Mice with AS160/TBC1D4-Thr649Ala knockin mutation are glucose intolerant with reduced insulin sensitivity and altered GLUT4 trafficking.
Mice with AS160/TBC1D4-Thr649Ala knockin mutation are glucose intolerant with reduced insulin sensitivity and altered GLUT4 trafficking.
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DOI：
10.1016/j.cmet.2010.12.005
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发表时间：
2011-01-05
期刊：
影响因子：
29
通讯作者：
Sakamoto K
中科院分区：
文献类型：
--
作者：
Chen S;Wasserman DH;MacKintosh C;Sakamoto K
AS 160通过控制GLUT 4运输而成为胰岛素介导的葡萄糖转运的关键参与者，GLUT 4运输被认为是通过胰岛素刺激的位点磷酸化进行调节，包括14-3-3结合磷酸化Thr 649（相当于人AS 160中的Thr 642）。为了确定AS 160-Thr 649磷酸化和14-3-3结合在葡萄糖稳态中的生理作用，我们在小鼠中通过敲入突变用不可磷酸化的丙氨酸取代该残基。突变蛋白表达在正常水平，而胰岛素刺激的AS 160结合14-3-3s在纯合子敲入小鼠中被废除。这些动物显示葡萄糖处置和胰岛素敏感性受损，这与体内葡萄糖摄取减少有关。胰岛素刺激的葡萄糖转运和细胞表面GLUT 4含量在离体肌肉中减少，但在脂肪细胞中不减少。这些结果提供了遗传学证据，表明胰岛素诱导的AS 160-Thr 649磷酸化和/或其与14-3-3的结合在调节全身葡萄糖稳态中起重要作用，至少部分通过调节肌肉中的GLUT 4运输。AS 160 Thr 649 →Ala基因敲入小鼠用于研究AS 160/14-3-3相互作用的作用。敲入小鼠显示葡萄糖耐量受损和胰岛素敏感性降低。肌肉中GLUT 4运输和葡萄糖摄取失调是这种表型的基础。这些发现为理解II型糖尿病的病理提供了新的线索。
AS160 has emerged as a key player in insulin-mediated glucose transport through controlling GLUT4 trafficking, which is thought to be regulated by insulin-stimulated phosphorylation of sites including the 14-3-3 binding phospho-Thr649 (equivalent to Thr642 in human AS160). To define physiological roles of AS160-Thr649 phosphorylation and 14-3-3 binding in glucose homeostasis, we substituted this residue by a nonphosphorylatable alanine by knockin mutation in mice. The mutant protein was expressed at normal levels, while insulin-stimulated AS160 binding to 14-3-3s was abolished in homozygous knockin mice. These animals displayed impaired glucose disposal and insulin sensitivity, which were associated with decreased glucose uptake in vivo. Insulin-stimulated glucose transport and cell surface GLUT4 content were reduced in isolated muscles, but not in adipocytes. These results provide genetic evidence that insulin-induced AS160-Thr649 phosphorylation and/or its binding to 14-3-3 play an important role in regulating whole-body glucose homeostasis, at least in part through regulating GLUT4 trafficking in muscle. ► AS160 Thr649→Ala knockin mice are made to study roles of AS160/14-3-3 interaction ► The knockin mice display impaired glucose tolerance and reduced insulin sensitivity ► Deregulated GLUT4 trafficking and glucose uptake in muscles underlie this phenotype ► These findings shed new light on understanding of the pathology of type II diabetes
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影响因子：
7.5
作者：
Hou, June Chunqiu;Pessin, Jeffrey E.
通讯作者：
Pessin, Jeffrey E.
在四种常用的近交小鼠菌株中的体内葡萄糖代谢。
影响因子：
7.7
作者：
Berglund, Eric D.;Li, Candice Y.;Poffenberger, Greg;Ayala, Julio E.;Fueger, Patrick T.;Willis, Shannon E.;Jewell, Marybeth M.;Powers, Alvin C.;Wasserman, David H.
通讯作者：
Wasserman, David H.
影响因子：
7.7
作者：
Karlsson HK;Chibalin AV;Koistinen HA;Yang J;Koumanov F;Wallberg-Henriksson H;Zierath JR;Holman GD
通讯作者：
Holman GD
影响因子：
4.8
作者：
Chavez, Jose A.;Roach, William G.;Lienhard, Gustav E.
通讯作者：
Lienhard, Gustav E.
影响因子：
29
作者：
Eguez, L;Lee, A;McGraw, TE
通讯作者：
McGraw, TE