Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2 (Nature, 2007, 449:366-369)

報告日期: 2007/11/20
報告時間: 15:10/16:00
報告學生: 李育誠
講評老師: 李碧雪

Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2


Nature, 2007, 449, 366-369

 Student: 李育誠

 Commentator: 李碧雪老師

 Date: 2007/11/20

 Place: Room 602



 Glucose homeostasis is regulated systemically by hormones such as insulin and glucagon. In the previous study, it has been demonstrated that the transcriptional regulator TORC2 (Transducer of Regulated CREB activity 2) as a pivotal component and may play an important role in gluconeogenic program. Glucagon (fasting state) suppresses the phosphorylation of TORC2 at Ser171 through phosphorylation and inhibition of SIKs by PKA. The dephosphorylation of TORC2 protein promote the translocation from cytoplasm to nucleus where it enhances CREB-dependent transcription regarding to increase the gluconeogenic gene expression, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) that consequentially elevate hepatic glucose output. In contrast, insulin (re-feeding state) increases the phosphorylation of TORC2 at Ser171 that results the TORC2 retaining in cytoplasm and inhibits the downstream gene expression. However, the mechanisms of how insulin signaling mediates TORC2 phosphorylation remains to be clarified. In this study, the authors demonstrated that insulin inhibits gluconeogenic gene expression during re-feeding by disrupting TORC2 activity through Akt2-mediated phosphorylation of Ser/Thr kinase SIK2 at Ser358. Activated SIK2 in turn stimulated TORC2 phosphorylation at Ser 171, cytoplasmic translocation and protein instability. COP1, an E3 ligase, was demonstrated to interact with phosphorylated TORC2 and to promote poly-ubiquitination of TORC2 at Lys 628 that is subsequently subjected for 26S proteasome degradation. Together, insulin plays a role in modulating gluconeogenesis through inhibiting the CREB coactivator TORC2 during re-feeding. Interestingly, insulin resistance often exhibits in type 2 diabetes that cause hyperglycaemia by elevating gluconeogenesis. The take-home message of this study is that manipulation of TORC2 phosphorylation or SIK2 or COP1 expression may serve as therapeutic targets for treating insulin resistance related diabetes.           


 1. Seung-Hoi Koo et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature. 2005, 7062:1109-11

2. Alan Cheng et al. More TORC for the gluconeogenic engine. BioEssays. 2006, 28:231–234