Morgan, SA, Sherlock, M, Gathercole, LL et al. (12 more authors) (2009) 11β-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid- induced insulin resistance in skeletal muscle. Diabetes, 58 (11). 2506 - 2515. ISSN 0012-1797
Abstract
OBJECTIVE - Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11β-hydroxysteroid dehydrogenase type 1 (11β-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 11β-HSD1 inhibitors improve insulin sensitivity. RESEARCH DESIGN AND METHODS - Rodent and human cell cultures, whole-tissue explants, and animal models were used to determine the impact of glucocorticoids and selective 11β-HSD1 inhibition upon insulin signaling and action. RESULTS - Dexamethasone decreased insulin-stimulated glucose uptake, decreased IRS1 mRNA and protein expression, and increased inactivating pSer307 insulin receptor substrate (IRS)-1. 11β-HSD1 activity and expression were observed in human and rodent myotubes and muscle explants. Activity was predominantly oxo-reductase, generating active glucocorticoid. A1 (selective 11β-HSD1 inhibitor) abolished enzyme activity and blocked the increase in pSer307 IRS1 and reduction in total IRS1 protein after treatment with 11DHC but not corticosterone. In C57Bl6/J mice, the selective 11β-HSD1 inhibitor, A2, decreased fasting blood glucose levels and improved insulin sensitivity. In KK mice treated with A2, skeletal muscle pSer307 IRS1 decreased and pThr308 Akt/PKB increased. In addition, A2 decreased both lipogenic and lipolytic gene expression. CONCLUSIONS - Prereceptor facilitation of glucocorticoid action via 11β-HSD1 increases pSer 307 IRS1 and may be crucial in mediating insulin resistance in skeletal muscle. Selective 11β-HSD1 inhibition decreases pSer307 IRS1, increases pThr308 Akt/PKB, and decreases lipogenic and lipolytic gene expression that may represent an important mechanism underpinning their insulin-sensitizing action.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2009, American Diabetes Association. Reproduced in accordance with the publisher's self-archiving policy. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial No Derivates (CC BY-NC-ND 3.0) licence, which permits others to download this work and share it with others, provided the original work is unchanged, properly cited and the use is non-commercial. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Medicine & Health Faculty Office (Leeds) > Faculty Office Functions (FOMH) (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 06 Nov 2014 09:33 |
Last Modified: | 17 Jan 2018 18:02 |
Published Version: | http://dx.doi.org/10.2337/db09-0525 |
Status: | Published |
Publisher: | American Diabetes Association |
Identification Number: | 10.2337/db09-0525 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:81089 |