Pre‐clinical Cushing's syndrome: an unexpected frequent cause of poor glycaemic control in obese diabetic patients
Abstract
OBJECTIVE: Autonomous cortisol secretion without clinical stigmata of Cushing's syndrome (CS) has been recently recognized and termed pre-clinical or sub-clinical CS. The common assumption is that CS is an extremely rare cause of uncontrolled diabetes; however, the prevalence of this entity has not been studied. We assessed the prevalence of pre-clinical CS among obese patients with uncontrolled diabetes. PATIENTS AND DESIGN: (1) In a retrospective analysis, the medical records of 63 patients with endogenous CS were reviewed. (2) In a cross-sectional study, 90 obese patients (BMI > 25 kg/m2) followed in a University Hospital and the local Health Fund endocrine and diabetes clinics, with poorly controlled diabetes (glycosylated haemoglobin > 9%), underwent an overnight 1 mg dexamethasone suppression. In patients with non-suppressible cortisol levels (> 140 nmol/l), Liddle's 2 and 8 mg dexamethasone suppression tests and imaging studies were performed. MEASUREMENTS: The prevalence of poorly controlled diabetes, the major presenting symptom of CS, was assessed in the retrospective analysis. The prevalence of "true' CS and the false positive rate in the overnight dexamethasone suppression test were calculated. The endocrine evaluation of the patients with pre-clinical CS and the effects of surgical cure on glycaemic control are described. RESULTS: In the retrospective analysis, 11 (17.5%) had diabetes and 2 (3.2%) lacked the classic physical characteristics of the syndrome. In the cross-sectional study, 4 patients failed to suppress plasma cortisol (< 140 nmol/l). In one patient the diagnosis of CS was not confirmed by a standard Liddle's test and was therefore considered false positive. In the other 3, the diagnosis of CS was confirmed (prevalence of 3.3%, 95% confidence interval 1-9%). In all other patients the overnight cortisol suppression test was normal (cortisol level 47.3 +/- 2.5 nmol/l (mean +/- SEM)). After surgical treatment of CS, glycaemic control was markedly improved in all 5 patients (2 from retrospective and 3 from cross-sectional studies). CONCLUSIONS: The prevalence of pre-clinical Cushing's syndrome in obese patients with poorly controlled diabetes appears to be considerably higher than previously believed. The overnight dexamethasone suppression test proved to be a simple, sensitive and highly specific screening test for Cushing's syndrome despite the presence of obesity and hyperglycaemia.
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The prevalence of previously unsuspected Cushing syndrome in patients with type 2 diabetes ranges from 0% to 9.4%.
“The association between DM and CS has been examined in various studies, which have shown a prevalence of previously unsuspected CS in patients with type DM ranging from % to .% (Table ) (-).”
From Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management (2017) · cites this paper as [245]
Available data do not support large-scale screening for Cushing syndrome in type 2 diabetes but may suggest case-finding for hypercortisolism in diabetic patients with certain features.
“Available data consequently do not support largescale screening for CS in patients with type DM but may suggest a case-finding approach for hypercortisolism in diabetic patients with certain features (i.e., uncontrolled DM despite appropriate treatment, drug-resistant hypertension, Cushingoid appearance, central obesity, osteoporosis, or polycystic ovary syndrome) (, ).”
From Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management (2017) · cites this paper as [245]
In 90 obese diabetic patients with poor metabolic control, Leibowitz et al. found a 3.3% prevalence of subclinical hypercortisolism, with one adrenal adenoma and two pituitary adenomas, using a 1-mg dexamethasone suppression test cutoff above 5.1 g/dl.
“In a cross-sectional study on 90 obese diabetic patients with poor metabolic control, Leibowitz et al. (63) found a 3.3% prevalence of SH due to an adrenal adenoma in one patient and a pituitary adenoma in two patients using 1-mg DST above 5.1 g/dl (140 nmol/liter) as a screening test.”
From Diagnosis and Treatment of Subclinical Hypercortisolism (2011) · cites this paper as [63]
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“require a more meticulous investigation of CS in populations with features such as obesity, hypertension, diabetes and the polycystic ovarian syndrome [”
BackgroundMedical Management of Persistent and Recurrent Cushing Disease
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“[13] reported three patients with subCS in a study of 90 overweight patients (body mass index > 25 kg/m(2)) with poorly controlled diabetes (HbA1c > 9%).”
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When to Suspect Hidden Hypercortisolism in Type 2 Diabetes: A Meta-Analysis
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Prevalencia, etiología y cuadro clínico del síndrome de Cushing
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Machado, M. C., Fragoso, M. C. B. V., Moreira, A. C., Boguszewski, C. L., Vieira Neto, L., Naves, L. A., Vilar, L., Araújo, L. A. D., Czepielewski, M. A., Gadelha, M. R., et al. (2016) · Archives of Endocrinology and Metabolism · doi:10.1590/2359-3997000000174 · Cited by 21 · see citing works
“3%) in a group of 2,381 diabetic patients from 12 studies (34-45).”
BackgroundDiscovery of Cushing’s Syndrome After Bariatric Surgery: Multicenter Series of 16 Patients
Javorsky, B. R., Carroll, T. B., Tritos, N. A., Salvatori, R., Heaney, A. P., Fleseriu, M., Biller, B. M. K., & Findling, J. W. (2015) · Obesity Surgery · doi:10.1007/s11695-015-1681-z · Cited by 22 · see citing works
“6 % [13–16].”
Cushing’s syndrome in type 2 diabetes patients with poor glycemic control
Güngüneş, A., Şahi̇n, M., Demirci, T., Uçan, B., Çakır, E., Arslan, M. S., Ünsal, İ. Ö., Karbek, B., Çalışkan, M., Özbek, M., et al. (2014) · Endocrine · doi:10.1007/s12020-014-0260-8 · Cited by 21 · see citing works
“[4] scanned 90 patients with type 2 diabetes for CS whose HbA1c [9 % and BMI [25, and 3 patients were diagnosed as CS (3.”
MethodCosta, D., Conceição, F. L., Leite, N. C., Ferreira, M. T., Salles, G. F., & Cardoso, C. R. L. (2016) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2016.05.006 · Cited by 22 · see citing works
Incidental and Metastatic Adrenal Masses
Mannelli, M., Colagrande, S., Valeri, A., & Parenti, G. (2010) · Seminars in Oncology · doi:10.1053/j.seminoncol.2010.10.018 · Cited by 20 · see citing works
Surgical and radiosurgical treatment strategies for Cushing’s disease
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Comorbidities in Mild Autonomous Cortisol Secretion – A Clinical Review of Literature
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“The clinical spectrum of Cushing’s disease (CD) is shifting as this rare diagnosis is being increasingly considered among different patient populations [1, 2]. Studies have shown that 2–3% of patients with poorly controlled type 2 diabetes mellitus have unrecognised CS [ 3 ].”
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“CRH and Endocrine ObesityObesity is a cardinal feature of Cushing’s hypercortisolism, and Cushing’s syndrome is a frequent consideration in the differential diagnosis of obesity [”
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Which type 2 diabetes mellitus patients should be screened for subclinical Cushing’s syndrome?
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Cushing′s surgery: Role of the anesthesiologist
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“[3] Leibowitz et al,[4] enrolled in their study 90 diabetic patients with a body mass index >25 and glycosylated hemoglobin >9%, definitely diagnosing CS in three patients (3.”
BackgroundInfluentialRole of salivary cortisol determinations in the diagnosis of Cushing syndrome
Raff, H. (2004) · Current Opinion in Endocrinology & Diabetes · doi:10.1097/01.med.0000132655.69704.8c · Cited by 15 · see citing works
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Subclinical Cushing’s Syndrome
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Issues in the diagnosis of Cushing's syndrome for the primary care physician
Schuff, K. G. (2003) · Primary Care Clinics in Office Practice · doi:10.1016/s0095-4543(03)00088-5 · Cited by 15 · see citing works
“4 to 10 per million population [1], one small study suggests it may have a prevalence of up to 3% to 4% in the obese, uncontrolled diabetic population [2].”
Background“Osler’s phenomenon”: misdiagnosing Cushing’s syndrome
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Budget impact of using midnight salivary cortisol in the diagnosis of hypercortisolism
León‐Justel, A., Mangas, M. Á., Fontan, R., Castro-Luque, J., Moreno, E. V., Madrazo‐Atutxa, A., del Rey, T. H., Martin‐Rodríguez, J. F., Soto‐Moreno, A., & Leal‐Cerro, A. (2011) · Clinica Chimica Acta · doi:10.1016/j.cca.2011.08.013 · Cited by 14 · see citing works
Incidence of Cushing’s syndrome in patients with significant hypercortisoluria
Hirsch, D., Tsvetov, G., Manisterski, Y., Aviran-Barak, N., Nadler, V., Alboim, S., & Kopel, V. (2016) · European Journal of Endocrinology · doi:10.1530/eje-16-0631 · Cited by 13 · see citing works
Relationship between type 2 diabetes mellitus and hypothalamic-pituitary-adrenal axis
Felšöci, M., Schroner, Z., Petrovičová, J., & Lazúrová, I. (2010) · Wiener klinische Wochenschrift · doi:10.1007/s00508-010-1497-8 · Cited by 13 · see citing works
- Authors
- Leibowitz, G., Tsur, A., Chayen, S. D., Salameh, M., Raz, I., Cerasi, E., & Gross, D. J.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Gross, David J.
- Venue
- Clinical Endocrinology
- Publisher
- Wiley
- Published
- 1996-06
- Volume
- 44
- Issue
- 6
- Pages
- 717-722
- ISSN
- 0300-0664 (ISSN-L)
- 1365-2265
- OpenAlex
- W2019770879
- Cited by
- 180
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 6 · 2016: 7 · 2015: 12 · 2014: 5 · 2013: 4 · 2012: 12
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- syndromes, uncontrolled diabetes, obesity, glycemic control, dexamethasone suppression test, prevalence, false positive rate, adrenalectomy, surgical treatment, screening test, glycosylated haemoglobin, hypercortisolism, adrenal incidentaloma
- MeSH terms
- Adult, Aged, Cross-Sectional Studies, Cushing Syndrome, Dexamethasone, Diabetes Mellitus, Female, Humans, Hydrocortisone, Male, Middle Aged, Obesity, Retrospective Studies, Prevalence
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