本期Nature 介绍了胰岛素调控肝葡萄糖生产的一个以前没有被发现的通道。在哺乳动物体内，葡萄糖水平通过胰腺激素对肝脏的糖生成作用的效应而被维持在一个很窄的范围内。这个新通道通过促进磷酸化和CREB共激发因子TORC2依赖于泛素的降解来帮助胰岛素抑制糖生成基因的表达。这个信号作用通道涉及激酶SIK2和E3连接酶COP1。这些发现表明，TORC2和SIK2在II-型糖尿病中是潜在的治疗目标。
原始出处：
Nature 449, 366-369 (20 September 2007) | doi:10.1038/nature06128; Received 22 March 2007; Accepted 27 July 2007; Published online 5 September 2007
Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2
Renaud Dentin1,4, Yi Liu1,4, Seung-Hoi Koo2, Susan Hedrick1, Thomas Vargas1, Jose Heredia1, John Yates, III3 & Marc Montminy1
Peptide Biology Laboratories, Salk Institute For Biological Studies, La Jolla, California 92037, USA
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 300 Chunchun-dong, Jangan-gu, Suwon, 440-746, Gyeonggi-do, Korea
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
These authors contributed equally to this work.
Correspondence to: Marc Montminy1 Correspondence and requests for materials should be addressed to M.M. (Email: montminy@salk.edu).
During feeding, increases in circulating pancreatic insulin inhibit hepatic glucose output through the activation of the Ser/Thr kinase AKT and subsequent phosphorylation of the forkhead transcription factor FOXO1 (refs 1–3). Under fasting conditions, FOXO1 increases gluconeogenic gene expression in concert with the cAMP responsive coactivator TORC2 (refs 4–8). In response to pancreatic glucagon, TORC2 is de-phosphorylated at Ser 171 and transported to the nucleus, in which it stimulates the gluconeogenic programme by binding to CREB. Here we show in mice that insulin inhibits gluconeogenic gene expression during re-feeding by promoting the phosphorylation and ubiquitin-dependent degradation of TORC2. Insulin disrupts TORC2 activity by induction of the Ser/Thr kinase SIK2, which we show here undergoes AKT2-mediated phosphorylation at Ser 358. Activated SIK2 in turn stimulated the Ser 171 phosphorylation and cytoplasmic translocation of TORC2. Phosphorylated TORC2 was degraded by the 26S proteasome during re-feeding through an association with COP1, a substrate receptor for an E3 ligase complex that promoted TORC2 ubiquitination at Lys 628. Because TORC2 protein levels and activity were increased in diabetes owing to a block in TORC2 phosphorylation, our results point to an important role for this pathway in the maintenance of glucose homeostasis.
