| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on October 24, 2006
Accepted on December 22, 2006
-HSD1 activity in vivo limits glucocorticoid exposure to human adipose tissue and decreases lipolysis
Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK. B15 2TT; Department of Clinical Chemistry & Immunology, Heart of England NHS Foundation Trust, Birmingham, UK, B9 5SS; Pfizer Global R&D, La Jolla Laboratories, 10646 Science Center Drive, San Diego, CA, 92121, USA
* To whom correspondence should be addressed. E-mail: J.W.Tomlinson{at}bham.ac.uk.
Context: The pathophysiological importance of glucocorticoids (GC) is exemplified by patients with Cushing's syndrome who develop hypertension, obesity and insulin resistance. At a cellular level, availability of GC to the glucocorticoid and mineralocorticoid receptors (GR and MR) is controlled by the isoforms of 11
-hydroxysteroid dehydrogenase. In liver and adipose tissue, 11-HSD1, converts endogenous, inactive cortisone to active cortisol, but also catalyses the bio-activation of the synthetic prednisone to prednisolone.
Objective: To compare markers of 11-HSD1 activity and to demonstrate that inhibition of 11-HSD1 activity limits glucocorticoid availability to adipose tissue.
Design and setting: Clinical study
Patients: 7 healthy male volunteers
Intervention: Carbenoxolone (CBX) single dose (100mg) and 72hrs of continuous treatment (300mg/day)
Main outcome measures: Inhibition of 11-HSD1 was monitored using five different mechanistic biomarkers (serum cortisol and prednisolone generation, urinary corticosteroid metabolite analysis by GC/MS and adipose tissue microdialysis examining cortisol generation and glucocorticoid mediated glycerol release).
Results: Each biomarker demonstrated reduced 11-HSD1 activity after CBX administration. After both a single dose and 72hrs of treatment with CBX, cortisol and prednisolone generation decreased as did the urinary THF+5
THF:THE ratio. Using adipose tissue microdialysis, we observed decreased interstitial fluid cortisol availability with CBX treatment. Furthermore, a functional consequence of 11-HSD1 inhibition was observed, namely decreased prednisone-induced glycerol release into adipose tissue interstitial fluid indicative of inhibition of GC mediated lipolysis.
Conclusion: CBX is able to rapidly inhibit the generation of active glucocorticoid in human adipose tissue. Importantly, limiting GC availability in vivo has functional consequences including decreased glycerol release.
-hydroxysteroid dehydrogenase •
lipolysis •
cortisol •
prednisolone •
carbenoxolone
This article has been cited by other articles:
 |
|
 |
|
  P. M Stewart, A. Stears, J. W Tomlinson, and M. J Brown Regulation--the real threat to clinical research BMJ, October 16, 2008; 337(oct16_2): a1732 - a1732. [Full Text]
|
|
|
|
 |
|
 Y. Liu, Y. Nakagawa, Y. Wang, L. Liu, H. Du, W. Wang, X. Ren, K. Lutfy, and T. C Friedman Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice J. Mol. Endocrinol., August 1, 2008; 41(2): 53 - 64. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Tomlinson, J. Finney, B. A. Hughes, S. V. Hughes, and P. M. Stewart Reduced Glucocorticoid Production Rate, Decreased 5{alpha}-Reductase Activity, and Adipose Tissue Insulin Sensitization After Weight Loss Diabetes, June 1, 2008; 57(6): 1536 - 1543. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. P Macfarlane, S. Forbes, and B. R Walker Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome J. Endocrinol., May 1, 2008; 197(2): 189 - 204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. J. Bujalska, K. N. Hewitt, D. Hauton, G. G. Lavery, J. W. Tomlinson, E. A. Walker, and P. M. Stewart Lack of Hexose-6-Phosphate Dehydrogenase Impairs Lipid Mobilization from Mouse Adipose Tissue Endocrinology, May 1, 2008; 149(5): 2584 - 2591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Courtney, P. M. Stewart, M. Toh, M.-N. Ndongo, R. A. Calle, and B. Hirshberg Modulation of 11{beta}-Hydroxysteroid Dehydrogenase (11{beta}HSD) Activity Biomarkers and Pharmacokinetics of PF-00915275, a Selective 11{beta}HSD1 Inhibitor J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 550 - 556. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. G. Bhat, N. Hosea, A. Fanjul, J. Herrera, J. Chapman, F. Thalacker, P. M. Stewart, and P. A. Rejto Demonstration of Proof of Mechanism and Pharmacokinetics and Pharmacodynamic Relationship with 4'-Cyano-biphenyl-4-sulfonic Acid (6-Amino-pyridin-2-yl)-amide (PF-915275), an Inhibitor of 11 -Hydroxysteroid Dehydrogenase Type 1, in Cynomolgus Monkeys J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 299 - 305. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Nuotio-Antar, D. L. Hachey, and A. H. Hasty Carbenoxolone treatment attenuates symptoms of metabolic syndrome and atherogenesis in obese, hyperlipidemic mice Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1517 - E1528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Wudy, M. F. Hartmann, and T. Remer Sexual dimorphism in cortisol secretion starts after age 10 in healthy children: urinary cortisol metabolite excretion rates during growth Am J Physiol Endocrinol Metab, October 1, 2007; 293(4): E970 - E976. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
