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Horm Metab Res 2019; 51(01): 62-68
DOI: 10.1055/a-0809-3647
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Hypercortisolism in Newly Diagnosed Type 2 Diabetes: A Prospective Study of 384 Newly Diagnosed Patients

Charlotte Steffensen
1   Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
,
Olaf M. Dekkers
2   Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
3   Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands
,
Johanne Lyhne
1   Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
,
Bodil G. Pedersen
4   Department of Radiology, Aarhus University Hospital, Aarhus, Denmark
,
Finn Rasmussen
4   Department of Radiology, Aarhus University Hospital, Aarhus, Denmark
,
Jørgen Rungby
5   Department of Clinical Pharmacology, Aarhus University, Aarhus, Denmark
6   Department of Endocrinology IC, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark
,
Per Løgstrup Poulsen
1   Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
,
Jens Otto Lunde Jørgensen
1   Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
› Author Affiliations
Further Information

Publication History

received 01 June 2018

accepted 22 November 2018

Publication Date:
06 December 2018 (online)

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Abstract

Cross-sectional studies in small and selected populations report a high prevalence of hypercortisolism in patients with type 2 diabetes (T2D), which could have therapeutic implications, if confirmed. We therefore estimated the prevalence of hypercortisolism in a large and unselected cohort of recently diagnosed T2D patients. Consecutive patients with recently diagnosed T2D first underwent an overnight dexamethasone (1 mg) suppression test (OD). Patients not suppressing serum cortisol ≤50 nmol/l proceeded with a 48-h low dose dexamethasone suppression test (LDDST) and 24-h urinary free cortisol collection (UFC). Patients with elevated cortisol levels according to LDDST and/or UFC underwent imaging guided by plasma ACTH levels, and assessment of bone mineral density. A total of 384 T2D patients (232male/152 females) with a mean age of 60±10 years were included. Eighty-five (22%) patients suppressed incompletely to OD of whom 20 (5%) failed to suppress after LDDST and/or had elevated UFC (=hypercortisolism). Patients with hypercortisolism did not differ as regards age, BMI, HbA1c, T-score or blood pressure, but a higher proportion of them received antihypertensive treatment (100% vs. 64%, p=0.001). Imaging revealed adrenal adenoma(s) in 9 cases and a pituitary macroadenoma in 1 case. We found a 5% prevalence of hypercortisolism in unselected, recently diagnosed T2D, which was not associated with a persuasive cushingoid phenotype. The clinical implications are therefore uncertain.

Key words

cortisol - Cushing’s syndrome - subclinical Cushing’s syndrome - Type 2 diabetes
 

  • References

  • 1 Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet 2006; 367: 1605-1617
    CrossrefPubMedSearch in Google Scholar
  • 2 Findling JW, Raff H. Diagnosis and differential diagnosis of Cushing’s syndrome. Endocrinol Metab Clin North Am 2001; 30: 729-747
    CrossrefPubMedSearch in Google Scholar
  • 3 Newell-Price J, Trainer P, Besser M, Grossman A. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev 1998; 19: 647-672
    PubMedSearch in Google Scholar
  • 4 Steffensen C, Bak AM, Rubeck KZ, Jørgensen JOL. Epidemiology of Cushing’s syndrome. Neuroendocrinology 2010; 92 (Suppl. 01) 1-5
    PubMedSearch in Google Scholar
  • 5 Lindholm J, Juul S, Jørgensen JOL, Astrup J, Bjerre P, Hagen C, Jørgensen J, Kosteljanetz M, Kristensen L, Laurberg P, Schmoidt K, Weeke J. Incidence and Late Prognosis of Cushing ’ s Syndrome : A Population-Based Study. J Clin Endocrinol Metab 2001; 86: 117-123
    PubMedSearch in Google Scholar
  • 6 Clayton RN, Raskauskiene D, Reulen RC, Jones PW. Mortality and morbidity in Cushing’s disease over 50 Years in Stoke-on-Trent, UK: Audit and meta-analysis of literature. J Clin Endocrinol Metab 2011; 96: 632-642
    CrossrefPubMedSearch in Google Scholar
  • 7 Dekkers OM, Horváth-Puho E, Jørgensen JOL, Cannegieter SC, Ehrenstein V, Vandenbroucke JP, Pereira AM, Sørensen HT. Multisystem morbidity and mortality in cushing’s syndrome: A cohort study. J Clin Endocrinol Metab 2013; 98: 2277-2284
    CrossrefPubMedSearch in Google Scholar
  • 8 Chiodini I. Clinical review: Diagnosis and treatment of subclinical hypercortisolism. J Clin Endocrinol Metab 2011; 96: 1223-1236
    CrossrefPubMedSearch in Google Scholar
  • 9 Terzolo M, Reimondo G, Bovio S, Angeli A. Subclinical Cushing’s syndrome. Pituitary 2004; 7: 217-223
    CrossrefPubMedSearch in Google Scholar
  • 10 Leibowitz G, Tsur A, Chayen SD, Salameh M, Raz I, Cerasi E, Gross DJ. Pre-clinical Cushing’s syndrome: An unexpected frequent cause of poor glycaemic control in obese diabetic patients. Clin Endocrinol (Oxf) 1996; 44: 717-722
    CrossrefPubMedSearch in Google Scholar
  • 11 Catargi B, Rigalleau V, Poussin A, Ronci-Chaix N, Bex V, Vergnot V, Gin H, Roger P, Tabarin A. Occult Cushing’s syndrome in type-2 diabetes. J Clin Endocrinol Metab 2003; 88: 5808-5813
    CrossrefPubMedSearch in Google Scholar
  • 12 Chiodini I, Torlontano M, Scillitani A, Arosio M, Bacci S, Di Lembo S, Epaminonda P, Augello G, Ambrosi B, Adda G, Trischitta V. Association of subclinical hypercortisolism with type 2 diabetes mellitus: A case-control study in hospitalized patients. Eur J Endocrinol 2005; 153: 837-844
    CrossrefPubMedSearch in Google Scholar
  • 13 Reimondo G, Pia A, Allasino B, Tassone F, Bovio S, Borretta G, Angeli A, Terzolo M. Screening of Cushing’s syndrome in adult patients with newly diagnosed diabetes mellitus. Clin Endocrinol (Oxf) 2007; 67: 225-229
    CrossrefPubMedSearch in Google Scholar
  • 14 Newsome S, Chen K, Hoang J, Wilson JD, Potter JM, Hickman PE. Cushing’s syndrome in a clinic population with diabetes. Intern Med J 2008; 38: 178-182
    CrossrefPubMedSearch in Google Scholar
  • 15 Rossi R, Tauchmanova L, Luciano A, Martino MDI, Battista C, Molecolare O. Subclinical Cushing’s Syndrome in Patients with Adrenal Incidentaloma : Clin Biochem Feat. 2014; 85: 1440-1448
    PubMedSearch in Google Scholar
  • 16 Osella G, Reimondo G, Terzolo M, Pia A, Ali A, Bovio S, Daffara F, Procopio M, Paccotti P, Borretta G, Angeli A. Adrenal Incidentaloma : A New Cause of the Metabolic Syndrome?. 2014; 87: 998-1003
    PubMedSearch in Google Scholar
  • 17 Steffensen C, Thomsen RW, Vaag A, Beck-Nielsen H, Christiansen JS, Hansen T, Pedersen O, Rungby J. The Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Project: Rationale and planned nationwide studies of genetic predictors, physical exercise, and individualized pharmacological treatment. Clin Epidemiol 2012; 4 (Suppl. 01) 7-13
    PubMedSearch in Google Scholar
  • 18 Levin KA. Study design III: Cross-sectional studies. Evid Based Dent 2006; 7: 24-25
    CrossrefPubMedSearch in Google Scholar
  • 19 Steffensen C, Pereira AM, Dekkers OM, Jørgensen JO. Prevalence of hypercortisolism in Type 2 Diabetes patients: A systematic review and meta-analysis. Eur J Endocrinol 2016; 175: 247-253
    CrossrefPubMedSearch in Google Scholar
  • 20 Cucak H, Grunnet LG, Rosendahl A. Accumulation of M1-like macrophages in type 2 diabetic islets is followed by a systemic shift in macrophage polarization. J Leukoc Biol 2014; 95: 149-160
    CrossrefPubMedSearch in Google Scholar
  • 21 Spranger J, Kroke A, Mo M, Hoffmann K, Bergmann MM. Inflammatory Cytokines and the Risk to Develop Type 2 Diabetes: Results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 2003; 52: 812-817
    CrossrefPubMedSearch in Google Scholar
  • 22 Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11: 98-107
    CrossrefPubMedSearch in Google Scholar
  • 23 De Feo P, Perriello G, Torlone E, Ventura MM, Fanelli C, Santeusanio F, Brunetti P, Gerich JE, Bolli GB. Contribution of cortisol to glucose counterregulation in humans. Am J Physiol 1989; 257: E35-E42
    PubMedSearch in Google Scholar
  • 24 Lindmark S, Burén J, Eriksson JW. Insulin resistance, endocrine function and adipokines in type 2 diabetes patients at different glycaemic levels: Potential impact for glucotoxicity in vivo. Clin Endocrinol (Oxf) 2006; 65: 301-309
    CrossrefPubMedSearch in Google Scholar
  • 25 Van Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab 1996; 81: 2468-2473
    PubMedSearch in Google Scholar
  • 26 Perry HM. The endocrinology of aging. Clin Chem 1999; 45 8 II 1369-1376
    CrossrefPubMedSearch in Google Scholar
  • 27 Hackett RA, Steptoe A, Kumari M. Association of diurnal patterns in salivary cortisol with type 2 diabetes in the Whitehall II study. J Clin Endocrinol Metab 2014; 99: 4625-4631
    CrossrefPubMedSearch in Google Scholar
  • 28 Chamarthi B, Kolatkar NS, Hunt SC, Williams JS, Seely EW, Brown NJ, Murphey LJ, Jeunemaitre X, Williams GH. Urinary free cortisol: An intermediate phenotype and a potential genetic marker for a salt-resistant subset of essential hypertension. J Clin Endocrinol Metab 2007; 92: 1340-1346
    CrossrefPubMedSearch in Google Scholar
  • 29 Reincke M, Nieke J, Krestin GP, Saeger W, Allolio B, Winkelmann W. Preclinical Cushings syndrome in adrenal "incidentalomas": Comparison with adrenal Cushing’s syndrome. 1992; 75: 826-832
    PubMedSearch in Google Scholar
  • 30 Terzolo M, Pia A, Reimondo G. Subclinical Cushing’s syndrome: Definition and management. Clin Endocrinol (Oxf) 2012; 76: 12-18
    CrossrefPubMedSearch in Google Scholar
  • 31 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: 2618-2620
    CrossrefPubMedSearch in Google Scholar
  • 32 Kloos R, Korobkin M, Thompson N, Francis I, Shapiro B, Gross M. Incidentally discovered adrenal masses. Cancer Treat Res 1997; 89: 263-292
    PubMedSearch in Google Scholar
  • 33 Barzon L, Sonino N, Fallo F, Palu G, Boscaro M. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol 2003; 149: 273-285
    CrossrefPubMedSearch in Google Scholar
  • 34 Nieman L, Biller B, Findling J, Newell-Price J, Savage M, Stewart PM, Montori VM. The diagnosis of Cushing’s syndrome: An endocrine society clinical practice guideline. Clin Endocrinol Metab 2008; 95: 1526-1540
    PubMedSearch in Google Scholar
  • 35 Grumbach MM, Biller BMK, Braunstein GD, Campbell KK, Carney JA, Godley PA, Harris EL, Lee JK, Oertel YC, Posner MC, Schlechte JA, Wieand HS. Management of the clinically inapparent adrenal mass. Ann Intern Med 2003; 138: 424-429
    PubMedSearch in Google Scholar
  • 36 Hiroi N, Sue M, Yoshihara A, Ichijo T, Yoshida-Hiroi M, Higa M, Yoshino G. Prevalence of adrenal masses in Japanese patients with type 2 diabetes mellitus. Diabetol Metab Syndr 2010; 20: 71
    PubMedSearch in Google Scholar
  • 37 Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, Tabarin A, Terzolo M, Tsagarakis S, Dekkers OM. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2016; 175: G1-G34
    CrossrefPubMedSearch in Google Scholar
  • 38 Terzolo M, Reimondo G, Chiodini I, Castello R, Giordano R, Ciccarelli E, Limone P, Crivellaro C, Martinelli I, Montini M, Disoteo O, Ambrosi B, Lanzi R, Arosio M, Senni S, Balestrieri A, Solaroli E, Madeo B, De Giovanni R, Strolle F, Battista R, Scorsone A, Giagulli VA, Collura D, Scillitani A, Cozzi R, Faustini-Fustini M, Pia A, Rinaldi R, Allasino B, Peraga G, Tassone F, Garofala P, Papini E, Borretta G. Screening of Cushing’s syndrome in outpatients with type 2 diabetes: Results of a prospective multicentric study in Italy. J Clin Endocrinol Metab 2012; 97: 3467-3475
    CrossrefPubMedSearch in Google Scholar
  • 39 Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Alì A, Giovagnetti M, Opocher G, Angeli A. A survey on adrenal incidentaloma in Italy. J Clin Endocrinol Metab 2000; 85: 637-644
    PubMedSearch in Google Scholar
  • 40 Mansmann G, Lau J, Balk E, Rothberg M, Miyachi Y, Bornstein SR. The clinically inapparent adrenal mass: Update in diagnosis and management. Endocr Rev 2004; 25: 309-340
    CrossrefPubMedSearch in Google Scholar
  • 41 Di Dalmazi G, Vicennati V, Rinaldi E, Morselli-Labate AM, Giampalma E, Mosconi C, Pagotto U, Pasquali R. Progressively increased patterns of subclinical cortisol hypersecretion in adrenal incidentalomas differently predict major metabolic and cardiovascular outcomes: A large cross-sectional study. Eur J Endocrinol 2012; 166: 669-677
    CrossrefPubMedSearch in Google Scholar
  • 42 Wilson JM, Jungner G. Principles and practice of screening for disease. In: Public Health Papers No. 34. World Health Organization Geneva 1968
    PubMed