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J. Biol. Chem., Vol. 280, Issue 36, 31516-31521, September 9, 2005

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Socs1 Deficiency Enhances Hepatic Insulin Signaling^*

Emma Jamieson, Mark M. W. Chong¶, Gregory R. Steinberg||, Valentina Jovanovska**, Barbara C. Fam**, Denise V. R. Bullen¶, Ye Chen¶, Bruce E. Kemp, Joseph Proietto**, Thomas W. H. Kay, and Sofianos Andrikopoulos**¶¶

From the St. Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia, ^¶The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia, the ^**Department of Medicine, (AH/NH), Heidelberg Repatriation Hospital, The University of Melbourne, Heidelberg Heights, Victoria, 3081, Australia, and CSIRO Health Sciences and Nutrition, 343 Royal Parade, Parkville, Victoria 3052, Australia

Suppressor of cytokine signaling 1 (SOCS1) is an intracellular inhibitor of cytokine, growth factor, and hormone signaling. Socs1^–/– mice die before weaning from a multiorgan inflammatory disease. Neonatal Socs1^–/– mice display severe hypoglycemia and hypoinsulinemia. Concurrent interferon gene deletion (Ifng^–/–) prevented inflammation and corrected the hypoglycemia. In hyperinsulinemic clamp studies, however, Socs1^–/–Ifng^–/– mice had enhanced hepatic insulin sensitivity demonstrated by greater suppression of endogenous glucose production compared with controls with no difference in glucose disposal. Socs1^–/–Ifng^–/– mice had elevated liver insulin receptor substrate 2 expression (IRS-2) and IRS-2 tyrosine phosphorylation. This was associated with lower phosphoenolpyruvate carboxykinase mRNA expression. These effects were not associated with elevated hepatic AMP-activated protein kinase activity. Hepatic insulin sensitivity and IRS-2 levels play central roles in the pathogenesis of type 2 diabetes. Socs1 deficiency increases IRS-2 expression and enhances hepatic insulin sensitivity in vivo indicating that inhibition of SOCS1 may be a logical strategy in type 2 diabetes.

Received for publication, February 25, 2005 , and in revised form, June 23, 2005.

^* This work was supported by the National Health and Medical Research Council of Australia and the Juvenile Diabetes Research Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| Supported by a "Target Obesity" Fellowship from the Canadian Institutes of Health Research and the Heart and Stroke Foundation.

^¶¶ Supported by a National Health and Medical Research Council of Australia RD Wright (Biomedical) Career Development Award.

To whom correspondence should be addressed. Tel.: 61-3-92882480; Fax: 61-3-94162676; E-mail: tkay{at}svi.edu.au.

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