1.9±0.2 [insulin] vs. GC 1.3±0.1 insulin+GC), p<0.05)

Conclusions: We have demonstrated tissue specific regulation of insulin signaling by GC. Within subcutaneous adipose tissue, GC augment insulin signaling yet in muscle cause insulin resistance. We propose that enhanced insulin action in adipose tissue increases adipocyte differentiation thereby contributing to GC induced obesity.