The Role of Cortisol in the Pathogenesis of the Metabolic Syndrome

In-Kyung Jeong

doi:10.4093/dmj.2012.36.3.207

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Editorial Obesity and Metabolic Syndrome The Role of Cortisol in the Pathogenesis of the Metabolic Syndrome: In-Kyung Jeong; Diabetes & Metabolism Journal 2012;36(3):207-210.
DOI: https://doi.org/10.4093/dmj.2012.36.3.207
Published online: June 14, 2012

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Division of Endocrinology & Metabolism, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea.

Corresponding author: In-Kyung Jeong. Division of Endocrinology & Metabolism, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, 892 Dongnam-ro, Gangdong-gu, Seoul 134-727, Korea. jik1016@dreamwiz.com

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Metabolic syndrome (MetS) is a constellation of metabolic derangements that includes insulin resistance, hyperglycemia, hypertension, reduced high density lipoprotein cholesterol (HDL-C), elevated triglycerides, and abdominal obesity. It was originally described by Reaven in 1988 as "syndrome X" or "insulin resistance syndrome" [1]. MetS increases the risk for development of type 2 diabetes mellitus as well as cardiovascular disease [2].

The prevalence of MetS has increased worldwide, with an increase from 19.6% in 1998 to 32.4% in 2009, according to the Korean National Health and Nutrition Examination Survey (NHANES) [3]. In spite of the increasing prevalence of MetS, there are no uniformly accepted diagnostic criteria for MetS. Different organizations have suggested their own criteria. The National Cholesterol Education Program (NCEP) Adult Treatment Panel-III (ATP III) guidelines [4] are the most widely used, and require at least three of the following: 1) central obesity (waist circumference ≥90 cm for Asian men or ≥80 cm for Asian women, 2) triglycerides ≥150 mg/dL, or receiving drug treatment for high triglycerides, 3) HDL-C <40 mg/dL for men or <50 mg/dL for women or receiving drug treatment for low HDL-C, 4) systolic/diastolic blood pressure ≥130/85 mm Hg or receiving drug treatment for high blood pressure, and 5) fasting plasma glucose ≥100 mg/dL or receiving drug treatment for high fasting plasma glucose levels. However, according to the International Diabetes Federation (IDF) criteria [5], abdominal obesity (waist circumference ≥90 cm for Asian men or ≥80 cm for Asian women) is a prerequisite for the diagnosis of MetS, in addition to at least two of the following components: 1) triglycerides ≥150 mg/dL or receiving drug treatment for high triglycerides, 2) HDL-C <40 mg/dL for men or <50 mg/dL for women or receiving drug treatment for low HDL-C, 3) systolic/diastolic blood pressure ≥130/85 mm Hg or receiving drug treatment for high blood pressure, and 4) fasting plasma glucose ≥100 mg/dL or receiving drug treatment for high fasting plasma glucose levels. Yoon et al. [6] compared the two criteria. All MetS patients who met the IDF criteria also met the revised NCEP criteria. Patients who met the NCEP criteria but not the IDF criteria were metabolically obese with normal waist circumferences and significantly worse metabolic profiles than the MetS-free group. This illustrates why the revised NCEP criteria are preferred to the IDF criteria for measuring the prevalence of MetS in Korea.

Even though the primary mechanism of MetS is insulin resistance, there is still controversy regarding the pathogenesis of MetS. Because the clinical features of MetS are shared by Cushing's syndrome (CS), mild hypercortisolism was proposed as one of the pathogenic mechanisms of MetS [7]. Shared features between MetS and CS are abdominal obesity, high triglycerides, low HDL-C, hypertension, and hyperglycemia.

Previous studies have evaluated the association between MetS and hypercortisolism by examining fasting plasma cortisol, 24-hour urinary free cortisol, cortisol reactivity to some stimuli, or profiles of cortisol patterns over the day [8-24]. More recently, salivary cortisol measurements have been used [24]. Because lack of circadian rhythmicity is one of the most sensitive indicators of the presence of CS, midnight serum cortisol is very helpful as a low dose dexamethasone suppression test, but it is impractical for screening outpatients [9]. Midnight salivary cortisol, on the other hand, is much more practical for screening. Cortisol circulates in the plasma largely bound to cortisol binding globulin or albumin. Less than 5% of circulating cortisol is free cortisol which is a physiologically active hormone. Since binding proteins are absent from saliva, the concentration of salivary cortisol is in equilibrium with plasma free cortisol [10]. Thus, the salivary cortisol test is a simple, reproducible, stress-free, non-invasive and reliable test [11]. Interestingly, salivary cortisol testing was first reported about 30 years ago. There is some variation in cutoff values for salivary cortisol because different commercially available methods are used, such as radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), and tandem mass spectrometry (LC-MS) [11].

Some evidence suggests that circulating cortisol concentrations are higher in patients with MetS compared to healthy control subjects. Higher concentrations of urinary free cortisol were reported in patients with MetS [12,13]. Increased urinary cortisone/cortisol ratios were reported in women with abdominal obesity compared to those with a high proportion of peripheral fat. Cortisol appears to play a role in abdominal adiposity in MetS. Another study [14] did not find any relationship between cortisol and waist circumference, in contrast with findings from earlier studies [15,16]. Other studies measured the response of hypothalamic-pituitary-adrenal (HPA) axis to the various stimuli. Increased response of the HPA axis during a low dose adrenocorticotropic hormone test [17] and corticotropin-releasing hormone-vasopressin test [18] is found in central obesity. Overall there seems to be a hyperactivity of the HPA axis in patients with abdominal obesity. Several reports also show an association between higher fasting cortisol levels and parameters of MetS such as blood pressure, fasting glucose, and high triglycerides [19-21]. Recently Jang et al. [22] reported an association between midnight salivary cortisol and MetS. Even though the sample size was small, their data supported the hypothesis that cortisol plays an important role in the pathogenesis of MetS.

In contrast, circulating cortisol levels are not always elevated in obese subjects, and in some studies, they are lower than in lean subjects [23-25]. DeSantis et al. [25] analyzed the association between salivary cortisol measured 18 times over 3 days and MetS, using data from the Multi-Ethnic Study of Atherosclerosis. The area under the curve of cortisol levels was lower in the MetS group compared with the control group and there was no consistent pattern between MetS components and cortisol levels. This might be partly explained by tissue-specific dysregulation of cortisol metabolism, because plasma cortisol concentration is determined by the rate of secretion, the rate of inactivation, and the rate of excretion of free cortisol.

11β-hydroxysteroid dehydrogenase (11β-HSD) catalyzes the conversion of the hormonally active cortisol to inactive cortisone. There are two isoforms of 11β-HSD. 11β-HSD type 1 (11β-HSD1) converts inactive cortisone to active cortisol in key targets such as liver, adipose tissue, gonadal tissue and the central nervous system. 11β-HSD2 is expressed in a number of tissues and converts cortisol to inactive cortisone. Mutations in the 11β-HSD2 gene cause a syndrome of apparent mineralocorticoid excess, reflecting insufficient inactivation of cortisol in the kidney.

The expression of 11β-HSD1 appears to be higher in omental than subcutaneous fat. Treatment with cortisol and insulin increased the activity of 11β-HSD1 in adipose stromal cells [26], suggesting central obesity may reflect higher 11β-HSD1 activity. Mice overexpressing 11β-HSD1 in adipocytes develop central obesity [27]. Furthermore, 11β-HSD1 knockout mice have a reduced risk of obesity and MetS [28]. However, expression of 11β-HSD1 in adipose tissue is not increased in obese humans. The activity of 11β-HSD1 inversely correlates with body mass index, but increased proliferation of preadipose tissue as a consequence of decreased 11β-HSD1 expression may contribute to increases in visceral adipose tissue in obese humans [29]. Recent studies showed enhanced expression of the 11β-HSD1 gene in adipose tissue is associated with obesity, insulin resistance, and increased levels of leptin, resistin, and cytokines [30]. Therefore, 11β-HSD1 might be a promising therapeutic target in obesity and MetS. Carbenoxolone, a non-selective inhibitor of 11β-HSD1, improves insulin sensitivity [31]. Pharmacological inhibition of 11β-HSD1 by metformin, rosiglitazone, and clofibrate could explain the beneficial effects of these drugs on insulin resistance [32]. Selective and potent inhibitors of 11β-HSD1 have been developed [33]. Experimental studies with 11β-HSD1 inhibitors might support the role of 11β-HSD1 in the pathogenesis of MetS.

In conclusion, MetS is a constellation of metabolic abnormalities which predisposes patients to the development of diabetes, atherosclerosis, and cancer. Because MetS shares clinical characteristics of CS, functional hypercortisolism is one of the proposed pathogenic mechanisms of MetS. Increased cortisol production, hyperreactivity of the HPA axis, and dysregulation of 11β-HSD1 seem to contribute to hypercortisolism and MetS. Inhibition of cortisol action might be a new therapeutic target in patients with MetS.

NOTES

No potential conflict of interest relevant to this article was reported.

REFERENCES

1. Reaven G. The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrinol Metab Clin North Am 2004;33:283-303. Article PubMed
2. Wilson PW, D'Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 2005;112:3066-3072. Article PubMed
3. Oh SW. Obesity and metabolic syndrome in Korea. Diabetes Metab J 2011;35:561-566. Article PubMed PMC
4. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F. American Heart Association. National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735-2752. Article PubMed
5. Zimmet P, M M Alberti KG, Serrano Rios M. A new international diabetes federation worldwide definition of the metabolic syndrome: the rationale and the results. Rev Esp Cardiol 2005;58:1371-1376. PubMed
6. Yoon YS, Lee ES, Park C, Lee S, Oh SW. The new definition of metabolic syndrome by the international diabetes federation is less likely to identify metabolically abnormal but non-obese individuals than the definition by the revised national cholesterol education program: the Korea NHANES study. Int J Obes (Lond) 2007;31:528-534. Article PubMed PDF
7. Pasquali R, Vicennati V, Cacciari M, Pagotto U. The hypothalamic-pituitary-adrenal axis activity in obesity and the metabolic syndrome. Ann N Y Acad Sci 2006;1083:111-128. Article PubMed
8. Walker BR. Cortisol: cause and cure for metabolic syndrome? Diabet Med 2006;23:1281-1288. Article PubMed
9. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526-1540. Article PubMed PMC
10. Kahn JP, Rubinow DR, Davis CL, Kling M, Post RM. Salivary cortisol: a practical method for evaluation of adrenal function. Biol Psychiatry 1988;23:335-349. Article PubMed
11. Alexandraki KI, Grossman AB. Novel insights in the diagnosis of Cushing's syndrome. Neuroendocrinology 2010;92(Suppl 1):35-43. Article PubMed PDF
12. Marin P, Darin N, Amemiya T, Andersson B, Jern S, Bjorntorp P. Cortisol secretion in relation to body fat distribution in obese premenopausal women. Metabolism 1992;41:882-886. Article PubMed
13. Pasquali R, Cantobelli S, Casimirri F, Capelli M, Bortoluzzi L, Flamia R, Labate AM, Barbara L. The hypothalamic-pituitary-adrenal axis in obese women with different patterns of body fat distribution. J Clin Endocrinol Metab 1993;77:341-346. Article PubMed
14. Weigensberg MJ, Toledo-Corral CM, Goran MI. Association between the metabolic syndrome and serum cortisol in overweight Latino youth. J Clin Endocrinol Metab 2008;93:1372-1378. Article PubMed PMC
15. Epel ES, McEwen B, Seeman T, Matthews K, Castellazzo G, Brownell KD, Bell J, Ickovics JR. Stress and body shape: stress-induced cortisol secretion is consistently greater among women with central fat. Psychosom Med 2000;62:623-632. Article PubMed
16. Pasquali R, Vicennati V. Activity of the hypothalamic-pituitary-adrenal axis in different obesity phenotypes. Int J Obes Relat Metab Disord 2000;24(Suppl 2):S47-S49. Article PDF
17. Duclos M, Gatta B, Corcuff JB, Rashedi M, Pehourcq F, Roger P. Fat distribution in obese women is associated with subtle alterations of the hypothalamic-pituitary-adrenal axis activity and sensitivity to glucocorticoids. Clin Endocrinol (Oxf) 2001;55:447-454. Article PubMed PDF
18. Pasquali R, Anconetani B, Chattat R, Biscotti M, Spinucci G, Casimirri F, Vicennati V, Carcello A, Labate AM. Hypothalamic-pituitary-adrenal axis activity and its relationship to the autonomic nervous system in women with visceral and subcutaneous obesity: effects of the corticotropin-releasing factor/arginine-vasopressin test and of stress. Metabolism 1996;45:351-356. Article PubMed
19. Sen Y, Aygun D, Yilmaz E, Ayar A. Children and adolescents with obesity and the metabolic syndrome have high circulating cortisol levels. Neuro Endocrinol Lett 2008;29:141-145. PubMed
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;13:1157-1166. Article PubMed
21. Phillips DI, Barker DJ, Fall CH, Seckl JR, Whorwood CB, Wood PJ, Walker BR. Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome? J Clin Endocrinol Metab 1998;83:757-760. Article PubMed
22. Jang YM, Lee EJ, Kim DL, Kim SK, Song KH. The association between midnight salivary cortisol and metabolic syndrome in Korean adults. Diabetes Metab J 2012;36:245-250.Article PubMed PMC
23. Rask E, Olsson T, Soderberg S, Andrew R, Livingstone DE, Johnson O, Walker BR. Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab 2001;86:1418-1421. Article PubMed
24. Travison TG, O'Donnell AB, Araujo AB, Matsumoto AM, McKinlay JB. Cortisol levels and measures of body composition in middle-aged and older men. Clin Endocrinol (Oxf) 2007;67:71-77. Article PubMed
25. DeSantis AS, DiezRoux AV, Hajat A, Golden SH, Jenny NS, Sanchez BN, Shea S, Seeman TE. Associations of salivary cortisol levels with metabolic syndrome and its components: the multi-ethnic study of atherosclerosis. J Clin Endocrinol Metab 2011;96:3483-3492. Article PubMed PMC
26. Bujalska IJ, Kumar S, Stewart PM. Does central obesity reflect "Cushing's disease of the omentum"? Lancet 1997;349:1210-1213. Article PubMed
27. Masuzaki H, Yamamoto H, Kenyon CJ, Elmquist JK, Morton NM, Paterson JM, Shinyama H, Sharp MG, Fleming S, Mullins JJ, Seckl JR, Flier JS. Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice. J Clin Invest 2003;112:83-90. Article PubMed PMC
28. Morton NM, Paterson JM, Masuzaki H, Holmes MC, Staels B, Fievet C, Walker BR, Flier JS, Mullins JJ, Seckl JR. Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice. Diabetes 2004;53:931-938. PubMed
29. Tomlinson JW, Stewart PM. The functional consequences of 11beta-hydroxysteroid dehydrogenase expression in adipose tissue. Horm Metab Res 2002;34:746-751. Article PubMed
30. Wake DJ, Rask E, Livingstone DE, Soderberg S, Olsson T, Walker BR. Local and systemic impact of transcriptional up-regulation of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue in human obesity. J Clin Endocrinol Metab 2003;88:3983-3988. PubMed
31. Andrews RC, Rooyackers O, Walker BR. Effects of the 11beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes. J Clin Endocrinol Metab 2003;88:285-291. PubMed
32. Mai K, Andres J, Bobbert T, Maser-Gluth C, Mohlig M, Bahr V, Pfeiffer AF, Spranger J, Diederich S. Rosiglitazone decreases 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue. Clin Endocrinol (Oxf) 2007;67:419-425. PubMed
33. 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;94:2692-2701. PubMed

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