Journal
DIABETES
Volume 58, Issue 11, Pages 2506-2515Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db09-0525
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Funding
- Wellcome Trust, U.K
- Biotechnology and Biological Sciences Research Council
- Medical Research Council
- Diabetes U.K.
- BBSRC [BB/G023468/1] Funding Source: UKRI
- MRC [G0601429] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [JF16994, BB/G023468/1] Funding Source: researchfish
- Medical Research Council [G0601429] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10356] Funding Source: researchfish
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OBJECTIVE-Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-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 11 beta-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 11 beta-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. 11 beta-HSD1 activity and expression were observed in human and rodent myotubes and muscle explants. Activity was predominantly oxo-reductase, generating active glucocorticoid. A1 (selective 11 beta-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 C57B16/J mice, the selective 11 beta-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 11 beta-HSD1 increases pSer(307) IRS1 and may be crucial in mediating insulin resistance in skeletal muscle. Selective 11 beta-HSD1 inhibition decreases pSer(307) IRS1, increases pThr(308) AkL/PKB, and decreases lipogenic and lipolytic gene expression that may represent an important mechanism underpinning their insulin-sensitizing action. Diabetes 58:2506-2515, 2009
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