Amelioration of glucose tolerance by hepatic inhibition of nuclear factor κB in db/db mice
Amelioration of glucose tolerance by hepatic inhibition of nuclear factor κB in db/db mice
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DOI：
10.1007/s00125-006-0467-1
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发表时间：
2006-11
期刊：
影响因子：
8.2
通讯作者：
Y. Tamura;T. Ogihara;T. Uchida;F. Ikeda;N. Kumashiro;T. Nomiyama;F. Sato;T. Hirose;Y. Tanaka;H. Mochizuki;R. Kawamori;H. Watada
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文献类型：
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作者：
Y. Tamura;T. Ogihara;T. Uchida;F. Ikeda;N. Kumashiro;T. Nomiyama;F. Sato;T. Hirose;Y. Tanaka;H. Mochizuki;R. Kawamori;H. Watada
目的/假设最近的研究发现IκB激酶抑制剂（IKK）参与了胰岛素抵抗的发病机制。为了研究其机制，我们检测了IKK的远端靶点核因子κB（NF-κB）在肝脏葡萄糖代谢中的作用。方法为了抑制NF-κB活性，用表达IκBα超阻遏物的腺病毒感染db/db小鼠。结果IκBα超阻遏物腺病毒感染引起肝脏NF-κB活性中度降低。该治疗与葡萄糖耐量改善、血清胰岛素水平降低、肝甘油三酯和糖原含量增加相关，但对胰岛素刺激的Akt磷酸化无影响。另一方面，肝脏中mRNA的定量显示，致凋亡基因（如编码磷酸烯醇丙酮酸羧激酶（PEPCK）和葡萄糖-6-磷酸酶的基因）的表达显著降低，同时编码过氧化物酶体增殖物激活受体γ共激活因子-1 α（PPARGC-1A，也称为PGC-1α）的基因表达降低。此外，超阻遏物IκBα的产生抑制了丙酮酸注射后血糖水平的升高。结论/解释我们的研究结果表明，适度抑制NF-κB通过减少B/db小鼠中与PGC-1α基因表达降低相关的细胞生成来改善葡萄糖耐量。并表明抑制NF-κ B的表达，肝脏中的κB活性是2型糖尿病患者血糖浓度正常化的潜在合适策略。
Aims/hypothesisRecent studies have identified the involvement of inhibitor IκB kinase (IKK) in the pathogenesis of insulin resistance. To investigate the mechanism involved, we examined the role of nuclear factor κB (NF-κB), the distal target of IKK, in hepatic glucose metabolism.MethodsTo inhibit NF-κB activity,db/dbmice were infected with adenovirus expressing the IκBα super-repressor.ResultsThe IκBα super-repressor adenovirus infection caused a moderate reduction of NF-κB activity in liver. The treatment was associated with improved glucose tolerance, reduction in the serum insulin level, and increased hepatic triacylglycerol and glycogen contents, but had no effect on insulin-stimulated phosphorylation of Akt. On the other hand, quantification of mRNA in the liver revealed marked reduction of expression of gluconeogenic genes, such as those encoding phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, concurrent with reduced expression of gene encoding peroxisome proliferator-activated receptor gamma coactivator-1α (PPARGC1A, also known asPGC-1α). Furthermore, the production of super-repressor IκBα suppressed the increase in blood glucose level after pyruvate injection.Conclusions/interpretationOur results indicate that moderate inhibition of NF-κB improved glucose tolerance through decreased gluconeogenesis associated with reducedPGC-1αgene expression indb/dbmice, and suggest that inhibition of NF-κB activity in liver is a potentially suitable strategy for the normalisation of blood glucose concentration in type 2 diabetes.