Endocrine Abstracts (2009) 19 OC5

Selective inhibition of 11[beta]-hydroxysteroid dehydrogenase type 1 improves insulin sensitivity in skeletal muscle through modulation of IRS1 serine phosphorylation

SA Morgan1, LL Gathercole1, GG Lavery1, M Sherlock1, IJ Bujalska1, JK Sethi3, K Hegyi3, PM Stewart1, DM Smith2 & JW Tomlinson1

1University of Birmingham, Birmingham, UK; 2AstraZeneca, Alderley Park, Cheshire, UK; 3University of Cambridge, Cambridge, UK.

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.