11beta-hydroxysteroid Dehydrogenase Type 1 Regulates Glucocorticoid-induced Insulin Resistance in Skeletal Muscle

Overview

Journal Diabetes

Specialty Endocrinology

Date 2009 Aug 14

PMID 19675138

Citations 61

Authors

Stuart A Morgan

Mark Sherlock

Laura L Gathercole

Gareth G Lavery

Carol Lenaghan

Iwona J Bujalska

David Laber

Alice Yu

Gemma Convey

Rachel Mayers

Krisztina Hegyi

Jaswinder K Sethi

Paul M Stewart

David M Smith

Jeremy W Tomlinson

Affiliations

Soon will be listed here.

Abstract

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.

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 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.

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