P50α/p55α phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity
P50α/p55α phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity
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DOI：
10.1128/mcb.24.1.320-329.2004
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发表时间：
2004-01-01
影响因子：
5.3
通讯作者：
Kahn, CR
中科院分区：
文献类型：
--
作者：
Chen, D;Mauvais-Jarvis, F;Kahn, CR
磷酸肌肽（PI） 3-激酶是由调控亚基和催化亚基组成的异源二聚体，对胰岛素的代谢作用至关重要。除了p85alpha和p85beta外，胰岛素敏感组织如脂肪、肌肉和肝脏也表达pik3r1基因、p50alpha和p55alpha的剪接变体。为了确定这些变异的作用，我们通过同源重组创造了p50alpha和p55a缺失的小鼠。这些小鼠可以存活，正常生长，维持正常的血糖水平，但空腹胰岛素水平较低。胰岛素耐量试验结果表明，p50alpha/p55alpha基因敲除小鼠体内胰岛素敏感性增强，离体指长伸肌组织和脂肪细胞中胰岛素刺激的葡萄糖转运增加。在肌肉中，p50α / p55α的缺失导致胰岛素刺激胰岛素受体底物1 （IRS-1）和磷酸酪氨酸相关PI - 3激酶水平降低，但irs -2相关PI - 3激酶和Akt激活水平升高，而在脂肪细胞中，胰岛素刺激PI - 3激酶和Akt水平不变。尽管如此，敲除小鼠的脂肪细胞更小，葡萄糖摄取增加，葡萄糖代谢途径改变。当用金硫葡萄糖处理时，p50alpha/p55alpha基因敲除小鼠变得像野生型小鼠一样贪食。然而，他们积累的脂肪较少，血糖升高的程度较轻，胰岛素升高的程度较低。综上所述，这些数据表明p50alpha和p55alpha在胰岛素信号传导和作用中发挥重要作用，特别是在脂质和葡萄糖代谢中。
Class la phosphoinositide (PI) 3-kinases are heterodimers composed of a regulatory and a catalytic subunit and are essential for the metabolic actions of insulin. In addition to p85alpha and p85beta, insulin-sensitive tissues such as fat, muscle, and liver express the splice variants of the pik3r1 gene, p50alpha and p55alpha. To define the role of these variants, we have created mice with a deletion of p50alpha and p55a by using homologous recombination. These mice are viable, grow normally, and maintain normal blood glucose levels but have lower fasting insulin levels. Results of an insulin tolerance test indicate that p50alpha/p55alpha knockout mice have enhanced insulin sensitivity in vivo, and there is an increase in insulin-stimulated glucose transport in isolated extensor digitorum longus muscle tissues and adipocytes. In muscle, loss of p50alpha/p55alpha results in reduced levels of insulin-stimulated insulin receptor substrate 1 (IRS-1) and phosphotyrosine-associated PI 3-kinase but enhanced levels of IRS-2-associated PI 3-kinase and Akt activation, whereas in adipocytes levels of both insulin-stimulated PI 3-kinase and Akt are unchanged. Despite this, adipocytes of the knockout mice are smaller and have increased glucose uptake with altered glucose metabolic pathways. When treated with gold thioglucose, p50alpha/p55alpha knockout mice become hyperphagic like their wild-type littermates. However, they accumulate less fat and become mildly less hyperglycemic and markedly less hyperinsulinemic. Taken together, these data indicate that p50alpha and p55alpha play an important role in insulin signaling and action, especially in lipid and glucose metabolism.