Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of Disease: selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 as a novel treatment for the metabolic syndrome

Nature Clinical Practice Endocrinology & Metabolism volume 1, pages 92–99 (2005)Cite this article

Abstract

The magnitude of the obesity and metabolic syndrome epidemic has heightened the need for the development of new and effective treatments. Although circulating cortisol concentrations are not elevated in obesity or in the metabolic syndrome, decreasing the tissue-specific generation of cortisol through inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been postulated as a therapeutic strategy. Observations in cohorts of obese patients, in comparison with those with type 2 diabetes, have suggested that the ability to decrease tissue-specific cortisol production might represent a protective mechanism to improve insulin sensitivity and prevent diabetes. In rodents, pharmacologic exploitation of this mechanism, through the development of inhibitors selective for 11β-HSD1 (in preference to the type 2 isoform), dramatically improves insulin sensitivity. Here we review the published data and the rationale for treatment in humans, as well as discussing potential problems and adverse effects of future selective 11β-HSD1 inhibitors.

Key Points

  • Isoenzymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) are tissue-specific regulators of cortisol metabolism

  • Nonselective 11β-HSD inhibitors cannot be used therapeutically because of systemic effects

  • Selective 11β-HSD1 inhibitors are effective in improving insulin sensitivity in rodents

  • Clinical trials are needed to test 11β-HSD1 inhibitors as therapy for type 2 diabetes and the metabolic syndrome

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cortisol generation within the endoplasmic reticulum lumen is mediated by the reductase activity (cortisone to cortisol) of 11β-hydroxysteroid dehydrogenase type 1
Figure 2: With increasing fat mass in simple obesity, the reductase activity of 11β-hydroxysteroid dehydrogenase type 1 decreases, preserving insulin sensitivity

Similar content being viewed by others

References

  1. World Health Organization [http://www.who.int/en/]

  2. Calle EE et al. (1999) Body-mass index and mortality in a prospective cohort of US adults. N Engl J Med 341: 1097–1105

    Article  CAS  Google Scholar 

  3. Hebert PR et al. (1997) Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA 278: 313–321

    Article  CAS  Google Scholar 

  4. Li Z et al. (2005) Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med 142: 532–546

    Article  CAS  Google Scholar 

  5. Van Gaal LF et al. (2005) Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365: 1389–1397

    Article  CAS  Google Scholar 

  6. Batterham RL et al. (2003) Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 349: 941–948

    Article  CAS  Google Scholar 

  7. Fraser R et al. (1999) Cortisol effects on body mass, blood pressure, and cholesterol in the general population. Hypertension 33: 1364–1368

    Article  CAS  Google Scholar 

  8. White PC et al. (1997) 11β-hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess. Endocr Rev 18: 135–156

    CAS  PubMed  Google Scholar 

  9. Odermatt A et al. (1999) The N-terminal anchor sequences of 11β-hydroxysteroid dehydrogenases determine their orientation in the endoplasmic reticulum membrane. J Biol Chem 274: 28762–28770

    Article  CAS  Google Scholar 

  10. Agarwal AK et al. (1990) Expression of 11β-hydroxysteroid dehydrogenase using recombinant vaccinia virus. Mol Endocrinol 4: 1827–1832

    Article  CAS  Google Scholar 

  11. Kotelevtsev Y et al. (1997) 11β-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. Proc Natl Acad Sci USA 94: 14924–14929

    Article  CAS  Google Scholar 

  12. Bujalska IJ et al. (2002) A switch in dehydrogenase to reductase activity of 11β-hydroxysteroid dehydrogenase type 1 upon differentiation of human omental adipose stromal cells. J Clin Endocrinol Metab 87: 1205–1210

    CAS  PubMed  Google Scholar 

  13. Masuzaki H et al. (2001) A transgenic model of visceral obesity and the metabolic syndrome. Science 294: 2166–2170

    Article  CAS  Google Scholar 

  14. Bujalska IJ et al. (1997) Does central obesity reflect “Cushing's disease of the omentum”? Lancet 349: 1210–1213

    Article  CAS  Google Scholar 

  15. Stewart PM et al. (1999) Cortisol metabolism in human obesity: impaired cortisone–cortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab 84: 1022–1027

    CAS  PubMed  Google Scholar 

  16. Rask E et al. (2001) Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab 86: 1418–1421

    Article  CAS  Google Scholar 

  17. Rask E et al. (2002) Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11β-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab 87: 3330–3336

    CAS  PubMed  Google Scholar 

  18. Valsamakis G et al. (2004) 11β-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus. J Clin Endocrinol Metab 89: 4755–4761

    Article  CAS  Google Scholar 

  19. Westerbacka J et al. (2003) Body fat distribution and cortisol metabolism in healthy men: enhanced 5β-reductase and lower cortisol/cortisone metabolite ratios in men with fatty liver. J Clin Endocrinol Metab 88: 4924–4931

    Article  CAS  Google Scholar 

  20. Sandeep TC et al. (2005) Increased in vivo regeneration of cortisol in adipose tissue in human obesity and effects of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor carbenoxolone. Diabetes 54: 872–879

    Article  CAS  Google Scholar 

  21. Tomlinson JW et al. (2002) Expression of 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue is not increased in human obesity. J Clin Endocrinol Metab 87: 5630–5635

    Article  CAS  Google Scholar 

  22. Wake DJ et al. (2003) Local and systemic impact of transcriptional up-regulation of 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue in human obesity. J Clin Endocrinol Metab 88: 3983–3988

    Article  CAS  Google Scholar 

  23. Paulmyer-Lacroix O et al. (2002) Expression of the mRNA coding for 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue from obese patients: an in situ hybridization study. J Clin Endocrinol Metab 87: 2701–2705

    CAS  PubMed  Google Scholar 

  24. Lindsay RS et al. (2003) Subcutaneous adipose 11β-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians. J Clin Endocrinol Metab 88: 2738–2744

    Article  CAS  Google Scholar 

  25. Kannisto K et al. (2004) Overexpression of 11β-hydroxysteroid dehydrogenase-1 in adipose tissue is associated with acquired obesity and features of insulin resistance: studies in young adult monozygotic twins. J Clin Endocrinol Metab 89: 4414–4421

    Article  CAS  Google Scholar 

  26. Drake AJ et al. (2005) Reduced adipose glucocorticoid reactivation and increased hepatic glucocorticoid clearance as an early adaptation to high-fat feeding in Wistar rats. Endocrinology 146: 913–919

    Article  CAS  Google Scholar 

  27. Morton NM et al. (2004) Down-regulation of adipose 11β-hydroxysteroid dehydrogenase type 1 by high-fat feeding in mice: a potential adaptive mechanism counteracting metabolic disease. Endocrinology 145: 2707–2712

    Article  CAS  Google Scholar 

  28. Liu Y et al. (2003) Leptin activation of corticosterone production in hepatocytes may contribute to the reversal of obesity and hyperglycemia in leptin-deficient ob/ob mice. Diabetes 52: 1409–1416

    Article  CAS  Google Scholar 

  29. Andrew R et al. (2002) Distinguishing the activities of 11β-hydroxysteroid dehydrogenases in vivo using isotopically labeled cortisol. J Clin Endocrinol Metab 87: 277–285

    CAS  PubMed  Google Scholar 

  30. Basu R et al. (2004) Splanchnic cortisol production occurs in humans: evidence for conversion of cortisone to cortisol via the 11-β hydroxysteroid dehydrogenase (11beta-hsd) type 1 pathway. Diabetes 53: 2051–2059

    Article  CAS  Google Scholar 

  31. Andrew R et al. (2005) The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans. Diabetes 54: 1364–1370

    Article  CAS  Google Scholar 

  32. Basu R et al. (2005) Obesity and type 2 diabetes do not alter splanchnic cortisol production in humans. J Clin Endocrinol Metab 90: 3919–3926

    Article  CAS  Google Scholar 

  33. Kerstens MN et al. (2000) Lack of relationship between 11β-hydroxysteroid dehydrogenase setpoint and insulin sensitivity in the basal state and after 24 h of insulin infusion in healthy subjects and type 2 diabetic patients. Clin Endocrinol (Oxf) 52: 403–411

    Article  CAS  Google Scholar 

  34. Diederich S et al. (2000) In the search for specific inhibitors of human 11β-hydroxysteroid-dehydrogenases (11β-HSDs): chenodeoxycholic acid selectively inhibits 11β-HSD-I. Eur J Endocrinol 142: 200–207

    Article  CAS  Google Scholar 

  35. Yang K and Yu M (1994) Evidence for distinct isoforms of 11β-hydroxysteroid dehydrogenase in the ovine liver and kidney. J Steroid Biochem Mol Biol 49: 245–250

    Article  CAS  Google Scholar 

  36. Walker BR et al. (1995) Carbenoxolone increases hepatic insulin sensitivity in man: a novel role for 11-oxosteroid reductase in enhancing glucocorticoid receptor activation. J Clin Endocrinol Metab 80: 3155–3159

    CAS  PubMed  Google Scholar 

  37. Andrews RC et al. (2003) Effects of the 11 β-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes. J Clin Endocrinol Metab 88: 285–291

    Article  CAS  Google Scholar 

  38. Maser E and Bannenberg G (1994) 11β-hydroxysteroid dehydrogenase mediates reductive metabolism of xenobiotic carbonyl compounds. Biochem Pharmacol 47: 1805–1812

    Article  CAS  Google Scholar 

  39. Szotakova B et al. (2000) Reduction of the potential anticancer drug oracin in the rat liver in-vitro. J Pharm Pharmacol 52: 495–500

    Article  CAS  Google Scholar 

  40. Hult M et al. (2001) Novel enzymological profiles of human 11β-hydroxysteroid dehydrogenase type 1. Chem Biol Interact 130–132: 805–814

    Article  Google Scholar 

  41. Oppermann UC and Maser E (2000) Molecular and structural aspects of xenobiotic carbonyl metabolizing enzymes. Role of reductases and dehydrogenases in xenobiotic phase I reactions. Toxicology 144: 71–81

    Article  CAS  Google Scholar 

  42. Bannenberg G et al. (2003) 11β-hydroxysteroid dehydrogenase type 1: tissue-specific expression and reductive metabolism of some anti-insect agent azole analogues of metyrapone. Chem Biol Interact 143–144: 449–457

    Article  Google Scholar 

  43. Maser E (1998) 11β-hydroxysteroid dehydrogenase responsible for carbonyl reduction of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in mouse lung microsomes. Cancer Res 58: 2996–3003

    CAS  PubMed  Google Scholar 

  44. Finckh C et al. (2001) Expression and NNK reducing activities of carbonyl reductase and 11β-hydroxysteroid dehydrogenase type 1 in human lung. Chem Biol Interact 130–132: 761–773

    Article  Google Scholar 

  45. Monder C and White PC (1993) 11β-hydroxysteroid dehydrogenase. Vitam Horm 47: 187–271

    Article  CAS  Google Scholar 

  46. Morris DJ et al. (2004) Effect of chenodeoxycholic acid on 11β-hydroxysteroid dehydrogenase in various target tissues. Metabolism 53: 811–816

    Article  CAS  Google Scholar 

  47. Shimoyama Y et al. (2003) Effects of glycyrrhetinic acid derivatives on hepatic and renal 11β-hydroxysteroid dehydrogenase activities in rats. J Pharm Pharmacol 55: 811–817

    Article  CAS  Google Scholar 

  48. Hult M et al. (1998) Selective inhibition of human type 1 11β-hydroxysteroid dehydrogenase by synthetic steroids and xenobiotics. FEBS Lett 441: 25–28

    Article  CAS  Google Scholar 

  49. Schweizer RA et al. (2003) A rapid screening assay for inhibitors of 11β-hydroxysteroid dehydrogenases (11beta-HSD): flavanone selectively inhibits 11β-HSD1 reductase activity. Mol Cell Endocrinol 212: 41–49

    Article  CAS  Google Scholar 

  50. Thieringer R et al. (2004) A novel non-steroidal inhibitor of 11β-hydroxysteroid dehydrogenase type 1 improves features of metabolic syndrome in murine disease models [abstract]. Endocr Abstr 7: P47

    Google Scholar 

  51. Barf T et al. (2002) Arylsulfonamidothiazoles as a new class of potential antidiabetic drugs. Discovery of potent and selective inhibitors of the 11β-hydroxysteroid dehydrogenase type 1. J Med Chem 45: 3813–3815

    Article  CAS  Google Scholar 

  52. Koch MA et al. (2004) Compound library development guided by protein structure similarity clustering and natural product structure. Proc Natl Acad Sci USA 101: 16721–16726

    Article  CAS  Google Scholar 

  53. Alberts P et al. (2002) Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycemic mice. Diabetologia 45: 1528–1532

    Article  CAS  Google Scholar 

  54. Alberts P et al. (2003) Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains. Endocrinology 144: 4755–4762

    Article  CAS  Google Scholar 

  55. Davani B et al. (2000) Type 1 11β-hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets. J Biol Chem 275: 34841–34844

    Article  CAS  Google Scholar 

  56. Davani B et al. (2004) Aged transgenic mice with increased glucocorticoid sensitivity in pancreatic β-cells develop diabetes. Diabetes 53 (Suppl 1): S51–S59

    Article  CAS  Google Scholar 

  57. Draper N et al. (2003) Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. Nat Genet 34: 434–439

    Article  CAS  Google Scholar 

  58. Jamieson PM et al. (1995) 11β-hydroxysteroid dehydrogenase is an exclusive 11β- reductase in primary cultures of rat hepatocytes: effect of physicochemical and hormonal manipulations. Endocrinology 136: 4754–4761

    Article  CAS  Google Scholar 

  59. Tomlinson JW et al. (2004) 11β-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev 25: 831–866

    Article  CAS  Google Scholar 

  60. Bujalska IJ et al. (2005) Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11β-hydroxysteroid dehydrogenase type 1. J Mol Endocrinol 34: 675–684

    Article  CAS  Google Scholar 

  61. Atanasov AG et al. (2004) Hexose-6-phosphate dehydrogenase determines the reaction direction of 11β-hydroxysteroid dehydrogenase type 1 as an oxoreductase. FEBS Lett 571: 129–133

    Article  CAS  Google Scholar 

  62. Banhegyi G et al. (2004) Cooperativity between 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase in the lumen of the endoplasmic reticulum. J Biol Chem 279: 27017–27021

    Article  CAS  Google Scholar 

  63. Cooper MS et al. (2000) Expression and functional consequences of 11β-hydroxysteroid dehydrogenase activity in human bone. Bone 27: 375–381

    Article  CAS  Google Scholar 

  64. Stokes J et al. (2000) Distribution of glucocorticoid and mineralocorticoid receptors and 11β-hydroxysteroid dehydrogenases in human and rat ocular tissues. Invest Ophthalmol Vis Sci 41: 1629–1638

    CAS  PubMed  Google Scholar 

  65. Rauz S et al. (2001) Expression and putative role of 11β-hydroxysteroid dehydrogenase isozymes within the human eye. Invest Ophthalmol Vis Sci 42: 2037–2042

    CAS  PubMed  Google Scholar 

  66. Sandeep TC et al. (2004) 11β-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics. Proc Natl Acad Sci USA 101: 6734–6739

    Article  CAS  Google Scholar 

  67. Rauz S et al. (2003) Inhibition of 11β-hydroxysteroid dehydrogenase type 1 lowers intraocular pressure in patients with ocular hypertension. QJM 96: 481–490

    Article  CAS  Google Scholar 

  68. Yau JL et al. (2001) Lack of tissue glucocorticoid reactivation in 11β-hydroxysteroid dehydrogenase type 1 knockout mice ameliorates age-related learning impairments. Proc Natl Acad Sci USA 98: 4716–4721

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Jeremy W Tomlinson & Paul M Stewart

Authors
  1. Jeremy W Tomlinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul M Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul M Stewart.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tomlinson, J., Stewart, P. Mechanisms of Disease: selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 as a novel treatment for the metabolic syndrome. Nat Rev Endocrinol 1, 92–99 (2005). https://doi.org/10.1038/ncpendmet0023

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpendmet0023

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing