Increased whole-body and sustained liver cortisol regeneration by 11beta-hydroxysteroid dehydrogenase type 1 in obese men with type 2 diabetes provides a target for enzyme inhibition.
OBJECTIVE
The cortisol-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies glucocorticoid levels in liver and adipose tissue. 11β-HSD1 inhibitors are being developed to treat type 2 diabetes. In obesity, 11β-HSD1 is increased in adipose tissue but decreased in liver. The benefits of pharmacological inhibition may be reduced if hepatic 11β-HSD1 is similarly decreased in obese patients with type 2 diabetes. To examine this, we quantified in vivo whole-body, splanchnic, and hepatic 11β-HSD1 activity in obese type 2 diabetic subjects.


METHODS
Ten obese men with type 2 diabetes and seven normal-weight control subjects were infused with 9,11,12,12-[(2)H](4)cortisol (40%) and cortisol (60%) at 1.74 mg/h. Adrenal cortisol secretion was suppressed with dexamethasone. Samples were obtained from the hepatic vein and an arterialized hand vein at steady state and after oral administration of cortisone (5 mg) to estimate whole-body and liver 11β-HSD1 activity using tracer dilution.


RESULTS
In obese type 2 diabetic subjects, the appearance rate of 9,12,12-[(2)H](3)cortisol in arterialized blood was increased (35 ± 2 vs. 29 ± 1 nmol/min, P < 0.05), splanchnic 9,12,12-[(2)H](3)cortisol production was not reduced (29 ± 6 vs. 29 ± 6 nmol/min), and cortisol appearance in the hepatic vein after oral cortisone was unchanged.


CONCLUSIONS
Whole-body 11β-HSD1 activity is increased in obese men with type 2 diabetes, whereas liver 11β-HSD1 activity is sustained, unlike in euglycemic obesity. This supports the concept that inhibitors of 11β-HSD1 are likely to be most effective in obese type 2 diabetic subjects.
Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, UK. roland.stimson@ed.ac.uk
Roland H
RH
Stimson
Ruth
R
Andrew
Norma C
NC
McAvoy
Dhiraj
D
Tripathi
Peter C
PC
Hayes
Brian R
BR
Walker
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001823:Body Composition / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D003907:Dexamethasone / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000097:blood* / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
D005938:Glucocorticoids; D003907:Dexamethasone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone
Endocrinology. 1995 Nov;136(11):4754-61
7588203
Diabetes. 2005 May;54(5):1364-70
15855321
Diabetes. 2006 Mar;55(3):667-74
16505229
J Clin Endocrinol Metab. 2004 Sep;89(9):4755-61
15356090
Obes Res. 2004 Jan;12(1):25-31
14742839
J Clin Endocrinol Metab. 1999 Mar;84(3):1022-7
10084590
Diabet Med. 2006 Dec;23(12):1281-8
17116176
J Clin Endocrinol Metab. 2002 Dec;87(12):5587-93
12466357
Diabetes. 2009 Jan;58(1):39-45
18852327
Science. 2001 Dec 7;294(5549):2166-70
11739957
Endocr Rev. 2004 Oct;25(5):831-66
15466942
J Exp Med. 2005 Aug 15;202(4):517-27
16103409
J Clin Endocrinol Metab. 2001 Mar;86(3):1418-21
11238541
Endocrinology. 2000 Feb;141(2):560-3
10650936
J Clin Endocrinol Metab. 2005 Jul;90(7):3919-26
15811928
Diabetes. 2009 Jan;58(1):46-53
18852329
J Clin Endocrinol Metab. 2006 Nov;91(11):4682-8
16954164
Diabetes. 2004 Aug;53(8):2051-9
15277385
J Clin Endocrinol Metab. 2002 Jul;87(7):3330-6
12107245
Int J Clin Pharmacol Ther. 1998 Sep;36(9):501-5
9760012
J Clin Endocrinol Metab. 2007 Nov;92(11):4480-4
17785367
Int J Obes (Lond). 2007 Dec;31(12):1826-31
17593901
J Clin Endocrinol Metab. 1998 May;83(5):1806-9
9589697
Proc Natl Acad Sci U S A. 2004 May 4;101(18):7088-93
15118095
J Clin Invest. 2003 Jul;112(1):83-90
12840062
J Clin Endocrinol Metab. 2002 Jun;87(6):2701-5
12050237
J Endocrinol. 2008 May;197(2):189-204
18434349
Am J Physiol Endocrinol Metab. 2001 Nov;281(5):E946-56
11595650
J Clin Endocrinol Metab. 2002 Jan;87(1):277-85
11788660
Expert Opin Investig Drugs. 2008 Apr;17(4):481-96
18363514
Diabetes. 2008 Oct;57(10):2652-60
18633104
Horm Metab Res. 2001 Jan;33(1):39-43
11280714
Metabolism. 1980 Oct;29(10):980-5
6999293
J Clin Endocrinol Metab. 2003 Jan;88(1):285-91
12519867
Diabetes. 2003 Jun;52(6):1409-16
12765951
J Clin Endocrinol Metab. 2001 May;86(5):2296-308
11344242
Diabetes. 2005 Mar;54(3):872-9
15734867
Endocr Res. 1996 Nov;22(4):751-5
8969937
Endocrinology. 2003 Nov;144(11):4755-62
12960099
J Clin Endocrinol Metab. 1995 Nov;80(11):3155-9
7593419
J Clin Endocrinol Metab. 2002 Oct;87(10):4686-90
12364459
Obes Surg. 2010 Jan;20(1):77-83
19690925
Endocrinology. 2007 May;148(5):2391-7
17272400