Glucocorticoid (GC) excess is characterized by increased adiposity, skeletal myopathy and insulin resistance. Despite increasing use of GCs as therapeutic agents, the precise molecular mechanisms that underpin GC-induced insulin resistance are unknown. Within skeletal muscle, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to the active GC, cortisol (corticosterone in rodents) and thus amplifies local GC action. Importantly, selective 11β-HSD1 inhibitors improve insulin sensitivity in rodents and their potential as anti-diabetic agents is being evaluated in clinical studies.
Treatment with the synthetic GC, Dexamethasone (Dex), decreased insulin-stimulated glucose uptake in human and rodent skeletal myotubes. Dex decreased IRS-1 mRNA and total protein expression (0.5-fold, P<0.05 and 2-fold, P<0.05 respectively) and increased inactivating serine-307 (4.5-fold, P<0.05), but not serine-24 phosphorylation. Similarly, the endogenous GC, corticosterone caused a dose and time dependent increase in serine-307 phosphorylation (3.9-fold (250 nM), 8.7-fold (500 nM), P<0.05; 1.3-fold (6 h), 2.0-fold (24 h)). 11β-HSD1 activity was observed in human and rodent myotubes, as well as in rodent muscle explants. The selective 11β-HSD1 inhibitor, A1 (human IC50=0.3 nM, mouse IC50=11.2 nM) abolished all enzyme activity (myotubes: 13.5±2.9 vs 0.5±0.1 pmol/mg per hour, P<0.05; explants: 164±24 vs 0 pmol/g per hour, P<0.05) as did the non-selective 11β-HSD inhibitor, Glycerrhetinic acid (GE). Importantly, A1 and GE were able to abolish the increase in IRS1 serine-307 phosphorylation and reduction in total protein following 11DHC treatment (that requires 11β-HSD1 activity for conversion to active corticosterone), but not that induced by corticosterone.
GCs have a novel action to increase IRS1 serine-307 phosphorylation that may be crucial in mediating insulin resistance in skeletal muscle. Functional 11β-HSD1 activity is present in rodent tissue explants as well as human and rodent myotubes. Selective 11β-HSD1 inhibitors, decrease IRS1 serine-307 phosphorylation and increase IRS1 total protein expression. We propose that this represents an important mechanism underpinning their action as insulin sensitizers and as potential anti-diabetic agents.