Increased insulin action in SKIP heterozygous knockout mice
Increased insulin action in SKIP heterozygous knockout mice
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DOI：
10.1128/mcb.01990-06
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发表时间：
2008-09-01
影响因子：
5.3
通讯作者：
Takenawa, Tadaomi
中科院分区：
文献类型：
--
作者：
Ijuin, Takeshi;Yu, Y. Eugene;Takenawa, Tadaomi
胰岛素控制葡萄糖稳态和脂质代谢，胰岛素损伤在糖尿病的发病机制中起着至关重要的作用。人骨骼肌和肾富集肌醇多磷酸磷酸酶(SKIP)是磷脂酰肌醇3,4,5-三磷酸磷酸酶家族的成员(T.Ijuin等人J.Biol.Chem.275:10870-10875, 2000；T.Ijuin和T.Takenawa，Mol.Cell.Biol.23： 1209-1220，2003）。先前的研究表明，SKIP负调节胰岛素诱导的磷脂酰肌醇3-激酶信号传导（Ijuin和Takenawa，Mol.Cell.Biol.23：1209-1220，2003）。现在，我们已经培育出了带有人类 SKIP 基因 Pps 小鼠直系同源基因靶向突变的小鼠。成年杂合 Pps 突变小鼠表现出胰岛素敏感性增加和饮食诱导的肥胖减少，骨骼肌中 Akt/蛋白激酶 B (PKB) 磷酸化增加，但脂肪组织中则不然。 Pps 突变小鼠中，胰岛素诱导的离体比目鱼肌对 2-脱氧葡萄糖的摄取显着增强。一项高胰岛素-正常血糖钳夹研究还显示，Pps 突变小鼠的全身葡萄糖处理率显着增加，而肝葡萄糖产生没有任何异常。此外，L6 成肌细胞的体外敲低研究表明，SKIP 表达水平的降低会增加胰岛素刺激的 Akt/PKB 磷酸化和 2-脱氧葡萄糖摄取。这些结果表明 SKIP 调节骨骼肌中的胰岛素信号传导。因此，SKIP可能是治疗胰岛素抵抗和糖尿病的有前途的药理学靶点。
Insulin controls glucose homeostasis and lipid metabolism, and insulin impairment plays a critical role in the pathogenesis of diabetes mellitus. Human skeletal muscle and kidney enriched inositol polyphosphate phosphatase (SKIP) is a member of the phosphatidylinositol 3,4,5-trisphosphate phosphatase family (T. Ijuin et al. J. Biol. Chem. 275: 10870-10875, 2000; T. Ijuin and T. Takenawa, Mol. Cell. Biol. 23: 1209-1220, 2003). Previous studies showed that SKIP negatively regulates insulin-induced phosphatidylinositol 3-kinase signaling (Ijuin and Takenawa, Mol. Cell. Biol. 23: 1209-1220, 2003). We now have generated mice with a targeted mutation of the mouse ortholog of the human SKIP gene, Pps. Adult heterozygous Pps mutant mice show increased insulin sensitivity and reduced diet-induced obesity with increased Akt/protein kinase B (PKB) phosphorylation in skeletal muscle but not in adipose tissue. The insulin-induced uptake of 2-deoxyglucose into the isolated soleus muscle was significantly enhanced in Pps mutant mice. A hyperinsulinemic-euglycemic clamp study also revealed a significant increase in the rate of systemic glucose disposal in Pps mutant mice without any abnormalities in hepatic glucose production. Furthermore, in vitro knockdown studies in L6 myoblast cells revealed that reduction of SKIP expression level increased insulin-stimulated Akt/PKB phosphorylation and 2-deoxyglucose uptake. These results imply that SKIP regulates insulin signaling in skeletal muscle. Thus, SKIP may be a promising pharmacologic target for the treatment of insulin resistance and diabetes.