Skip to main content

Advertisement

SpringerLink
Log in

Is metabolic syndrome a mild form of Cushing’s syndrome?

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

Abstract

The Metabolic Syndrome is a diagnosis of increasing prevalence that is noted to share multiple clinical features with Cushing’s syndrome. Several studies suggest abnormalities in the Hypothalamic-Pituitary-Adrenal axis to be associated with this disease and tissue-specific hypercortisolemia is being investigated as a possible contributing factor. More research is needed to explore the relation between cortisol and the metabolic syndrome which, if confirmed, will have major therapeutic and public health implications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kolovou GD, Anagnostopoulou KK, Salpea KD, Mikhailidis DP. The prevalence of metabolic syndrome in various populations. Am J Med Sci. 2007;333(6):362–71.

    Article  PubMed  Google Scholar 

  2. Bertagna X, Guignat L, Groussin L, Bertherat J. Cushing’s disease. Best practice & research. 2009;23(5):607–23.

    CAS  Google Scholar 

  3. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). Jama 2001;285(19):2486–97.

    Google Scholar 

  4. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. Jama. 2002;288(21):2709–16.

    Article  PubMed  Google Scholar 

  5. Fonseca VA. The metabolic syndrome, hyperlipidemia, and insulin resistance. Clin Cornerstone. 2005;7(2–3):61–72.

    Article  PubMed  Google Scholar 

  6. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15(7):539–53.

    Article  CAS  PubMed  Google Scholar 

  7. Grundy SM, Brewer Jr HB, Cleeman JI, Smith Jr SC, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Arterioscler Thromb Vasc Biol. 2004;24(2):e13–8.

    Article  CAS  PubMed  Google Scholar 

  8. Findling JW, Raff H. Screening and diagnosis of Cushing’s syndrome. Endocrinol Metab Clin N Am. 2005;34(2):385–402. ix–x.

    Article  Google Scholar 

  9. Raff H, Findling JW. A physiologic approach to diagnosis of the Cushing syndrome. Ann Intern Med. 2003;138(12):980–91.

    PubMed  Google Scholar 

  10. Findling JW, Raff H. Diagnosis and differential diagnosis of Cushing’s syndrome. Endocrinol Metab Clin North Am. 2001;30(3):729–47.

    Article  CAS  PubMed  Google Scholar 

  11. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526–40.

    Article  CAS  PubMed  Google Scholar 

  12. Terzolo M, Bovio S, Pia A, et al. Subclinical Cushing’s syndrome. Arq Bras Endocrinol Metabol. 2007;51(8):1272–9.

    PubMed  Google Scholar 

  13. Young Jr WF. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med. 2007;356(6):601–10.

    Article  CAS  PubMed  Google Scholar 

  14. Peppa M, Boutati E, Koliaki C, et al. Insulin resistance and metabolic syndrome in patients with nonfunctioning adrenal incidentalomas: a cause-effect relationship? Metabolism: clinical and experimental 2010.

  15. Terzolo M, Osella G, Ali A, et al. Subclinical Cushing’s syndrome in adrenal incidentaloma. Clin Endocrinol. 1998;48(1):89–97.

    Article  CAS  Google Scholar 

  16. Anagnostis P, Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. Clinical review: the pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J Clin Endocrinol Metab. 2009;94(8):2692–701.

    Article  CAS  PubMed  Google Scholar 

  17. Marin P, Darin N, Amemiya T, Andersson B, Jern S, Bjorntorp P. Cortisol secretion in relation to body fat distribution in obese premenopausal women. Metab, Clin Exp. 1992;41(8):882–6.

    CAS  Google Scholar 

  18. Rosmond R, Dallman MF, Bjorntorp P. Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities. J Clin Endocrinol Metab. 1998;83(6):1853–9.

    Article  CAS  PubMed  Google Scholar 

  19. Pasquali R, Ambrosi B, Armanini D, et al. Cortisol and ACTH response to oral dexamethasone in obesity and effects of sex, body fat distribution, and dexamethasone concentrations: a dose-response study. J Clin Endocrinol Metab. 2002;87(1):166–75.

    Article  CAS  PubMed  Google Scholar 

  20. Duclos M, Marquez Pereira P, Barat P, Gatta B, Roger P. Increased cortisol bioavailability, abdominal obesity, and the metabolic syndrome in obese women. Obes Res. 2005;13(7):1157–66.

    Article  CAS  PubMed  Google Scholar 

  21. Raff H. Utility of salivary cortisol measurements in Cushing’s syndrome and adrenal insufficiency. J Clin Endocrinol Metab. 2009;94(10):3647–55.

    Article  CAS  PubMed  Google Scholar 

  22. Weaver JU, Kopelman PG, McLoughlin L, Forsling ML, Grossman A. Hyperactivity of the hypothalamo-pituitary-adrenal axis in obesity: a study of ACTH, AVP, beta-lipotrophin and cortisol responses to insulin-induced hypoglycaemia. Clin Endocrinol. 1993;39(3):345–50.

    Article  CAS  Google Scholar 

  23. Morton NM. Obesity and corticosteroids: 11beta-hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease. Mol Cell Endocrinol. 2010;316(2):154–64.

    Article  CAS  PubMed  Google Scholar 

  24. Staab CA, Maser E. 11beta-Hydroxysteroid dehydrogenase type 1 is an important regulator at the interface of obesity and inflammation. J Steroid Biochem Mol Biol;119(1–2):56–72.

  25. Ferrari P, Lovati E, Frey FJ. The role of the 11beta-hydroxysteroid dehydrogenase type 2 in human hypertension. J Hypertens. 2000;18(3):241–8.

    Article  CAS  PubMed  Google Scholar 

  26. Inada M, Iwasaki K, Imai C, Hashimoto S. Two elderly patients with mineralocorticoid excess due to 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) impairment. Internal medicine (Tokyo, Japan). 2008;47(7):631–6.

    Google Scholar 

  27. Masuzaki H, Paterson J, Shinyama H, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science (New York, NY). 2001;294(5549):2166–70.

    CAS  Google Scholar 

  28. Baudrand R, Carvajal CA, Riquelme A, et al. Overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in hepatic and visceral adipose tissue is associated with metabolic disorders in morbidly obese patients. Obes Surg;20(1):77-83.

  29. Munoz R, Carvajal C, Escalona A, et al. 11beta-hydroxysteroid dehydrogenase type 1 is overexpressed in subcutaneous adipose tissue of morbidly obese patients. Obes Surg. 2009;19(6):764–70.

    Article  PubMed  Google Scholar 

  30. Paulsen SK, Pedersen SB, Fisker S, Richelsen B. 11Beta-HSD type 1 expression in human adipose tissue: impact of gender, obesity, and fat localization. Obesity (Silver Spring, Md). 2007;15(8):1954–60.

    Article  CAS  Google Scholar 

  31. Desbriere R, Vuaroqueaux V, Achard V, et al. 11beta-hydroxysteroid dehydrogenase type 1 mRNA is increased in both visceral and subcutaneous adipose tissue of obese patients. Obesity (Silver Spring, Md). 2006;14(5):794–8.

    Article  CAS  Google Scholar 

  32. Whorwood CB, Donovan SJ, Flanagan D, Phillips DI, Byrne CD. Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome. Diabetes. 2002;51(4):1066–75.

    Article  CAS  PubMed  Google Scholar 

  33. Mattsson C, Reynolds RM, Simonyte K, Olsson T, Walker BR. Combined receptor antagonist stimulation of the hypothalamic-pituitary-adrenal axis test identifies impaired negative feedback sensitivity to cortisol in obese men. J Clin Endocrinol Metab. 2009;94(4):1347–52.

    Article  CAS  PubMed  Google Scholar 

  34. Cooper MS, Stewart PM. 11Beta-hydroxysteroid dehydrogenase type 1 and its role in the hypothalamus-pituitary-adrenal axis, metabolic syndrome, and inflammation. J Clin Endocrinol Metab. 2009;94(12):4645–54.

    Article  CAS  PubMed  Google Scholar 

  35. Paterson JM, Morton NM, Fievet C, et al. Metabolic syndrome without obesity: hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in transgenic mice. Proc Natl Acad Sci USA. 2004;101(18):7088–93.

    Article  CAS  PubMed  Google Scholar 

  36. Michailidou Z, Jensen MD, Dumesic DA, et al. Omental 11beta-hydroxysteroid dehydrogenase 1 correlates with fat cell size independently of obesity. Obesity (Silver Spring, Md). 2007;15(5):1155–63.

    Article  CAS  Google Scholar 

  37. Kannisto K, Pietilainen KH, Ehrenborg E, et al. Overexpression of 11beta-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. 2004;89(9):4414–21.

    Article  CAS  PubMed  Google Scholar 

  38. Tomlinson JW, Sinha B, Bujalska I, Hewison M, Stewart PM. Expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue is not increased in human obesity. J Clin Endocrinol Metab. 2002;87(12):5630–5.

    Article  CAS  PubMed  Google Scholar 

  39. Basu R, Basu A, Grudzien M, et al. Liver is the site of splanchnic cortisol production in obese nondiabetic humans. Diabetes. 2009;58(1):39–45.

    Article  CAS  PubMed  Google Scholar 

  40. Engeli S, Bohnke J, Feldpausch M, et al. Regulation of 11beta-HSD genes in human adipose tissue: influence of central obesity and weight loss. Obes Res. 2004;12(1):9–17.

    Article  CAS  PubMed  Google Scholar 

  41. Andersson T, Simonyte K, Andrew R, et al. Tissue-specific increases in 11beta-hydroxysteroid dehydrogenase type 1 in normal weight postmenopausal women. PLoS ONE. 2009;4(12):e8475.

    Article  PubMed  Google Scholar 

  42. Wilson EA, Jawad MJ, Donaldson ES. Corticosteroid-binding globulin as a biologic assay for endogenous estrogen in patients with and without endometrial carcinoma. Am J Obstet Gynecol. 1981;139(6):661–4.

    CAS  PubMed  Google Scholar 

  43. Dieudonne MN, Sammari A, Dos Santos E, Leneveu MC, Giudicelli Y, Pecquery R. Sex steroids and leptin regulate 11beta-hydroxysteroid dehydrogenase I and P450 aromatase expressions in human preadipocytes: sex specificities. J Steroid Biochem Mol Biol. 2006;99(4–5):189–96.

    Article  CAS  PubMed  Google Scholar 

  44. Simonyte K, Olsson T, Naslund I, et al. Weight loss after gastric bypass surgery in women is followed by a metabolically favorable decrease in 11beta-hydroxysteroid dehydrogenase 1 expression in subcutaneous adipose tissue. J Clin Endocrinol Metab. 2010;95(7):3527–31.

    Article  CAS  PubMed  Google Scholar 

  45. Dovio A, Roveda E, Sciolla C, et al. Intense physical exercise increases systemic 11beta-hydroxysteroid dehydrogenase type 1 activity in healthy adult subjects. Eur J Appl Physiol. 2010;108(4):681–7.

    Article  CAS  PubMed  Google Scholar 

  46. Michailidou Z, Coll AP, Kenyon CJ, et al. Peripheral mechanisms contributing to the glucocorticoid hypersensitivity in proopiomelanocortin null mice treated with corticosterone. J Endocrinol. 2007;194(1):161–70.

    Article  CAS  PubMed  Google Scholar 

  47. Huizenga NA, Koper JW, De Lange P, et al. A polymorphism in the glucocorticoid receptor gene may be associated with and increased sensitivity to glucocorticoids in vivo. J Clin Endocrinol Metab. 1998;83(1):144–51.

    Article  CAS  PubMed  Google Scholar 

  48. Dobson MG, Redfern CP, Unwin N, Weaver JU. The N363S polymorphism of the glucocorticoid receptor: potential contribution to central obesity in men and lack of association with other risk factors for coronary heart disease and diabetes mellitus. J Clin Endocrinol Metab. 2001;86(5):2270–4.

    Article  CAS  PubMed  Google Scholar 

  49. Stewart PM. Is subclinical Cushing’s syndrome an entity or a statistical fallout from diagnostic testing? Consensus surrounding the diagnosis is required before optimal treatment can be defined. J Clin Endocrinol Metab. 2010;95(6):2618–20.

    Article  CAS  PubMed  Google Scholar 

  50. Walker BR. Cortisol—cause and cure for metabolic syndrome? Diabet Med. 2006;23(12):1281–8.

    Article  CAS  PubMed  Google Scholar 

  51. Mai K, Andres J, Bobbert T, et al. Rosiglitazone decreases 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue. Clin Endocrinol. 2007;67(3):419–25.

    Article  CAS  Google Scholar 

  52. Iwasaki Y, Takayasu S, Nishiyama M, et al. Is the metabolic syndrome an intracellular Cushing state? Effects of multiple humoral factors on the transcriptional activity of the hepatic glucocorticoid-activating enzyme (11beta-hydroxysteroid dehydrogenase type 1) gene. Mol Cell Endocrinol. 2008;285(1–2):10–8.

    Article  CAS  PubMed  Google Scholar 

  53. Ye YL, Zhou Z, Zou HJ, et al. Discovery of novel dual functional agent as PPARgamma agonist and 11beta-HSD1 inhibitor for the treatment of diabetes. Bioorg Med Chem. 2009;17(15):5722–32.

    Article  CAS  PubMed  Google Scholar 

  54. Lloyd DJ, Helmering J, Cordover D, et al. Antidiabetic effects of 11beta-HSD1 inhibition in a mouse model of combined diabetes, dyslipidaemia and atherosclerosis. Diab Obes Metab. 2009;11(7):688–99.

    Article  CAS  Google Scholar 

  55. Berthiaume M, Laplante M, Festuccia WT, Berger JP, Thieringer R, Deshaies Y. Additive action of 11beta-HSD1 inhibition and PPAR-gamma agonism on hepatic steatosis and triglyceridemia in diet-induced obese rats. Int J Obes (2005). 2009;33(5):601–4.

    Article  CAS  Google Scholar 

  56. Sundbom M, Kaiser C, Bjorkstrand E, et al. Inhibition of 11betaHSD1 with the S-phenylethylaminothiazolone BVT116429 increases adiponectin concentrations and improves glucose homeostasis in diabetic KKAy mice. BMC Pharmacol. 2008;8:3.

    Article  PubMed  Google Scholar 

  57. Andrews RC, Rooyackers O, Walker BR. Effects of the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes. J Clin Endocrinol Metab. 2003;88(1):285–91.

    Article  CAS  PubMed  Google Scholar 

  58. Courtney R, Stewart PM, Toh M, Ndongo MN, Calle RA, Hirshberg B. Modulation of 11beta-hydroxysteroid dehydrogenase (11betaHSD) activity biomarkers and pharmacokinetics of PF-00915275, a selective 11betaHSD1 inhibitor. J Clin Endocrinol Metab. 2008;93(2):550–6.

    Article  CAS  PubMed  Google Scholar 

  59. Tiwari A. INCB-13739, an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor for the treatment of type 2 diabetes. IDrugs;13(4):266–75.

Download references

Author information

Authors and Affiliations

  1. Division of Clinical and Molecular Endocrinology, Case Western Reserve University, Case Medical Center, 11100 Euclid Ave, Cleveland, OH, 44106, USA

    Armand Krikorian & Mehreen Khan

Authors
  1. Armand Krikorian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mehreen Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Armand Krikorian.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krikorian, A., Khan, M. Is metabolic syndrome a mild form of Cushing’s syndrome?. Rev Endocr Metab Disord 11, 141–145 (2010). https://doi.org/10.1007/s11154-010-9142-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11154-010-9142-4

Keywords

Search

Navigation