, Volume 41, Issue 3, pp 415–423

Glucose metabolism in patients with subclinical Cushing’s syndrome

  • Roberta Giordano
  • Federica Guaraldi
  • Rita Berardelli
  • Ioannis Karamouzis
  • Valentina D’Angelo
  • Elisa Marinazzo
  • Andreea Picu
  • Ezio Ghigo
  • Emanuela Arvat
Mini Review


This clinical review will summarize the available data regarding the effect of either physiological or increased glucocorticoid concentrations on glucose metabolism and insulin-sensitivity, in order to clarify the role, if any, of subclinical Cushing’s syndrome (SCS), a status of altered hypothalamic–pituitary–adrenal axis secretion in the absence of the classical signs or symptoms of overt cortisol excess, in patients with adrenal incidentalomas (AI) and diabetes mellitus type 2. Focusing on patients with SCS associated to AI, while there is convincing evidence in the literature that even a mild hyper cortisolemia is associated with alterations of glucose metabolism, evidence is insufficient to conclude that the simple correction of chronic, even mild, hypercortisolism can completely revert metabolic, mainly glycemic alterations. At the same time, considering the variability of the prevalence of Cushing’s syndrome in patients with diabetes mellitus type 2 reported in the literature, no agreement does exist whether screening for CS can be useful and recommended in those patients.


Glucose Insulin Diabetes mellitus HPA axis Subclinical Cushing’s syndrome 


  1. 1.
    M. Reincke, Subclinical Cushing’s syndrome. Endocrinol. Metab. Clin. North Am. 29, 47–56 (2000)CrossRefGoogle Scholar
  2. 2.
    M. Terzolo, G. Reimondo, S. Bovio, A. Angeli, Subclinical Cushing’s syndrome. Pituitary 7, 217–223 (2004)PubMedCrossRefGoogle Scholar
  3. 3.
    S. Tsagarakis, D. Vassiliadi, N. Thalassinos, Endogenous subclinical hypercortisolism: diagnostic uncertainties and clinical implications. J. Endocrinol. Invest. 29, 471–482 (2006)PubMedGoogle Scholar
  4. 4.
    I. Chiodini, Diagnosis and treatment of subclinical hypercortisolism. J. Clin. Endocrinol. Metab. 96, 1223–1236 (2011)PubMedCrossRefGoogle Scholar
  5. 5.
    L.K. Nieman, B.M. Biller, J.W. Findling, J. Newell-Price, M.O. Savage, P.M. Stewart, V.M. Montori, The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 93, 1526–1540 (2008)PubMedCrossRefGoogle Scholar
  6. 6.
    J.W. Funder, Glucocorticoid and mineralcorticoid receptors: biology and clinical relevance. Annu. Rev. Med. 48, 231–240 (1997)PubMedCrossRefGoogle Scholar
  7. 7.
    C.M. Bamberger, H.M. Schulte, G.P. Chrousos, Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr. Rev. 17, 245–261 (1996)PubMedGoogle Scholar
  8. 8.
    R.H. DeRijk, M. Schaaf, E.R. de Kloet, Glucocorticoid receptor variants: clinical implications. J. Steroid. Biochem. Mol. Biol. 81, 103–122 (2002)PubMedCrossRefGoogle Scholar
  9. 9.
    J.R. Seckl, 11beta-hydroxysteroid dehydrogenases: changing glucocorticoid action. Curr. Opin. Pharmacol. 4, 597–602 (2004)PubMedCrossRefGoogle Scholar
  10. 10.
    R.C. Andrews, B.R. Walker, Glucocorticoids and insulin resistance: old hormones, new targets. Clin. Sci. 96, 513–523 (1999)PubMedCrossRefGoogle Scholar
  11. 11.
    D.H. van Raalte, D.M. Ouwens, M. Diamant, Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options? Eur. J. Clin. Invest. 38, 81–93 (2009)CrossRefGoogle Scholar
  12. 12.
    M.F. Dallman, A.M. Strack, S.F. Akana, M.J. Bradbury, E.S. Hanson, K.A. Scribner, M. Smith, Feast and famine: critical role of glucocorticoids with insulin in daily energy fow. Front. Neuroendocrinol. 14, 303–347 (1993)PubMedCrossRefGoogle Scholar
  13. 13.
    D. Qi, B. Rodrigues, Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism. Am. J. Physiol. Endocrinol. Metab. 292, E654–E667 (2007)PubMedCrossRefGoogle Scholar
  14. 14.
    T. Lemberger, B. Staels, R. Saladin, B. Desvergne, J. Auwerx, W. Wahli, Regulation of the peroxisome proliferator-activated receptor alpha gene by glucocorticoids. J. Biol. Chem. 269, 24527–24530 (1994)PubMedGoogle Scholar
  15. 15.
    R. Patel, M. Patel, R. Tsai, V. Lin, A.L. Bookout, Y. Zhang, L. Magomedova, T. Li, J.F. Chan, C. Budd, D.J. Mangelsdorf, C.L. Cummins, LXRbeta is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice. J. Clin. Invest. 121, 431–441 (2011)PubMedCrossRefGoogle Scholar
  16. 16.
    F. Delaunay, A. Khan, A. Cintra, B. Davani, Z.C. Ling, A. Andersson, C.G. Ostenson, J. Gustafsson, S. Efendic, S. Okret, Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids. J. Clin. Invest. 100, 2094–2098 (1997)PubMedCrossRefGoogle Scholar
  17. 17.
    D.H. van Raalte, M. Brands, N.J. van der Zijl, M.H. Muskiet, P.J.W. Pouwels, M.T. Ackermans, H.P. Sauerwein, M.J. Serlie, M. Diamant, Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism in healthy humans: a randomised controlled trial. Diabetologia 54, 2103–2112 (2011)PubMedCrossRefGoogle Scholar
  18. 18.
    M. Stubbs, D.A. York, Central glucocorticoid regulation of parasympathetic drive to pancreatic B-cells in the obese fa/fa rat. Int. J. Obes. 15, 547–553 (1991)PubMedGoogle Scholar
  19. 19.
    R. Pivonello, M. De Leo, P. Vitale, A. Cozzolino, C. Simeoli, M.C. De Martino, G. Lombardi, A. Colao, Pathophysiology of diabetes mellitus in Cushing’s syndrome. Neuroendocrinology 92(Suppl 1), 77–81 (2010)PubMedCrossRefGoogle Scholar
  20. 20.
    G. Mazziotti, C. Gazzaruso, A. Giustina, Diabetes in Cushing syndrome: basic and clinical aspects. Trends Endocrinol. Metab. 17, 144–149 (2011)CrossRefGoogle Scholar
  21. 21.
    G.T. Griffing, Editorial A-I-D-S: the new endocrine epidemic. J. Clin. Endocrinol. Metab. 79, 1530–1531 (1994)PubMedCrossRefGoogle Scholar
  22. 22.
    R.T. Kloos, M.D. Gross, I.R. Francis, M. Korobkin, B. Shapiro, Incidentally discovered adrenal masses. Endocr. Rev. 16, 460–484 (1995)PubMedGoogle Scholar
  23. 23.
    R.M. Chidiac, D.C. Aron, Incidentaloma a disease of modern technology. Endocrinol. Metab. Clin. North Am. 26, 233–253 (1997)PubMedCrossRefGoogle Scholar
  24. 24.
    M.M. Grumbach, B.M.K. Biller, G.D. Braunstein, K.K. Campbell, J.A. Carney, P.A. Godley, E.L. Harris, J.K.T. Lee, Y.C. Oertel, M.C. Posner, J.A. Schlechte, H.S. Wieand, Management of the clinically inapparent adrenal mass (‘Incidentaloma’). Ann. Intern. Med. 138, 424–429 (2003)PubMedGoogle Scholar
  25. 25.
    G. Mansmann, J. Lau, E. Balk, M. Rothberg, Y. Miyachi, S.R. Bornstein, The clinically inapparent adrenal mass: update in diagnosis and management. Endocr. Rev. 25, 309–340 (2004)PubMedCrossRefGoogle Scholar
  26. 26.
    W.F. Young Jr, Clinical practice. The incidentally discovered adrenal mass. N. Engl. J. Med. 356, 601–610 (2007)PubMedCrossRefGoogle Scholar
  27. 27.
    A. Tabarin, S. Bardet, J. Bertherat, B. Dupas, O. Chabre, E. Hamoir, F. Laurent, F. Tenenbaum, M. Cazalda, H. Lefebvre, N. Valli, V. Rohmer, Exploration and management of adrenal incidentalomas. French Society of Endocrinology Consensus. Ann. Endocrinol. 69, 487–500 (2008)CrossRefGoogle Scholar
  28. 28.
    L.K. Nieman, Approach to the patient with an adrenal incidentaloma. J. Clin. Endocrinol. Metab. 95, 4106–4113 (2010)PubMedCrossRefGoogle Scholar
  29. 29.
    M. Terzolo, A. Stigliano, I. Chiodini, P. Loli, L. Furlani, G. Arnaldi, G. Reimondo, A. Pia, V. Toscano, M. Zini, G. Borretta, E. Papini, P. Garofalo, B. Allolio, B. Dupas, F. Mantero, A. Tabarin, Italian Association of Clinical Endocrinologists. AME position statement on adrenal incidentaloma. Eur. J. Endocrinol. 164, 851–870 (2011)PubMedCrossRefGoogle Scholar
  30. 30.
    R. Rossi, L. Tauchmanova, A. Luciano, M. Di Martino, C. Battista, L. Del Viscovo, V. Nuzzo, G. Lombardi, Subclinical Cushing’s syndrome in patients with adrenal incidentaloma: clinical and biochemical features. J. Clin. Endocrinol. Metab. 85, 1440–1448 (2000)PubMedCrossRefGoogle Scholar
  31. 31.
    F. Mantero, M. Terzolo, G. Arnaldi, G. Osella, A.M. Masini, A. Alì, M. Giovagnetti, G. Opocher, A. Angeli, A survey on adrenal incidentaloma in Italy. J. Clin. Endocrinol. Metab. 85, 637–644 (2000)PubMedCrossRefGoogle Scholar
  32. 32.
    M. Terzolo, A. Pia, A. Alì, G. Osella, G. Reimondo, S. Bovio, F. Daffara, M. Procopio, P. Paccotti, G. Borretta, A. Angeli, Adrenal incidentaloma: a new cause of the metabolic syndrome? J. Clin. Endocrinol. Metab. 87, 998–1003 (2002)PubMedCrossRefGoogle Scholar
  33. 33.
    L. Tauchmanovà, R. Rossi, B. Biondi, M. Pulcrano, V. Nuzzo, E.A. Palmieri, S. Fazio, G. Lombardi, Patients with subclinical Cushing’s syndrome due to adrenal adenoma have increased cardiovascular risk. J. Clin. Endocrinol. Metab. 87, 4872–4878 (2002)PubMedCrossRefGoogle Scholar
  34. 34.
    M. Terzolo, S. Bovio, G. Reimondo, A. Pia, G. Osella, G. Borretta, A. Angeli, Subclinical Cushing’s syndrome in adrenal incidentalomas. Endocrinol. Metab. Clin. North. Am. 34, 423–439 (2005)PubMedCrossRefGoogle Scholar
  35. 35.
    G. Mazziotti, A. Angeli, J.P. Bilezikian, E. Canalis, A. Giustina, Glucocorticoid-induced osteoporosis: an update. Trends Endocrinol. Metab. 17, 144–149 (2006)PubMedCrossRefGoogle Scholar
  36. 36.
    R. Emral, A.R. Uysal, M. Asik, S. Gullu, D. Corapcioglu, V. Tonyukuk, G. Erdogan, Prevalence of subclinical Cushing’s syndrome in 70 patients with adrenal incidentaloma: clinical, biochemical and surgical outcomes. Endocr. J. 50, 399–408 (2003)PubMedCrossRefGoogle Scholar
  37. 37.
    V. Morelli, B. Masserini, A.S. Salcuni, C. Eller-Vainicher, C. Savoca, R. Viti, F. Coletti, G. Guglielmi, C. Battista, L. Iorio, P. Beck-Peccoz, B. Ambrosi, M. Arosio, A. Scillitani, I. Chiodini, Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects. Clin. Endocrinol. 73, 161–166 (2010)Google Scholar
  38. 38.
    G.P. Bernini, A. Moretti, C. Oriandini, M. Bardini, C. Taurino, A. Salvetti, Long-term morphological and hormonal follow-up in a single unit on 115 patients with adrenal incidentalomas. Br. J. Cancer 92, 1104–1109 (2005)PubMedCrossRefGoogle Scholar
  39. 39.
    M. Terzolo, S. Bovio, A. Pia, P.A. Conton, G. Reimondo, C. Dall’Asta, D. Bemporad, A. Angeli, G. Opocher, M. Mannelli, B. Ambrosi, F. Mantero, Midnight serum cortisol as a marker of increased cardiovascular risk in patients with a clinically inapparent adrenal adenoma. Eur. J. Endocrinol. 153, 307–315 (2005)PubMedCrossRefGoogle Scholar
  40. 40.
    M. Sereg, A. Szappanos, J. Toke, K. Karlinger, K. Feldman, E. Kaszper, I. Varga, E. Gláz, K. Rácz, M. Tóth, Atherosclerotic risk factors and complications in patients with non-functioning adrenal adenomas treated with or without adrenalectomy: a long-term follow-up study. Eur. J. Endocrinol. 160, 647–655 (2009)PubMedCrossRefGoogle Scholar
  41. 41.
    E. Vassilatou, A. Vryonidou, S. Michalopoulou, J. Manolis, J. Caratzas, C. Phenekos, I. Tzavara, Hormonal activity of adrenal incidentalomas: results from a long-term follow-up study. Clin. Endocrinol. 70, 674–679 (2009)CrossRefGoogle Scholar
  42. 42.
    R. Giordano, E. Marinazzo, R. Berardelli, A. Picu, M. Maccario, E. Ghigo, E. Arvat, Long-term morphological, hormonal, and clinical follow-up in a single unit on 118 patients with adrenal incidentalomas. Eur. J. Endocrinol. 162, 779–785 (2010)PubMedCrossRefGoogle Scholar
  43. 43.
    A. Comlekci, S. Yener, S. Ertilav, M. Secil, B. Akinci, T. Demir, L. Kebapcilar, F. Bayraktar, S. Yesil, S. Eraslan, Adrenal incidentaloma, clinical, metabolic, follow-up aspects: single centre experience. Endocrine 37, 40–46 (2010)PubMedCrossRefGoogle Scholar
  44. 44.
    M. Reincke, M. Fassnacht, S. Vath, P. Mora, B. Allolio, Adrenal incidentalomas: a manifestation of the metabolic syndrome? Endocr. Res. 22, 757–761 (1996)PubMedGoogle Scholar
  45. 45.
    G. Muscogiuri, G.P. Sorice, A. Prioletta, T. Mezza, C. Cipolla, E. Salomone, A. Giaccari, A. Pontecorvi, C.S. Della, The size of adrenal incidentalomas correlates with insulin resistance. Is there a cause-effect relationship? Clin. Endocrinol. 74, 300–305 (2011)CrossRefGoogle Scholar
  46. 46.
    S. Midorikawa, H. Sanada, S. Hashimoto, T. Suzuki, T. Watanabe, The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection. Clin. Endocrinol. 54, 797–804 (2001)CrossRefGoogle Scholar
  47. 47.
    G. Bernini, A. Moretti, P. Iacconi, P. Miccoli, R. Nami, B. Lucani, A. Salvetti, Anthropometric, haemodynamic, humoral and hormonal evaluation in patients with incidental adrenocortical adenomas before and after surgery. Eur. J. Endocrinol. 148, 213–219 (2003)PubMedCrossRefGoogle Scholar
  48. 48.
    Y. Erbil, E. Ademoglu, N. Ozbey, U. Barbaros, B.T. Yanik, A. Salmaslioglu, A. Bozbora, S. Ozarmagan, Evaluation of the cardiovascular risk in patients with subclinical Cushing syndrome before and after surgery. World J. Surg. 30, 1665–1671 (2006)PubMedCrossRefGoogle Scholar
  49. 49.
    I.C. Mitchell, R.J. Auchus, K. Juneja, A.Y. Chang, S.A. Holt, W.H. Snyder, F.E. Nwariaku, “Subclinical Cushing’s syndrome” is not subclinical: improvement after adrenalectomy in 9 patients. Surgery 142, 900–905 (2007)PubMedCrossRefGoogle Scholar
  50. 50.
    M. Tsuiki, A. Tanabe, S. Takagi, M. Naruse, K. Takano, Cardiovascular risks and their long-term clinical outcome in patients with subclinical Cushing’s syndrome. Endocr. J. 55, 737–745 (2008)PubMedCrossRefGoogle Scholar
  51. 51.
    A. Toniato, I. Merante-Boschin, G. Opocher, M.R. Pelizzo, F. Schiavi, E. Ballotta, Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study. Ann. Surg. 249, 388–391 (2009)PubMedCrossRefGoogle Scholar
  52. 52.
    I. Chiodini, V. Morelli, A.S. Salcuni, C. Eller-Vainicher, M. Torlontano, F. Coletti, L. Iorio, A. Cuttitta, A. Ambrosio, L. Vicentini, F. Pellegrini, M. Copetti, P. Beck-Peccoz, M. Arosio, B. Ambrosi, V. Trischitta, A. Scillitani, Beneficial metabolic effects of prompt surgical treatment in patients with an adrenal incidentaloma causing biochemical hypercortisolism. J. Clin. Endocrinol. Metab. 95, 2736–2745 (2010)PubMedCrossRefGoogle Scholar
  53. 53.
    M.A. Zeiger, G.B. Thompson, Q.Y. Duh, A.H. Hamrahian, P. Angelos, D. Elaraj, E. Fishman, J. Kharlip, The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas. Endocr. Pract. 15, 1–20 (2009)PubMedGoogle Scholar
  54. 54.
    D.A. Vassiliadi, G. Ntali, T. Stratigou, M. Adali, S. Tsagarakis, Aberrant cortisol responses to physiological stimuli in patients presenting with bilateral adrenal incidentalomas. Endocrine 40, 437–444 (2011)PubMedCrossRefGoogle Scholar
  55. 55.
    O.G. Cameron, B. Thomas, D. Tiongco, M. Hariharan, J.F. Greden, Hypercortisolism in diabetes mellitus. Diabetes Care 10, 662–664 (1987)PubMedGoogle Scholar
  56. 56.
    C. Tsigos, R.J. Young, A. White, Diabetic neuropathy is associated with increased activity of the hypothalamic-pituitary-adrenal axis. J. Clin. Endocrinol. Metab. 76, 554–558 (1993)PubMedCrossRefGoogle Scholar
  57. 57.
    M.S. Roy, A. Roy, W.T. Gallucci, B. Collier, K. Young, T.C. Kamilaris, G.P. Chrousos, The ovine corticotropin-releasing hormone-stimulation test in type I diabetic patients and controls: suggestion of mild chronic hypercortisolism. Metabolism 42, 696–700 (1993)PubMedCrossRefGoogle Scholar
  58. 58.
    G. Leibowitz, A. Tsur, S.D. Chayen, M. Salameh, I. Raz, E. Cerasi, D.J. Gross, Pre-clinical Cushing’s syndrome: an unexpected frequent cause of poor glycaemic control in obese diabetic patients. Clin. Endocrinol. 44, 717–722 (1996)CrossRefGoogle Scholar
  59. 59.
    L.N. Contreras, E. Cardoso, M.P. Lozano, J. Pozzo, P. Pagano, H. Claus-Hermbeg, Detection of preclinical Cushing’s syndrome in overweight type 2 diabetic patients. Medicina (B Aires) 60, 326–330 (2000)Google Scholar
  60. 60.
    B. Catargi, V. Rigalleau, A. Poussin, N. Ronci-Chaix, V. Bex, V. Vergnot, H. Gin, P. Roger, A. Tabarin, Occult Cushing’s syndrome in type-2 diabetes. J. Clin. Endocrinol. Metab. 88, 5808–5813 (2003)PubMedCrossRefGoogle Scholar
  61. 61.
    I. Chiodini, M. Torlontano, A. Scillitani, M. Arosio, S. Bacci, S. Di Lembo, P. Epaminonda, G. Augello, R. Enrini, B. Ambrosi, G. Adda, V. Trischitta, Association of subclinical hypercortisolism with type 2 diabetes mellitus: a case-control study in hospitalized patients. Eur. J. Endocrinol. 153, 837–844 (2005)PubMedCrossRefGoogle Scholar
  62. 62.
    H. Liu, D.M. Bravata, J. Cabaccan, H. Raff, E. Ryzen, Elevated late-night salivary cortisol levels in elderly male type 2 diabetic veterans. Clin. Endocrinol. 63, 642–649 (2005)CrossRefGoogle Scholar
  63. 63.
    G. Reimondo, A. Pia, B. Allasino, F. Tassone, S. Bovio, G. Borretta, A. Angeli, M. Terzolo, Screening of Cushing’s syndrome in adult patients with newly diagnosed diabetes mellitus. Clin. Endocrinol. 67, 225–229 (2007)CrossRefGoogle Scholar
  64. 64.
    T. Taniguchi, A. Hamasaki, M. Okamoto, Subclinical hypercortisolism in hospitalized patients with type 2 diabetes mellitus. Endocr. J. 55, 429–432 (2008)PubMedCrossRefGoogle Scholar
  65. 65.
    S. Newsome, K. Chen, J. Hoang, J.D. Wilson, J.M. Potter, P.E. Hickman, Cushing’s syndrome in a clinic population with diabetes. Intern. Med. J. 38, 178–182 (2008)PubMedCrossRefGoogle Scholar
  66. 66.
    L. Gagliardi, I.M. Chapman, P. O’ Loughlin, D.J. Torpy, Screening for subclinical Cushing’s syndrome in type 2 diabetes mellitus: low false-positive rates with nocturnal salivary cortisol. Horm. Metab. Res. 42, 280–284 (2010)PubMedCrossRefGoogle Scholar
  67. 67.
    K. Mullan, N. Black, A. Thiraviaraj, P.M. Bell, C. Burgess, S.J. Hunter, D.R. McCance, H. Leslie, B. Sheridan, A.B. Atkinson, Is there a value in routine screening for Cushing’s syndrome in patients with diabetes? J. Clin. Endocrinol. Metab. 95, 2262–2265 (2010)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Roberta Giordano
    • 1
  • Federica Guaraldi
    • 2
  • Rita Berardelli
    • 2
  • Ioannis Karamouzis
    • 2
  • Valentina D’Angelo
    • 2
  • Elisa Marinazzo
    • 2
  • Andreea Picu
    • 2
  • Ezio Ghigo
    • 2
  • Emanuela Arvat
    • 2
  1. 1.Division of Endocrinology, Diabetology and Metabolism, Department of Internal Medicine and Department of Clinical and Biological SciencesUniversity of TurinTorinoItaly
  2. 2.Division of Endocrinology, Diabetology and Metabolism, Department of Internal MedicineUniversity of TurinTorinoItaly

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