11beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle.
OBJECTIVE
Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning glucocorticoid-induced insulin resistance in skeletal muscle and indentify how 11beta-HSD1 inhibitors improve insulin sensitivity.


METHODS
Rodent and human cell cultures, whole-tissue explants, and animal models were used to determine the impact of glucocorticoids and selective 11beta-HSD1 inhibition upon insulin signaling and action.


RESULTS
Dexamethasone decreased insulin-stimulated glucose uptake, decreased IRS1 mRNA and protein expression, and increased inactivating pSer(307) insulin receptor substrate (IRS)-1. 11beta-HSD1 activity and expression were observed in human and rodent myotubes and muscle explants. Activity was predominantly oxo-reductase, generating active glucocorticoid. A1 (selective 11beta-HSD1 inhibitor) abolished enzyme activity and blocked the increase in pSer(307) IRS1 and reduction in total IRS1 protein after treatment with 11DHC but not corticosterone. In C57Bl6/J mice, the selective 11beta-HSD1 inhibitor, A2, decreased fasting blood glucose levels and improved insulin sensitivity. In KK mice treated with A2, skeletal muscle pSer(307) IRS1 decreased and pThr(308) Akt/PKB increased. In addition, A2 decreased both lipogenic and lipolytic gene expression.


CONCLUSIONS
Prereceptor facilitation of glucocorticoid action via 11beta-HSD1 increases pSer(307) IRS1 and may be crucial in mediating insulin resistance in skeletal muscle. Selective 11beta-HSD1 inhibition decreases pSer(307) IRS1, increases pThr(308) Akt/PKB, and decreases lipogenic and lipolytic gene expression that may represent an important mechanism underpinning their insulin-sensitizing action.
Morgan
Stuart A
SA
Centre for Endocrinology, Diabetes and Metabolism, Institute of Biomedical Research, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, U.K.
Sherlock
Mark
M
Gathercole
Laura L
LL
Lavery
Gareth G
GG
Lenaghan
Carol
C
Bujalska
Iwona J
IJ
Laber
David
D
Yu
Alice
A
Convey
Gemma
G
Mayers
Rachel
R
Hegyi
Krisztina
K
Sethi
Jaswinder K
JK
Stewart
Paul M
PM
Smith
David M
DM
Tomlinson
Jeremy W
JW
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D003847:Deoxyglucose / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D032446:Myoblasts / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D005938:Glucocorticoids; D007328:Insulin; D012333:RNA, Messenger; D012313:RNA; D003907:Dexamethasone; D003847:Deoxyglucose; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1
J Clin Invest. 1995 Sep;96(3):1473-83
7544807
Mol Endocrinol. 2004 Aug;18(8):2024-34
15143153
Endocr Rev. 2004 Oct;25(5):831-66
15466942
Nature. 1994 Nov 10;372(6502):186-90
7526222
Diabetologia. 2003 Nov;46(11):1532-42
14579029
Am J Physiol Endocrinol Metab. 2007 Oct;293(4):E1045-52
17666487
Clin Endocrinol (Oxf). 2006 Dec;65(6):800-5
17121533
Biochem Biophys Res Commun. 2006 Apr 21;342(4):1183-7
16516141
J Clin Invest. 2004 Sep;114(6):823-7
15372106
Diabetes. 2008 Oct;57(10):2652-60
18633104
J Biol Chem. 2002 Dec 27;277(52):50230-6
12006582
J Biol Chem. 2004 Apr 23;279(17):17070-8
14764603
Endocrinology. 2003 Nov;144(11):4755-62
12960099
J Clin Endocrinol Metab. 1996 Dec;81(12):4428-32
8954054
J Nutr. 2001 Sep;131(9):2242-7
11533261
Diabetes Metab Res Rev. 2009 Mar;25(3):250-8
19222059
J Clin Invest. 1993 May;91(5):2020-30
7683695
J Biol Chem. 2003 Apr 25;278(17):14599-602
12637568
Diabetes. 2006 Aug;55(8):2392-7
16873706
J Biol Chem. 1997 Mar 14;272(11):7455-63
9054447
J Exp Med. 2005 Aug 15;202(4):517-27
16103409
Hypertension. 1999 Jun;33(6):1364-8
10373217
Biochem J. 2007 Oct 15;407(2):231-41
17617058
J Clin Invest. 1993 Oct;92(4):2065-72
7691892
Biochem Biophys Res Commun. 2005 Sep 30;335(3):819-25
16099431
J Biol Chem. 2006 Mar 10;281(10):6546-51
16356929
Biochim Biophys Acta. 2004 Mar 11;1697(1-2):3-16
15023346
J Biol Chem. 2002 Jan 11;277(2):1531-7
11606564
Diabetologia. 2005 Oct;48(10):2119-30
16078016
Am J Physiol Endocrinol Metab. 2002 Jul;283(1):E172-7
12067858
J Biol Chem. 2000 Mar 24;275(12):9047-54
10722755
J Biol Chem. 2000 Dec 15;275(50):38990-4
10995761
Am J Physiol Endocrinol Metab. 2008 Jul;295(1):E46-54
18430968
J Biol Chem. 2001 Nov 2;276(44):41293-300
11546766
Diabetes. 2008 Oct;57(10):2644-51
18633112
Eur J Clin Invest. 2005 Oct;35(10):627-34
16178882
QJM. 2000 Feb;93(2):105-11
10700481
Diabetologia. 2007 Apr;50(4):840-9
17279354
Mol Endocrinol. 2006 Aug;20(8):1838-52
16574739
Endocr Rev. 2004 Apr;25(2):177-204
15082519
Mol Cell Biochem. 2009 Apr;324(1-2):147-55
19118409
J Pharmacol Exp Ther. 2008 Jan;324(1):299-305
17921190
J Biol Chem. 2008 Apr 25;283(17):11226-33
18285345
Diabetes. 2002 Apr;51(4):1066-75
11916927
J Biol Chem. 2004 Aug 20;279(34):35298-305
15199052
J Clin Endocrinol Metab. 2007 Aug;92(8):3314-20
17519316
Endocrine. 2003 Jul;21(2):115-22
12897373
J Clin Invest. 2000 Jan;105(2):199-205
10642598
Endocrinology. 2007 May;148(5):2391-7
17272400