Human evidence for the involvement of insulin-induced gene 1 in the regulation of plasma glucose concentration
Human evidence for the involvement of insulin-induced gene 1 in the regulation of plasma glucose concentration
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DOI：
10.1007/s00125-006-0479-x
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发表时间：
2007-01-01
期刊：
影响因子：
8.2
通讯作者：
van't Hooft, F. M.
中科院分区：
文献类型：
--
作者：
Krapivner, S.;Chernogubova, E.;van't Hooft, F. M.
胰岛素诱导基因1 （INSIG1）是一种阻断甾醇调节元件结合蛋白（SREBPs）蛋白水解激活的蛋白，SREBPs是激活调节胆固醇和脂肪酸代谢的基因的转录因子，也可能是参与葡萄糖稳态的基因。为了寻找这些过程的遗传调控，我们检测了人类INSIG1的常见多态性，并分析了它们与脂质和葡萄糖代谢相关的生化参数的关联。在618名50岁的健康男性中分析了INSIG1常见多态性与几个生化参数之间的关系。对472名健康中年男性进行了重复分析。在181名受试者中分析了一个启动子多态性对口服葡萄糖耐量的影响。采用小干扰RNA （siRNA）抑制法检测INSIG1对人Huh7肝癌细胞基因表达的影响。在一个高度保守的启动子片段中发现了一个潜在的功能多态性，即-169位置的C到T替换。在两组健康中年男性中，-169C > T多态性与血浆葡萄糖浓度之间存在显著相关性（p < 0.01和p < 0.02）。-169T等位基因与较低的负荷后血浆葡萄糖浓度相关。siRNA抑制INSIG1后，在人Huh7肝癌细胞中观察到磷酸烯醇丙酮酸羧激酶（PCK2）的表达显著降低（Ce=0.02）。群体研究表明，INSIG1在葡萄糖稳态中起作用。siRNA实验表明，INSIG1的这种作用与srebp介导的PCK2调控有关。
Insulin-induced gene 1 (INSIG1) is a protein that blocks proteolytic activation of sterol regulatory element-binding proteins (SREBPs), transcription factors that activate genes regulating cholesterol and fatty acid metabolism and possibly genes involved in glucose homeostasis. In search of genetic regulation of these processes we examined human INSIG1 for common polymorphisms and analysed their associations with biochemical parameters related to lipid and glucose metabolism.Associations between common polymorphisms in INSIG1 and several biochemical parameters were analysed in a group of 618 healthy, 50-year-old men. A replication analysis was performed in a cohort of 472 healthy, middle-aged men. The impact of one promoter polymorphism on oral glucose tolerance was analysed in a subset of 181 subjects. Small interfering RNA (siRNA) inhibition was used to test the significance of INSIG1 for gene expression in human Huh7 hepatoma cells.A potentially functional polymorphism, a C to T substitution at position -169, was discovered in a highly conserved section of the promoter. Significant relationships between the -169C > T polymorphism and plasma glucose concentration were found in two cohorts of healthy, middle-aged men (p < 0.01 and p < 0.02, respectively). The -169T allele was associated with significantly lower post-load plasma glucose concentrations. A significant (Ce=0.02) reduction in expression of phosphoenolpyruvate carboxykinase (PCK2) was observed following siRNA inhibition of INSIG1 in human Huh7 hepatoma cells.Population studies demonstrate that INSIG1 plays a role in glucose homeostasis. Experiments with siRNA suggest that this action of INSIG1 is related to SREBP-mediated regulation of PCK2.