11β-Hydroxysteroid Dehydrogenase Type 1 Regulates Glucocorticoid-Induced Insulin Resistance in Skeletal Muscle

  1. Stuart A. Morgan1,
  2. Mark Sherlock1,
  3. Laura L. Gathercole1,
  4. Gareth G. Lavery1,
  5. Carol Lenaghan2,
  6. Iwona J. Bujalska1,
  7. David Laber2,
  8. Alice Yu2,
  9. Gemma Convey2,
  10. Rachel Mayers2,
  11. Krisztina Hegyi3,
  12. Jaswinder K. Sethi3,
  13. Paul M. Stewart1,
  14. David M. Smith2 and
  15. Jeremy W. Tomlinson1
  1. 1Centre for Endocrinology, Diabetes and Metabolism, Institute of Biomedical Research, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, U.K.;
  2. 2AstraZeneca Diabetes & Obesity Drug Discovery, Mereside, Alderley Park, Macclesfield, Cheshire, U.K.;
  3. 3Department of Clinical Biochemistry, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
  1. Corresponding author: Jeremy W. Tomlinson, j.w.tomlinson{at}bham.ac.uk.

Abstract

OBJECTIVE Glucocorticoid 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 (11β-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning glucocorticoid-induced insulin resistance in skeletal muscle and indentify how 11β-HSD1 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 glucocorticoids and selective 11β-HSD1 inhibition upon insulin signaling and action.

RESULTS Dexamethasone decreased insulin-stimulated glucose uptake, decreased IRS1 mRNA and protein expression, and increased inactivating pSer307 insulin receptor substrate (IRS)-1. 11β-HSD1 activity and expression were observed in human and rodent myotubes and muscle explants. Activity was predominantly oxo-reductase, generating active glucocorticoid. A1 (selective 11β-HSD1 inhibitor) abolished enzyme activity and blocked the increase in pSer307 IRS1 and reduction in total IRS1 protein after 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 pThr308 Akt/PKB increased. In addition, A2 decreased both lipogenic and lipolytic gene expression.

CONCLUSIONS Prereceptor facilitation of glucocorticoid 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 pThr308 Akt/PKB, and decreases lipogenic and lipolytic gene expression that may represent an important mechanism underpinning their insulin-sensitizing action.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received April 9, 2009.
    • Accepted July 16, 2009.
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This Article

  1. Diabetes vol. 58 no. 11 2506-2515
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