Clinical Science| Volume 62, ISSUE 6, P786-792, June 2013

Nondiabetic patients with either subclinical Cushing's or nonfunctional adrenal incidentalomas have lower insulin sensitivity than healthy controls: Clinical implications

Published:January 18, 2013DOI:



      The aim of this study was to estimate insulin sensitivity (IS) in nondiabetic patients with adrenal incidentalomas (AI): nonfunctional adrenal incidentalomas (NAI) and patients with AI and subclinical Cushing's syndrome (SCS).


      Based on the inclusion criteria (normal fasting glucose levels, no previous history of impaired fasting glucose and/or diabetes, and no medications or concomitant relevant diseases) and the exclusion criteria (pheochromocytoma, overt hypercortisolism, hyperaldosteronism, adrenal carcinoma, metastasis of extra-adrenal tumors, extra-adrenal malignancies), 142 subjects were drawn from a series of patients with AI. The subjects were age-, sex- and body mass index (BMI)-matched: 70 with NAI (50 women and 20 men), 37 with AI and SCS (31 women and 6 men) and 35 healthy control (HC) subjects (30 women and 5 men).
      The oral glucose tolerance test (OGTT) and several indices of insulin sensitivity (IS) were used: homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI), triglycerides and glucose index (TyG), index of whole-body insulin sensitivity (ISI-composite) and glucose to insulin ratio (G/I).


      There was a significant difference in IS between subjects with NAI and HC (HOMA, p=0.049; QUICKI, p=0.036; TyG, p=0.002; ISI-composite, p=0.024) and subjects with SCS and HC (AUC insulin, p=0.01; HOMA, p=0.003; QUICKI, p=0.042; TyG, p=0.008; ISI-composite, p=0.002). There was no difference in the tested indices of IS between subjects with NAI and SCS (p>0.05). However, subjects with SCS had a significantly higher prevalence of impaired glucose tolerance and higher area under the curve for glucose than subjects with NAI (p=0.0174). The linear regression analysis showed that 1 mg-DST cannot be used as a predictor of HOMA (R2=0.004, F=0.407, p=0.525). Significant relationship was found between 1 mg-DST and ISI-composite (R2=0.042, F=4.981, p=0.028) but this relationship was weak and standard error of estimate was high. The linear regression model also showed that ACTH cannot be used as a predictor of HOMA (R2=0.001, F=0.005, p=0.943) or ISI-composite (R2=0.015, F=1.819, p=0.187).


      Insulin resistance is a major cardiovascular risk factor; therefore, the assessment of IS in patients with AI, even nonfunctional, has a valuable place in the endocrine workup of these patients.


      AI (adrenal incidentalomas), SCS (subclinical Cushing's syndrome), NAI (nonfunctional adrenal incidentaloma), HC (healthy control), IS (insulin sensitivity), IR (insulin resistance), HOMA (homeostasis model assessment), QUICKI (quantitative insulin sensitivity check index), G/I (glucose to insulin ratio), TyG (the product of triglycerides and glucose), ISI-composite (whole-body insulin sensitivity), OGTT (oral glucose tolerance test), ACTH (adrenocorticotrophic hormone), IGT (impaired glucose tolerance), IFG (impaired fasting glucose), 1mg-DST (overnight low dose dexamethasone suppression test), MSC (midnight serum cortisol), AUC (area under the curve), BMI (body mass index), CV (coefficient of variance)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Metabolism - Clinical and Experimental
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Linos D.
        Adrenal incidentaloma (adrenaloma).
        Hormones (Athens). 2003; 2: 12-21
        • Nawar R.
        • Aron D.
        Adrenal incidentalomas — a continuing management dilemma.
        Endocr Relat Cancer. 2005; 12: 585-598
        • Ivović M.
        • Vujović S.
        • Penezić Z.
        • et al.
        Insulin sensitivity in patients with adrenal incidentaloma.
        Srp Arh Celok Lek. 2006; 134: 315-319
        • Angeli A.
        • Terzolo M.
        Adrenal incidentaloma—a modern disease with old complications.
        J Clin Endocrinol Metab. 2002; 87: 4869-4871
        • Rossi R.
        • Tauchmanova L.
        • Luciano A.
        • et al.
        Subclinical Cushing's syndrome in patients with adrenal incidentaloma: clinical and biochemical features.
        J Clin Endocrinol Metab. 2000; 85: 1440-1448
        • Terzolo M.
        • Bovio S.
        • Reimondo G.
        • et al.
        Subclinical Cushing's syndrome in adrenal incidentalomas.
        Endocrinol Metab Clin North Am. 2005; 34: 423-439
        • Grundy S.M.
        • Brewer Jr., H.B.
        • Cleeman J.I.
        • et al.
        Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition.
        Circulation. 2004; 109: 433-438
        • Reaven G.
        • Abbasi F.
        • McLaughlin T.
        Obesity, insulin resistance, and cardiovascular disease.
        Recent Prog Horm Res. 2004; 59: 207-223
        • DeFronzo R.A.
        • Tobin J.D.
        • Andres R.
        Glucose clamp technique: a method for quantifying insulin secretion and resistance.
        Am J Physiol Endocrinol Metab. 1979; 237: E214-E223
        • Matthews D.R.
        • Hosker J.P.
        • Rudenski A.S.
        • et al.
        Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man.
        Diabetologia. 1985; 28: 412-419
        • Bloomgarden Z.
        Measures of insulin sensitivity.
        Clin Lab Med. 2006; 26: 611-633
        • Katz A.
        • Nambi S.S.
        • Mather K.
        • et al.
        Quantitative insulin sensitivity check index: a simple accurate method for assessing insulin sensitivity in humans.
        J Clin Endocrinol Metab. 2000; 85: 2402-2410
        • Chen H.
        • Sullivan G.
        • Quon M.J.
        Assessing the predictive accuracy of QUICKI as a surrogate index for insulin sensitivity using a calibration model.
        Diabetes. 2005; 54: 1914-1925
        • Legro R.S.
        • Finegood D.
        • Dunaif A.
        A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome.
        J Clin Endocrinol Metab. 1998; 83: 2694-2698
        • Chu M.
        • Cosper P.
        • Orio F.
        • et al.
        Insulin resistance in postmenopausal women with metabolic syndrome and the measurements of adiponectin, leptin, resistin, and ghrelin.
        Am J Obstet Gynecol. 2006; 194: 100-104
        • Guerrero-Romero F.
        • Simental-Mendia L.E.
        • Gonzalez-Ortiz M.
        • et al.
        The product of triglycerides and glucose, a simple measure of insulin sensitivity.
        J Clin Endocrinol Metab. 2010; 95: 3347-3351
        • Matsuda M.
        • DeFronzo R.A.
        Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.
        Diabetes Care. 1999; 22: 1462-1470
      1. Porter R. Kaplan J. The Merck manual of diagnosis and therapy. Merck Sharp & Dohme Corp, Whitehouse Station, NJ2011: 800-801
        • Mulatero P.
        • Rabbia F.
        • Milan A.
        • et al.
        Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism.
        Hypertension. 2002; 40: 897-902
        • Association A D
        Standards of medical care in diabetes—2009.
        Diabetes Care. 2009; 32: S13-S61
        • Eller-Vainicher C.
        • Morelli V.
        • Salcuni A.S.
        • et al.
        Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma.
        Eur J Endocrinol. 2010; 163: 925-935
        • Terzolo M.
        • Bovio S.
        • Pia A.
        • et al.
        Management of adrenal incidentaloma.
        Best Pract Res Clin Endocrinol Metab. 2009; 23: 233-243
        • Morioka M.
        • Fujii T.
        • Matsuki T.
        • et al.
        Preclinical Cushing's syndrome: report of seven cases and a review of the literature.
        Int J Urol. 2000; 7: 126-132
        • Valli N.
        • Catargi B.
        • Ronci N.
        • et al.
        Biochemical screening for subclinical cortisol-secreting adenomas amongst adrenal incidentalomas.
        Eur J Endocrinol. 2001; 144: 401-408
        • Murai M.
        • Kikuchi E.
        • Yanaihara H.
        • et al.
        Current management of incidentally discovered adrenal masses, with a review of Japanese literature.
        Biomed Pharmacother. 2000; 54: 133s-139s
        • Carmina E.
        • Lobo R.
        Use of fasting blood to assess the prevalence of insulin resistance in women with polycystic ovary syndrome.
        Fertil Steril. 2004; 82: 661-665
        • Allison D.
        • Paultre F.
        • Maggio C.
        • et al.
        The use of areas under curves in diabetes research.
        Diabetes Care. 1995; 18: 245-250
        • Tai M.
        A mathematical model for the determination of total area under glucose tolerance and other metabolic curves.
        Diabetes Care. 1994; 17: 152-154
        • Terzolo M.
        • Reimondo G.
        • Angeli A.
        Definition of an optimal strategy to evaluate and follow-up adrenal incidentalomas: time for further research.
        Eur J Endocrinol. 2009; 161: 529-532
        • Saely C.H.
        • Aczel S.
        • Marte T.
        • et al.
        The metabolic syndrome, insulin resistance, and cardiovascular risk in diabetic and nondiabetic patients.
        J Clin Endocrinol Metab. 2005; 90: 5698-5703
      2. 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: 2486-2497
        • Fernández-Real J.M.
        • Engel W.R.
        • Simó R.
        • et al.
        Study of glucose tolerance in consecutive patients harbouring incidental adrenal tumours.
        Clin Endocrinol (Oxf). 1998; 49: 53-61
        • Garrapa G.G.M.
        • Pantanetti P.
        • Arnaldi G.
        • et al.
        Body composition and metabolic features in women with adrenal incidentaloma or Cushing's syndrome.
        J Clin Endocrinol Metab. 2001; 86: 5301-5306
        • Erbil Y.
        • Ozbey N.
        • Barabaros U.
        • et al.
        Cardiovascular risk in patients with nonfunctional adrenal incidentaloma: myth or reality?.
        World J Surg. 2009; 33: 2099-2105
        • Peppa M.
        • Boutati E.
        • Koliaki C.
        • et al.
        Insulin resistance and metabolic syndrome in patients with nonfunctioning adrenal incidentalomas: a cause–effect relationship?.
        Metabolism. 2010; 59: 1435-1441
        • Caro J.
        Insulin resistance in obese and nonobese man.
        J Clin Endocrinol Metab. 1991; 73: 691-695
        • Ferrannini E.
        • Natali A.
        • Bell P.
        • et al.
        Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR).
        J Clin Invest. 1997; 100: 1166-1173
        • Tauchmanova L.
        • Rossi R.
        • Biondi B.
        • et al.
        Patients with subclinical Cushing's syndrome due to adrenal adenoma have increased cardiovascular risk.
        J Clin Endocrinol Metab. 2002; 87: 4872-4878
        • Terzolo M.
        • Pia A.
        • Ali A.
        • et al.
        Adrenal incidentaloma: a new cause of the metabolic syndrome?.
        J Clin Endocrinol Metab. 2002; 87: 998-1003
        • Terzolo M.
        • Reimondo G.
        • Bovio S.
        • et al.
        Subclinical Cushing's syndrome.
        Pituitary. 2004; 7: 217-223
        • Chiodini I.
        Diagnosis and treatment of subclinical hypercortisolism.
        J Clin Endocrinol Metab. 2011; 96: 1223-1236
        • Chiodini I.
        • Morelli V.
        • Salcuni A.S.
        • et al.
        Beneficial metabolic effects of prompt surgical treatment in patients with an adrenal incidentaloma causing biochemical hypercortisolism.
        J Clin Endocrinol Metab. 2010; 95: 2736-2745
        • Morelli V.
        • Donadio F.
        • Eller-Vainicher C.
        • et al.
        Role of glucocorticoid receptor polymorphism in adrenal incidentalomas.
        Eur J Clin Invest. 2010; 40: 803-811
        • Pivonello R.
        • De Leo M.
        • Vitale P.
        • et al.
        Pathophysiology of diabetes mellitus in Cushing's syndrome.
        Neuroendocrinology. 2010; 92: 77-81