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Am J Physiol Endocrinol Metab 297: E1137-E1146, 2009. First published August 25, 2009; doi:10.1152/ajpendo.00158.2009
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Novel liver-specific TORC2 siRNA corrects hyperglycemia in rodent models of type 2 diabetes

Maziyar Saberi,1 David Bjelica,1 Simon Schenk,1 Takeshi Imamura,1 Gautam Bandyopadhyay,1 Pingping Li,1 Vasant Jadhar,2 Chandra Vargeese,2 Weimin Wang,2 Keith Bowman,2 Ye Zhang,2 Barry Polisky,2 and Jerrold M. Olefsky1

1Department of Medicine, University of California-San Diego, La Jolla; and 2Research and Development, Sirna Therapeutics, Inc., San Francisco, California

Submitted 12 March 2009 ; accepted in final form 18 August 2009

The transcription factor TORC2 [transducer of regulated cAMP-responsive element-binding protein (CREB) activity 2] is a major regulator of hepatic gluconeogenesis and is increased in hyperglycemic rodent models. Because chronic hyperglycemia and increased hepatic glucose production, via increased gluconeogenesis, is a key feature of type 2 diabetes, an effective in vivo method to efficiently knock down TORC2 could provide a potential therapy for treating hyperglycemia and type 2 diabetes. To assess this, primary mouse hepatocytes, high-fat diet (HFD)-fed mice, and Zucker diabetic fatty (ZDF) rats were treated with a siRNA against TORC2 (siTORC2), which was delivered via a novel lipid nanoparticle system, or control siRNA (siCON). Compared with siCON, administration of siTORC2 resulted in highly efficient, sustained (1–3 wk) knockdown of TORC2 and its gluconeogenic target genes phosphoenolpyruvate carboxykinase and glucose-6-phophatase in primary mouse hepatocytes and in the livers of HFD-fed mice. In mice, this knockdown was specific to the liver and did not occur in kidney, skeletal muscle, or adipose tissue. In HFD-fed mice, siTORC2 reduced in vivo gluconeogenic capacity, fasting hepatic glucose production, and hyperglycemia, and led to improved hepatic and skeletal muscle insulin sensitivity. siTORC2 treatment also improved systemic hyperglycemia in ZDF rats. In conclusion, these results demonstrate the importance of TORC2 in modulating HGP in vivo and highlight a novel, liver-specific siRNA approach for the potential treatment of hyperglycemia and type 2 diabetes.

transducer of regulated cAMP-responsive element-binding protein activity 2; diabetes; small interfering RNA


Address for reprint requests and other correspondence: M. Saberi and D. Bjelica contributed equally to this work. Jerrold M. Olefsky, Univ. of California-San Diego, Dept. of Medicine, 9500 Gilman Dr., SCR225, La Jolla CA 92093 (e-mail: jolefsky{at}ucsd.edu).






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