Abstract

Objective: Glucocorticoid (GC) excess is characterized by increased adiposity, skeletal myopathy and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) converts cortisone (11-dehydrocorticosterone, 11DHC in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning GC-induced insulin resistance in skeletal muscle and indentify how 11βHSD1 inhibitors improve insulin sensitivity.

Research Design and Methods: Rodent and human cell cultures, whole tissue explants and animal models were used to determine the impact of GCs and selective 11β-HSD1 inhibition upon insulin signalling and action.

Results: Dexamethasone (Dex), decreased insulin-stimulated glucose uptake, decreased IRS1 mRNA and protein expression and increased inactivating pSer307 IRS1. 11β-HSD1 activity and expression were observed in human and rodent myotubes and muscle explants. Activity was predominantly oxo-reductase, generating active GC. A1 (selective 11β-HSD1 inhibitor) abolished enzyme activity and blocked the increase in pSer307 IRS1 and reduction in total IRS1 protein following treatment with 11DHC, but not corticosterone. In C57Bl6/J mice, the selective 11β-HSD1 inhibitor, A2, decreased fasting blood glucose levels and improved insulin sensitivity. In KK mice treated with A2, skeletal muscle pSer307 IRS1 decreased and pTh308 Akt/PKB increased. In addition, A2 decreased both lipogenic and lipolytic gene expression.

Conclusion: Pre-receptor facilitation of GC action via 11β-HSD1 increases pSer307 IRS1 and may be crucial in mediating insulin resistance in skeletal muscle. Selective 11β-HSD1 inhibition decreases pSer307 IRS1, increases pTh308 Akt/PKB and decreases lipogenic and lipolytic gene expression which may represent an important mechanism underpinning their insulin sensitizing action.