Novel liver-specific TORC2 siRNA corrects hyperglycemia in rodent models of type 2 diabetes.
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.
Saberi
Maziyar
M
Univ. of California-San Diego, Dept. of Medicine, 9500 Gilman Dr., SCR225, La Jolla CA 92093, USA. jolefsky@ucsd.edu
Bjelica
David
D
Schenk
Simon
S
Imamura
Takeshi
T
Bandyopadhyay
Gautam
G
Li
Pingping
P
Jadhar
Vasant
V
Vargeese
Chandra
C
Wang
Weimin
W
Bowman
Keith
K
Zhang
Ye
Y
Polisky
Barry
B
Olefsky
Jerrold M
JM
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D005943:Gluconeogenesis / Q000187:drug effects; D015309:Glucose Clamp Technique; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006943:Hyperglycemia / Q000188:drug therapy*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D019289:Pyruvic Acid / Q000378:metabolism; D034741:RNA, Small Interfering / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011924:Rats, Zucker; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*
D001786:Blood Glucose; C545700:CRTC2 protein, rat; C504923:Crtc2 protein, mouse; D007328:Insulin; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014157:Transcription Factors; D019289:Pyruvic Acid
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