Skip to main content
Top
Published in: Diabetologia 5/2007

01-05-2007 | Article

Cortisol clearance and associations with insulin sensitivity, body fat and fatty liver in middle-aged men

Authors: H. B. Holt, S. H. Wild, A. D. Postle, J. Zhang, G. Koster, M. Umpleby, F. Shojaee-Moradie, K. Dewbury, P. J. Wood, D. I. Phillips, C. D. Byrne

Published in: Diabetologia | Issue 5/2007

Login to get access

Abstract

Aims/hypothesis

The regulation of cortisol metabolism in vivo is not well understood. We evaluated the relationship between cortisol metabolism and insulin sensitivity, adjusting for total and regional fat content and for non-alcoholic fatty liver disease.

Materials and methods

Twenty-nine middle-aged healthy men with a wide range of BMI were recruited. We measured fat content by dual-energy X-ray absorptiometry and magnetic resonance imaging (MRI), liver fat by ultrasound and MRI, the hypothalamic-pituitary-adrenal axis by adrenal response to ACTH1-24, unconjugated urinary cortisol excretion, corticosteroid-binding globulin, and cortisol clearance by MS. We assessed insulin sensitivity by hyperinsulinaemic-euglycaemic clamp and by OGTT.

Results

Cortisol clearance was strongly inversely correlated with insulin sensitivity (M value) (r = −0.61, p = 0.002). Cortisol clearance was increased in people with fatty liver compared with those without (mean±SD: 243 ± 10 vs 158 ± 36 ml/min; p = 0.014). Multiple regression modelling showed that the relationship between cortisol clearance and insulin sensitivity was independent of body fat. The relationship between fatty liver and insulin sensitivity was significantly influenced by body fat and cortisol clearance.

Conclusions/interpretation

Cortisol clearance is strongly associated with insulin sensitivity, independently of the amount of body fat. The relationship between fatty liver and insulin sensitivity is mediated in part by both fatness and cortisol clearance.
Appendix
Available only for authorised users
Literature
1.
go back to reference Strain GW, Zumoff B, Kream J, Strain JJ, Levin J, Fukushima D (1982) Sex difference in the influence of obesity on the 24 hr mean plasma concentration of cortisol. Metabolism 31:209–212PubMedCrossRef Strain GW, Zumoff B, Kream J, Strain JJ, Levin J, Fukushima D (1982) Sex difference in the influence of obesity on the 24 hr mean plasma concentration of cortisol. Metabolism 31:209–212PubMedCrossRef
2.
go back to reference Jessop DS, Dallman MF, Fleming D, Lightman SL (2001) Resistance to glucocorticoid feedback in obesity. J Clin Endocrinol Metab 86:4109–4114PubMedCrossRef Jessop DS, Dallman MF, Fleming D, Lightman SL (2001) Resistance to glucocorticoid feedback in obesity. J Clin Endocrinol Metab 86:4109–4114PubMedCrossRef
3.
go back to reference Purnell JQ, Brandon DD, Isabelle LM, Loriaux DL, Samuels MH (2004) Association of 24-hour cortisol production rates, cortisol-binding globulin, and plasma-free cortisol levels with body composition, leptin levels, and aging in adult men and women. J Clin Endocrinol Metab 89:281–287PubMedCrossRef Purnell JQ, Brandon DD, Isabelle LM, Loriaux DL, Samuels MH (2004) Association of 24-hour cortisol production rates, cortisol-binding globulin, and plasma-free cortisol levels with body composition, leptin levels, and aging in adult men and women. J Clin Endocrinol Metab 89:281–287PubMedCrossRef
4.
go back to reference Andrew R, Phillips DI, Walker BR (1998) Obesity and gender influence cortisol secretion and metabolism in man. J Clin Endocrinol Metab 83:1806–1809PubMedCrossRef Andrew R, Phillips DI, Walker BR (1998) Obesity and gender influence cortisol secretion and metabolism in man. J Clin Endocrinol Metab 83:1806–1809PubMedCrossRef
5.
go back to reference Lottenberg SA, Giannella-Neto D, Derendorf H et al (1998) Effect of fat distribution on the pharmacokinetics of cortisol in obesity. Int J Clin Pharmacol Ther 36:501–505PubMed Lottenberg SA, Giannella-Neto D, Derendorf H et al (1998) Effect of fat distribution on the pharmacokinetics of cortisol in obesity. Int J Clin Pharmacol Ther 36:501–505PubMed
6.
go back to reference Reynolds RM, Walker BR, Syddall HE et al (2001) Altered control of cortisol secretion in adult men with low birth weight and cardiovascular risk factors. J Clin Endocrinol Metab 86:245–250PubMedCrossRef Reynolds RM, Walker BR, Syddall HE et al (2001) Altered control of cortisol secretion in adult men with low birth weight and cardiovascular risk factors. J Clin Endocrinol Metab 86:245–250PubMedCrossRef
7.
go back to reference Walker BR, Soderberg S, Lindahl B, Olsson T (2000) Independent effects of obesity and cortisol in predicting cardiovascular risk factors in men and women. J Intern Med 247:198–204PubMedCrossRef Walker BR, Soderberg S, Lindahl B, Olsson T (2000) Independent effects of obesity and cortisol in predicting cardiovascular risk factors in men and women. J Intern Med 247:198–204PubMedCrossRef
8.
go back to reference Ahmed MH, Byrne CD (2005) Non alcoholic steatohepatitis. In: Byrne CD, Wild SH (eds) The metabolic syndrome, 1st edn. Wiley, Chichester, pp 279–303 Ahmed MH, Byrne CD (2005) Non alcoholic steatohepatitis. In: Byrne CD, Wild SH (eds) The metabolic syndrome, 1st edn. Wiley, Chichester, pp 279–303
10.
go back to reference Holt HB, Wild SH, Wood PJ et al (2006) Non-esterified fatty acid concentrations are independently associated with hepatic steatosis in obese subjects. Diabetologia 49:141–148PubMedCrossRef Holt HB, Wild SH, Wood PJ et al (2006) Non-esterified fatty acid concentrations are independently associated with hepatic steatosis in obese subjects. Diabetologia 49:141–148PubMedCrossRef
11.
go back to reference Utzschneider KM, Kahn SE (2006) The role of insulin resistance in non-alcoholic fatty liver disease. J Clin Endocrinol Metab 91:4753–4761PubMedCrossRef Utzschneider KM, Kahn SE (2006) The role of insulin resistance in non-alcoholic fatty liver disease. J Clin Endocrinol Metab 91:4753–4761PubMedCrossRef
12.
go back to reference Zoppini G, Targher G, Venturi C, Zamboni C, Muggeo M (2004) Relationship of nonalcoholic hepatic steatosis to overnight low-dose dexamethasone suppression test in obese individuals. Clin Endocrinol (Oxf) 61:711–715CrossRef Zoppini G, Targher G, Venturi C, Zamboni C, Muggeo M (2004) Relationship of nonalcoholic hepatic steatosis to overnight low-dose dexamethasone suppression test in obese individuals. Clin Endocrinol (Oxf) 61:711–715CrossRef
13.
go back to reference Saruc M, Yuceyar H, Ayhan S, Turkel N, Tuzcuoglu I, Can M (2003) The association of dehydroepiandrosterone, obesity, waist-hip ratio and insulin resistance with fatty liver in postmenopausal women—a hyperinsulinemic euglycemic insulin clamp study. Hepatogastroenterology 50:771–774PubMed Saruc M, Yuceyar H, Ayhan S, Turkel N, Tuzcuoglu I, Can M (2003) The association of dehydroepiandrosterone, obesity, waist-hip ratio and insulin resistance with fatty liver in postmenopausal women—a hyperinsulinemic euglycemic insulin clamp study. Hepatogastroenterology 50:771–774PubMed
14.
go back to reference Westerbacka J, Yki-Jarvinen H, Vehkavaara S et al (2003) Body fat distribution and cortisol metabolism in healthy men: enhanced 5beta-reductase and lower cortisol/cortisone metabolite ratios in men with fatty liver. J Clin Endocrinol Metab 88:4924–4931PubMedCrossRef Westerbacka J, Yki-Jarvinen H, Vehkavaara S et al (2003) Body fat distribution and cortisol metabolism in healthy men: enhanced 5beta-reductase and lower cortisol/cortisone metabolite ratios in men with fatty liver. J Clin Endocrinol Metab 88:4924–4931PubMedCrossRef
15.
go back to reference Targher G, Bertolini L, Rodella S, Zoppini G, Zenari L, Falezza G (2006) Associations between liver histology and cortisol secretion in subjects with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf) 64:337–341CrossRef Targher G, Bertolini L, Rodella S, Zoppini G, Zenari L, Falezza G (2006) Associations between liver histology and cortisol secretion in subjects with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf) 64:337–341CrossRef
16.
go back to reference DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E223PubMed DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E223PubMed
17.
go back to reference Powrie JK, Smith GD, Hennessy TR et al (1992) Incomplete suppression of hepatic glucose production in non-insulin dependent diabetes mellitus measured with [6,6-2H2]glucose enriched glucose infusion during hyperinsulinaemic-euglycaemic clamps. Eur J Clin Invest 22:244–253CrossRef Powrie JK, Smith GD, Hennessy TR et al (1992) Incomplete suppression of hepatic glucose production in non-insulin dependent diabetes mellitus measured with [6,6-2H2]glucose enriched glucose infusion during hyperinsulinaemic-euglycaemic clamps. Eur J Clin Invest 22:244–253CrossRef
18.
go back to reference Finegood DT, Bergman RN (1983) Optimal segments: a method for smoothing tracer data to calculate metabolic fluxes. Am J Physiol 244:E472–E479PubMed Finegood DT, Bergman RN (1983) Optimal segments: a method for smoothing tracer data to calculate metabolic fluxes. Am J Physiol 244:E472–E479PubMed
19.
go back to reference Steele R (1959) Influences of glucose loading and of injected insulin on hepatic glucose output. Ann N Y Acad Sci 82:420–430PubMedCrossRef Steele R (1959) Influences of glucose loading and of injected insulin on hepatic glucose output. Ann N Y Acad Sci 82:420–430PubMedCrossRef
20.
go back to reference Finegood DT, Bergman RN, Vranic M (1988) Modeling error and apparent isotope discrimination confound estimation of endogenous glucose production during euglycemic glucose clamps. Diabetes 37:1025–1034PubMedCrossRef Finegood DT, Bergman RN, Vranic M (1988) Modeling error and apparent isotope discrimination confound estimation of endogenous glucose production during euglycemic glucose clamps. Diabetes 37:1025–1034PubMedCrossRef
21.
go back to reference Belfiore F, Iannello S, Volpicelli G (1998) Insulin sensitivity indices calculated from basal and OGTT-induced insulin, glucose, and FFA levels. Mol Genet Metab 63:134–141PubMedCrossRef Belfiore F, Iannello S, Volpicelli G (1998) Insulin sensitivity indices calculated from basal and OGTT-induced insulin, glucose, and FFA levels. Mol Genet Metab 63:134–141PubMedCrossRef
22.
go back to reference Moore A, Aitken R, Burke C et al (1985) Cortisol assays: guidelines for the provision of a clinical biochemistry service. Ann Clin Biochem 22:435–454PubMed Moore A, Aitken R, Burke C et al (1985) Cortisol assays: guidelines for the provision of a clinical biochemistry service. Ann Clin Biochem 22:435–454PubMed
23.
go back to reference Jerjes WK, Cleare AJ, Peters TJ, Taylor NF (2006) Circadian rhythm of urinary steroid metabolites. Ann Clin Biochem 43:287–294PubMedCrossRef Jerjes WK, Cleare AJ, Peters TJ, Taylor NF (2006) Circadian rhythm of urinary steroid metabolites. Ann Clin Biochem 43:287–294PubMedCrossRef
24.
go back to reference Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461–470PubMed Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461–470PubMed
25.
go back to reference Bright GM (1995) Corticosteroid-binding globulin influences kinetic parameters of plasma cortisol transport and clearance. J Clin Endocrinol Metab 80:770–775PubMedCrossRef Bright GM (1995) Corticosteroid-binding globulin influences kinetic parameters of plasma cortisol transport and clearance. J Clin Endocrinol Metab 80:770–775PubMedCrossRef
26.
go back to reference Tait JF (1963) Review: the use of isotopic steroids for the measurement of production rates in vivo. J Clin Endocrinol Metab 23:1285–1297PubMedCrossRef Tait JF (1963) Review: the use of isotopic steroids for the measurement of production rates in vivo. J Clin Endocrinol Metab 23:1285–1297PubMedCrossRef
27.
go back to reference Kleinbaum D, Kupper L, Muller K, Nizam A (1998) Multiple regression analysis: general considerations. In: Applied regression analysis and other multivariate methods. Duxberry, Pacific Grove, CA, pp 237–245 Kleinbaum D, Kupper L, Muller K, Nizam A (1998) Multiple regression analysis: general considerations. In: Applied regression analysis and other multivariate methods. Duxberry, Pacific Grove, CA, pp 237–245
28.
go back to reference Clasey JL, Bouchard C, Teates CD et al (1999) The use of anthropometric and dual-energy X-ray absorptiometry (DXA) measures to estimate total abdominal and abdominal visceral fat in men and women. Obes Res 7:256–264PubMed Clasey JL, Bouchard C, Teates CD et al (1999) The use of anthropometric and dual-energy X-ray absorptiometry (DXA) measures to estimate total abdominal and abdominal visceral fat in men and women. Obes Res 7:256–264PubMed
29.
go back to reference Aldhahi W, Mun E, Goldfine AB (2004) Portal and peripheral cortisol levels in obese humans. Diabetologia 47:833–836PubMedCrossRef Aldhahi W, Mun E, Goldfine AB (2004) Portal and peripheral cortisol levels in obese humans. Diabetologia 47:833–836PubMedCrossRef
30.
go back to reference Saverymuttu SH, Joseph AE, Maxwell JD (1986) Ultrasound scanning in the detection of hepatic fibrosis and steatosis. Br Med J (Clin Res Ed) 292:13–15CrossRef Saverymuttu SH, Joseph AE, Maxwell JD (1986) Ultrasound scanning in the detection of hepatic fibrosis and steatosis. Br Med J (Clin Res Ed) 292:13–15CrossRef
31.
go back to reference Targher G, Bertolini L, Zoppini G, Zenari L, Falezza G (2005) Relationship of non-alcoholic hepatic steatosis to cortisol secretion in diet-controlled type 2 diabetic patients. Diabet Med 22:1146–1150PubMedCrossRef Targher G, Bertolini L, Zoppini G, Zenari L, Falezza G (2005) Relationship of non-alcoholic hepatic steatosis to cortisol secretion in diet-controlled type 2 diabetic patients. Diabet Med 22:1146–1150PubMedCrossRef
32.
go back to reference Pasquali R, Ambrosi B, Armanini D et al (2002) Cortisol and ACTH response to oral dexamethasone in obesity and effects of sex, body fat distribution, and dexamethasone concentrations: a dose–response study. J Clin Endocrinol Metab 87:166–175PubMedCrossRef Pasquali R, Ambrosi B, Armanini D et al (2002) Cortisol and ACTH response to oral dexamethasone in obesity and effects of sex, body fat distribution, and dexamethasone concentrations: a dose–response study. J Clin Endocrinol Metab 87:166–175PubMedCrossRef
33.
go back to reference Cassidy F, Ritchie JC, Verghese K, Carroll BJ (2000) Dexamethasone metabolism in dexamethasone suppression test suppressors and nonsuppressors. Biol Psychiatry 47:677–680PubMedCrossRef Cassidy F, Ritchie JC, Verghese K, Carroll BJ (2000) Dexamethasone metabolism in dexamethasone suppression test suppressors and nonsuppressors. Biol Psychiatry 47:677–680PubMedCrossRef
34.
go back to reference Tsuei SE, Moore RG, Ashley JJ, McBride WG (1979) Disposition of synthetic glucocorticoids. I. Pharmacokinetics of dexamethasone in healthy adults. J Pharmacokinet Biopharm 7:249–264PubMedCrossRef Tsuei SE, Moore RG, Ashley JJ, McBride WG (1979) Disposition of synthetic glucocorticoids. I. Pharmacokinetics of dexamethasone in healthy adults. J Pharmacokinet Biopharm 7:249–264PubMedCrossRef
35.
go back to reference Huizenga NA, Koper JW, de Lange P et al (1998) Interperson variability but intraperson stability of baseline plasma cortisol concentrations, and its relation to feedback sensitivity of the hypothalamo-pituitary-adrenal axis to a low dose of dexamethasone in elderly individuals. J Clin Endocrinol Metab 83:47–54PubMedCrossRef Huizenga NA, Koper JW, de Lange P et al (1998) Interperson variability but intraperson stability of baseline plasma cortisol concentrations, and its relation to feedback sensitivity of the hypothalamo-pituitary-adrenal axis to a low dose of dexamethasone in elderly individuals. J Clin Endocrinol Metab 83:47–54PubMedCrossRef
36.
go back to reference Kutemeyer S, Schurmeyer TH, von zur Muhlen A (1994) Effect of liver damage on the pharmacokinetics of dexamethasone. Eur J Endocrinol 131:594–597PubMed Kutemeyer S, Schurmeyer TH, von zur Muhlen A (1994) Effect of liver damage on the pharmacokinetics of dexamethasone. Eur J Endocrinol 131:594–597PubMed
37.
go back to reference Lewis JG, Shand BI, Elder PA, Scott RS (2004) Plasma sex hormone-binding globulin rather than corticosteroid-binding globulin is a marker of insulin resistance in obese adult males. Diabetes Obes Metab 6:259–263PubMedCrossRef Lewis JG, Shand BI, Elder PA, Scott RS (2004) Plasma sex hormone-binding globulin rather than corticosteroid-binding globulin is a marker of insulin resistance in obese adult males. Diabetes Obes Metab 6:259–263PubMedCrossRef
38.
go back to reference Fernandez-Real JM, Pugeat M, Grasa M et al (2002) Serum corticosteroid-binding globulin concentration and insulin resistance syndrome: a population study. J Clin Endocrinol Metab 87:4686–4690PubMedCrossRef Fernandez-Real JM, Pugeat M, Grasa M et al (2002) Serum corticosteroid-binding globulin concentration and insulin resistance syndrome: a population study. J Clin Endocrinol Metab 87:4686–4690PubMedCrossRef
39.
go back to reference Fernandez-Real JM, Pugeat M, Lopez-Bermejo A, Bornet H, Ricart W (2005) Corticosteroid-binding globulin affects the relationship between circulating adiponectin and cortisol in men and women. Metabolism 54:584–589PubMedCrossRef Fernandez-Real JM, Pugeat M, Lopez-Bermejo A, Bornet H, Ricart W (2005) Corticosteroid-binding globulin affects the relationship between circulating adiponectin and cortisol in men and women. Metabolism 54:584–589PubMedCrossRef
40.
go back to reference Wake DJ, Walker BR (2006) Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 in obesity. Endocrine 29:101–108PubMedCrossRef Wake DJ, Walker BR (2006) Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 in obesity. Endocrine 29:101–108PubMedCrossRef
41.
go back to reference Whorwood CB, Donovan SJ, Wood PJ, Phillips DI (2001) Regulation of glucocorticoid receptor alpha and beta isoforms and type I 11beta-hydroxysteroid dehydrogenase expression in human skeletal muscle cells: a key role in the pathogenesis of insulin resistance? J Clin Endocrinol Metab 86:2296–2308PubMedCrossRef Whorwood CB, Donovan SJ, Wood PJ, Phillips DI (2001) Regulation of glucocorticoid receptor alpha and beta isoforms and type I 11beta-hydroxysteroid dehydrogenase expression in human skeletal muscle cells: a key role in the pathogenesis of insulin resistance? J Clin Endocrinol Metab 86:2296–2308PubMedCrossRef
42.
go back to reference Reynolds RM, Chapman KE, Seckl JR, Walker BR, McKeigue PM, Lithell HO (2002) Skeletal muscle glucocorticoid receptor density and insulin resistance. JAMA 287:2505–2506PubMedCrossRef Reynolds RM, Chapman KE, Seckl JR, Walker BR, McKeigue PM, Lithell HO (2002) Skeletal muscle glucocorticoid receptor density and insulin resistance. JAMA 287:2505–2506PubMedCrossRef
43.
go back to reference Whorwood CB, Donovan SJ, Flanagan D, Phillips DI, Byrne CD (2002) Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome. Diabetes 51:1066–1075PubMedCrossRef Whorwood CB, Donovan SJ, Flanagan D, Phillips DI, Byrne CD (2002) Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome. Diabetes 51:1066–1075PubMedCrossRef
44.
go back to reference Reynolds RM, Fischbacher C, Bhopal R et al (2006) Differences in cortisol concentrations in South Asian and European men living in the United Kingdom. Clin Endocrinol (Oxf) 64:530–534CrossRef Reynolds RM, Fischbacher C, Bhopal R et al (2006) Differences in cortisol concentrations in South Asian and European men living in the United Kingdom. Clin Endocrinol (Oxf) 64:530–534CrossRef
45.
go back to reference Bjorntorp P, Holm G, Rosmond R (1999) Hypothalamic arousal, insulin resistance and type 2 diabetes mellitus. Diabet Med 16:373–383PubMedCrossRef Bjorntorp P, Holm G, Rosmond R (1999) Hypothalamic arousal, insulin resistance and type 2 diabetes mellitus. Diabet Med 16:373–383PubMedCrossRef
Metadata
Title
Cortisol clearance and associations with insulin sensitivity, body fat and fatty liver in middle-aged men
Authors
H. B. Holt
S. H. Wild
A. D. Postle
J. Zhang
G. Koster
M. Umpleby
F. Shojaee-Moradie
K. Dewbury
P. J. Wood
D. I. Phillips
C. D. Byrne
Publication date
01-05-2007
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 5/2007
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-007-0629-9

Other articles of this Issue 5/2007

Diabetologia 5/2007 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.