Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes:: Potential role of PGC1 and NRF1
Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes:: Potential role of PGC1 and NRF1
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DOI：
10.1073/pnas.1032913100
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发表时间：
2003-07-08
影响因子：
11.1
通讯作者：
Mandarino, LJ
中科院分区：
文献类型：
--
作者：
Patti, ME;Butte, AJ;Mandarino, LJ
2型糖尿病（DM）的特征是胰岛素抵抗和胰腺β细胞功能障碍。在高危受试者中，最早可检测到的异常是骨骼肌中的胰岛素抵抗。受损的胰岛素介导的信号传导、基因表达、糖原合成和肌细胞内甘油三酯的积累都与胰岛素抵抗有关，但在人类中尚未发现导致胰岛素抵抗和DM的特异性缺陷。为了确定在DM发病机制中潜在重要的基因，我们分析了健康代谢特征的非糖尿病（DM家族史阴性和阳性）和糖尿病墨西哥裔美国人受试者骨骼肌中的基因表达。我们证明，胰岛素抵抗和DM与多核呼吸因子-1（NRF-1）依赖性基因表达减少相关，这些基因编码氧化代谢和线粒体功能中的关键酶。尽管NRF-1表达仅在糖尿病受试者中降低，但NRF-1和PPARgamma依赖性转录的共激活因子PPARgamma共激活因子1-α和PPARgamma共激活因子1-β（PGC 1-α/PPARGC 1和PGC 1-β/PERC）的表达在糖尿病受试者和家族史阳性的非糖尿病受试者中均降低。PGC 1表达的降低可能导致NRF依赖性基因表达的降低，从而导致胰岛素抵抗和DM的代谢紊乱。
Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic beta cell dysfunction. in high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican-American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. Although NRF-1 expression is decreased only in diabetic subjects, expression of both PPARgamma coactivator 1-alpha and-beta (PGC1-alpha/PPARGC1 and PGC1-beta/PERC), coactivators of NRF-1 and PPARgamma-dependent transcription, is decreased in both diabetic subjects and family history-positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.