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Published in: Cardiovascular Diabetology 1/2012

Open Access 01-12-2012 | Original investigation

Does insulin resistance co-exist with glucocorticoid resistance in the metabolic syndrome? Studies comparing skin sensitivity to glucocorticoids in individuals with and without acanthosis nigricans

Authors: Surujpal Teelucksingh, Sarada Jaimungal, Lexley Pinto Pereira, Terence Seemungal, Shivananda Nayak

Published in: Cardiovascular Diabetology | Issue 1/2012

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Abstract

Background

The metabolic syndrome is associated with increased risk for both diabetes and coronary artery disease, which insulin resistance alone does not satisfactorily explain. We propose an additional and complementary underlying mechanism of glucocorticoid resistance.

Results

Using acanthosis nigricans (AN) and skin vasoconstrictor (SVC) response to topically applied beclomethasone dipropionate as markers of insulin and glucocorticoid resistance, respectively, we compared anthropometric, biochemical, pro-inflammatory markers and the SVC response in subjects with AN in two studies: STUDY 1 was used to compare subjects with AN (Grade 4, n = 32), with those without AN (n = 68) while STUDY 2 compared these responses among a cross-section of diabetic patients (n = 109) with varying grades of AN (grade 0, n = 30; grade 1, n = 24; grade 2, n = 18; grade 3, n = 25; grade 4, n = 12).

Findings

In both studies there was an inverse relationship between AN Grade 4 and the SVC response, (P < 0.001). In STUDY 1, AN Grade 4 was associated with age, waist circumference, BMI, fasting blood glucose, plasma lipids and hs-CRP (P < 0.05). SVC was an independent predictor of CRP and those with combined AN and a negative SVC response, CRP levels were highest. In Study 2 when the SVC response in subjects with type 2 diabetes mellitus with varying degrees of AN was studied, it showed that for any degree of AN, the SVC response is more likely to be negative and was independent of gender and ethnicity.

Conclusion

An absent SVC response represents a new biomarker for the metabolic syndrome and the exaggerated inflammatory response, which characterizes the metabolic syndrome, may be an outcome of deficient glucocorticoid action in vascular tissue.
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Literature
1.
go back to reference Hossain P, Kawar B, El Nahas M: Obesity and diabetes in the developing world- a growing challenge. New Engl J Med. 2007, 356: 213-215. 10.1056/NEJMp068177.CrossRefPubMed Hossain P, Kawar B, El Nahas M: Obesity and diabetes in the developing world- a growing challenge. New Engl J Med. 2007, 356: 213-215. 10.1056/NEJMp068177.CrossRefPubMed
2.
go back to reference Enzi G, Busetto L, Inelman EM, Coin A, Sergi G: Historical perspective: visceral obesity and related comorbidity in Joannes Baptista Morgagni's "De Sedibus et causis morborum per anatomen indagata". J Obes. 2003, 27: 534-535. 10.1038/sj.ijo.0802268.CrossRef Enzi G, Busetto L, Inelman EM, Coin A, Sergi G: Historical perspective: visceral obesity and related comorbidity in Joannes Baptista Morgagni's "De Sedibus et causis morborum per anatomen indagata". J Obes. 2003, 27: 534-535. 10.1038/sj.ijo.0802268.CrossRef
3.
go back to reference Reaven GM: Banting Lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988, 37 (12): 1595-1607. 10.2337/diabetes.37.12.1595.CrossRefPubMed Reaven GM: Banting Lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988, 37 (12): 1595-1607. 10.2337/diabetes.37.12.1595.CrossRefPubMed
4.
go back to reference Grundy SM: Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol. 2008, 28 (4): 629-636. 10.1161/ATVBAHA.107.151092.CrossRefPubMed Grundy SM: Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol. 2008, 28 (4): 629-636. 10.1161/ATVBAHA.107.151092.CrossRefPubMed
5.
go back to reference Gerstein HC: More insights on the dysglycaemia-cardiovascular connection. Lancet. 2010, 375: 2195-2196. 10.1016/S0140-6736(10)60973-7.CrossRefPubMed Gerstein HC: More insights on the dysglycaemia-cardiovascular connection. Lancet. 2010, 375: 2195-2196. 10.1016/S0140-6736(10)60973-7.CrossRefPubMed
6.
go back to reference Stern MP: Diabetes and cardiovascular disease. The "common soil" hypothesis. Diabetes. 1995, 44: 369-374. 10.2337/diabetes.44.4.369.CrossRefPubMed Stern MP: Diabetes and cardiovascular disease. The "common soil" hypothesis. Diabetes. 1995, 44: 369-374. 10.2337/diabetes.44.4.369.CrossRefPubMed
7.
go back to reference Sam S, Feinstein S, Haffner S, Kondos G, Davidson MH, Perez A, et al: Relation of abdominal fat depots to systemic markers of inflammation in Type 2 Diabetes. Diabetes Care. 2009, 32: 932-937. 10.2337/dc08-1856.PubMedCentralCrossRefPubMed Sam S, Feinstein S, Haffner S, Kondos G, Davidson MH, Perez A, et al: Relation of abdominal fat depots to systemic markers of inflammation in Type 2 Diabetes. Diabetes Care. 2009, 32: 932-937. 10.2337/dc08-1856.PubMedCentralCrossRefPubMed
8.
go back to reference Kolb H, Mandrup-Poulsen T: The global diabetes epidemic as a consequence of lifestyle-induced low grade inflammation. Diabetologia. 2010, 53: 10-20. 10.1007/s00125-009-1573-7.CrossRefPubMed Kolb H, Mandrup-Poulsen T: The global diabetes epidemic as a consequence of lifestyle-induced low grade inflammation. Diabetologia. 2010, 53: 10-20. 10.1007/s00125-009-1573-7.CrossRefPubMed
9.
go back to reference Pickup JC: Inflammation and activated innate immunity in the pathogenesis of Type 2 diabetes. Diabetes Care. 2004, 27 (3): 813-823. 10.2337/diacare.27.3.813.CrossRefPubMed Pickup JC: Inflammation and activated innate immunity in the pathogenesis of Type 2 diabetes. Diabetes Care. 2004, 27 (3): 813-823. 10.2337/diacare.27.3.813.CrossRefPubMed
10.
go back to reference Tataranni PA, Ortega E: A burning question: does an adipokine-induced activation of the immune system mediate the effect of overnutrition on type 2 diabetes?. Diabetes. 2005, 54: 917-927. 10.2337/diabetes.54.4.917.CrossRefPubMed Tataranni PA, Ortega E: A burning question: does an adipokine-induced activation of the immune system mediate the effect of overnutrition on type 2 diabetes?. Diabetes. 2005, 54: 917-927. 10.2337/diabetes.54.4.917.CrossRefPubMed
11.
go back to reference Walker BR: Cortisol- cause and cure for metabolic syndrome?. Diabet Med. 2008, 23: 1281-1288.CrossRef Walker BR: Cortisol- cause and cure for metabolic syndrome?. Diabet Med. 2008, 23: 1281-1288.CrossRef
12.
go back to reference van den Akker EL, Koper JW, van Rossum EFC, Dekker MJH, Russcher H, de Jong FH, et al: Glucocorticoid receptor gene and risk of cardiovascular disease. Arch Intern Med. 2008, 168: 33-39. 10.1001/archinternmed.2007.41.CrossRefPubMed van den Akker EL, Koper JW, van Rossum EFC, Dekker MJH, Russcher H, de Jong FH, et al: Glucocorticoid receptor gene and risk of cardiovascular disease. Arch Intern Med. 2008, 168: 33-39. 10.1001/archinternmed.2007.41.CrossRefPubMed
13.
go back to reference Seckl JR, Morton NM, Chapmen KE, Walker BR: Glucocorticoids and 11 beta-hydroxysteroid dehydrogenase in adipose tissue. Recent Prog Horm Res. 2004, 59: 359-393. 10.1210/rp.59.1.359.CrossRefPubMed Seckl JR, Morton NM, Chapmen KE, Walker BR: Glucocorticoids and 11 beta-hydroxysteroid dehydrogenase in adipose tissue. Recent Prog Horm Res. 2004, 59: 359-393. 10.1210/rp.59.1.359.CrossRefPubMed
14.
go back to reference Anagnostis P, Athros VG, Tziomalos K, Karagiannis A, Mikhailidis DP: The pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J Clin Endocrinol Metab. 2009, 94: 2692-2701. 10.1210/jc.2009-0370.CrossRefPubMed Anagnostis P, Athros VG, Tziomalos K, Karagiannis A, Mikhailidis DP: The pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J Clin Endocrinol Metab. 2009, 94: 2692-2701. 10.1210/jc.2009-0370.CrossRefPubMed
15.
go back to reference Burke JP, Hale DE, Hazuda HP, Stern MP: A quantitative scale of acanthosis nigricans. Diabetes Care. 1999, 22: 1655-1659. 10.2337/diacare.22.10.1655.CrossRefPubMed Burke JP, Hale DE, Hazuda HP, Stern MP: A quantitative scale of acanthosis nigricans. Diabetes Care. 1999, 22: 1655-1659. 10.2337/diacare.22.10.1655.CrossRefPubMed
16.
go back to reference Brown PH, Teelucksingh S, Matusiewicz SP, Greening AP, Crompton GK, Edwards CRW: Cutaneous vasoconstrictor response to glucocorticoids in asthma. Lancet. 1991, 337: 576-580. 10.1016/0140-6736(91)91639-C.CrossRefPubMed Brown PH, Teelucksingh S, Matusiewicz SP, Greening AP, Crompton GK, Edwards CRW: Cutaneous vasoconstrictor response to glucocorticoids in asthma. Lancet. 1991, 337: 576-580. 10.1016/0140-6736(91)91639-C.CrossRefPubMed
17.
go back to reference Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM, et al: The syndromes of insulin resistance and acanthosis nigricans. Insulin- receptor disorders in man. New Engl J Med. 1976, 294: 739-745. 10.1056/NEJM197604012941401.CrossRefPubMed Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM, et al: The syndromes of insulin resistance and acanthosis nigricans. Insulin- receptor disorders in man. New Engl J Med. 1976, 294: 739-745. 10.1056/NEJM197604012941401.CrossRefPubMed
18.
go back to reference Stuart CA, Gilkison CR, Keenan BS, Nagamani M: Hyperinsulinemia and acanthosis nigricans in African Americans. J Natl Med Assoc. 1997, 89 (8): 523-527.PubMedCentralPubMed Stuart CA, Gilkison CR, Keenan BS, Nagamani M: Hyperinsulinemia and acanthosis nigricans in African Americans. J Natl Med Assoc. 1997, 89 (8): 523-527.PubMedCentralPubMed
19.
go back to reference Pinheiro AC, Rojas P, Carrasco F, Gomez P, Mayas N, Morales I: Acanthosis nigricans as an indicator of insulin resistance in Chilean adult population. Nutr Hosp. 2011, 26 (5): 940-944.PubMed Pinheiro AC, Rojas P, Carrasco F, Gomez P, Mayas N, Morales I: Acanthosis nigricans as an indicator of insulin resistance in Chilean adult population. Nutr Hosp. 2011, 26 (5): 940-944.PubMed
20.
go back to reference McKenzie AW, Stoughton RB: Method for comparing percutaneous absorption of steroids. Arch Dermatol. 1962, 86: 608-610. 10.1001/archderm.1962.01590110044005.CrossRef McKenzie AW, Stoughton RB: Method for comparing percutaneous absorption of steroids. Arch Dermatol. 1962, 86: 608-610. 10.1001/archderm.1962.01590110044005.CrossRef
21.
go back to reference Walker BR, Best R, Shackleton CHL, Padfield P, Edwards CRW: Increased v asoconstrictor sensitivity to glucocorticoids in essential hypertension. Hypertension. 1996, 27: 190-196.CrossRefPubMed Walker BR, Best R, Shackleton CHL, Padfield P, Edwards CRW: Increased v asoconstrictor sensitivity to glucocorticoids in essential hypertension. Hypertension. 1996, 27: 190-196.CrossRefPubMed
22.
go back to reference Barry BW, Woodford R: Activity and bioavailability of topical steroids: In vivo/in vitro correlations for the vasoconstrictor test. J Clin Pharmac. 1978, 3: 43-65. Barry BW, Woodford R: Activity and bioavailability of topical steroids: In vivo/in vitro correlations for the vasoconstrictor test. J Clin Pharmac. 1978, 3: 43-65.
23.
go back to reference Teelucksingh S, Mackie ADR, Burt D, McIntyre MA, Brett L, Edwards CRW: Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet. 1990, 335: 1060-1063. 10.1016/0140-6736(90)92633-S.CrossRefPubMed Teelucksingh S, Mackie ADR, Burt D, McIntyre MA, Brett L, Edwards CRW: Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet. 1990, 335: 1060-1063. 10.1016/0140-6736(90)92633-S.CrossRefPubMed
24.
go back to reference Teelucksingh S: Glucocorticoids and the skin. PhD thesis. 1995, University of Edinburgh, Scotland Teelucksingh S: Glucocorticoids and the skin. PhD thesis. 1995, University of Edinburgh, Scotland
25.
go back to reference Panarelli M, Holloway CD, Fraser R, Connell JMC, Ingram MC, et al: Glucorticoid receptor polymorphism, skin vasoconstriction, and other metabolic intermediate phenotypes in normal human subjects. J Clin Endocrinol Metab. 1998, 83: 1846-1852. 10.1210/jc.83.6.1846.PubMed Panarelli M, Holloway CD, Fraser R, Connell JMC, Ingram MC, et al: Glucorticoid receptor polymorphism, skin vasoconstriction, and other metabolic intermediate phenotypes in normal human subjects. J Clin Endocrinol Metab. 1998, 83: 1846-1852. 10.1210/jc.83.6.1846.PubMed
26.
go back to reference Johansson S-A, Andersson K-E, Brattsand R, Gruvstav E, Hedner P: Topical and systemic potencies of budesonide and beclomethasone dipropionate in man. Eur J Clin Pharmacol. 1982, 22: 523-529. 10.1007/BF00609625.CrossRefPubMed Johansson S-A, Andersson K-E, Brattsand R, Gruvstav E, Hedner P: Topical and systemic potencies of budesonide and beclomethasone dipropionate in man. Eur J Clin Pharmacol. 1982, 22: 523-529. 10.1007/BF00609625.CrossRefPubMed
27.
go back to reference Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS: A transgenic model of visceral obesity and the metabolic syndrome. Science. 2001, 294 (5549): 2166-2170. 10.1126/science.1066285.CrossRefPubMed Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS: A transgenic model of visceral obesity and the metabolic syndrome. Science. 2001, 294 (5549): 2166-2170. 10.1126/science.1066285.CrossRefPubMed
28.
go back to reference Hermanowski-Vosatka A, Balkovec JM, Cheng K, Chen HY, Hernandez M, Koo GC, Legrand CB, et al: 11beta-hydroxsteroid dehydrogenase 1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med. 2005, 202 (4): 517-527. 10.1084/jem.20050119.PubMedCentralCrossRefPubMed Hermanowski-Vosatka A, Balkovec JM, Cheng K, Chen HY, Hernandez M, Koo GC, Legrand CB, et al: 11beta-hydroxsteroid dehydrogenase 1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med. 2005, 202 (4): 517-527. 10.1084/jem.20050119.PubMedCentralCrossRefPubMed
29.
go back to reference Edwards CR, Benediktsson R, Lindsay RS, Seckl JR: 11beta-hydroxysteroid dehydrogenases: Key enzymes in determining tissue-specific glucocorticoid effects. Steroids. 1996, 61 (4): 263-269. 10.1016/0039-128X(96)00033-5.CrossRefPubMed Edwards CR, Benediktsson R, Lindsay RS, Seckl JR: 11beta-hydroxysteroid dehydrogenases: Key enzymes in determining tissue-specific glucocorticoid effects. Steroids. 1996, 61 (4): 263-269. 10.1016/0039-128X(96)00033-5.CrossRefPubMed
30.
go back to reference Freeman AI, Munn HL, Lyons V, Dammermann A, Seckl JR, Chapman KE: Glucocorticoid down-regulation of rat glucocorticoid receptor does not involve differential promoter regulation. J Endocrinol. 2004, 183 (2): 365-374. 10.1677/joe.1.05773.CrossRefPubMed Freeman AI, Munn HL, Lyons V, Dammermann A, Seckl JR, Chapman KE: Glucocorticoid down-regulation of rat glucocorticoid receptor does not involve differential promoter regulation. J Endocrinol. 2004, 183 (2): 365-374. 10.1677/joe.1.05773.CrossRefPubMed
31.
go back to reference Hansson GK, Libby P, Schonbeck U, Yan Z-Q: Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res. 2002, 91: 281-291. 10.1161/01.RES.0000029784.15893.10.CrossRefPubMed Hansson GK, Libby P, Schonbeck U, Yan Z-Q: Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res. 2002, 91: 281-291. 10.1161/01.RES.0000029784.15893.10.CrossRefPubMed
32.
go back to reference Manco M, Castagneto M, Nanni G, Guidone C, Tondolo V, Greco AV, et al: Biliopancreatic diversion as a novel approach to the HAIR-AN syndrome. Obes Surg. 2005, 15: 286-289. 10.1381/0960892053268435.CrossRefPubMed Manco M, Castagneto M, Nanni G, Guidone C, Tondolo V, Greco AV, et al: Biliopancreatic diversion as a novel approach to the HAIR-AN syndrome. Obes Surg. 2005, 15: 286-289. 10.1381/0960892053268435.CrossRefPubMed
33.
go back to reference Martin-Cordero L, et al: The interleukin-6 and noradrenaline mediated inflammation-stress feedback mechanism is dysregulated in metabolic syndrome: Effect of exercise. Cardiovasc Diabetol. 2011, 10: 42-10.1186/1475-2840-10-42.PubMedCentralCrossRefPubMed Martin-Cordero L, et al: The interleukin-6 and noradrenaline mediated inflammation-stress feedback mechanism is dysregulated in metabolic syndrome: Effect of exercise. Cardiovasc Diabetol. 2011, 10: 42-10.1186/1475-2840-10-42.PubMedCentralCrossRefPubMed
34.
go back to reference Bujalska IJ, Kumar S, Stewart PM: Does central obesity reflect "Cushing's disease of the omentum". Lancet. 1997, 349: 1210-1213. 10.1016/S0140-6736(96)11222-8.CrossRefPubMed Bujalska IJ, Kumar S, Stewart PM: Does central obesity reflect "Cushing's disease of the omentum". Lancet. 1997, 349: 1210-1213. 10.1016/S0140-6736(96)11222-8.CrossRefPubMed
Metadata
Title
Does insulin resistance co-exist with glucocorticoid resistance in the metabolic syndrome? Studies comparing skin sensitivity to glucocorticoids in individuals with and without acanthosis nigricans
Authors
Surujpal Teelucksingh
Sarada Jaimungal
Lexley Pinto Pereira
Terence Seemungal
Shivananda Nayak
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2012
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/1475-2840-11-31

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