Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice:: insulin sensitivity in the liver
Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice:: insulin sensitivity in the liver
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DOI：
10.1007/s00125-005-0105-3
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发表时间：
2006-03-01
期刊：
影响因子：
8.2
通讯作者：
Khan, A
中科院分区：
文献类型：
--
作者：
Bryzgalova, G;Gao, H;Khan, A
目的/假设：我们使用雌激素受体- α (ER α)敲除（ERKO）和受体- β (ER β)敲除（BERKO）小鼠来研究雌激素对葡萄糖稳态影响的机制。方法：采用血糖-高胰岛素钳法测定ERKO小鼠的内源性葡萄糖生成（EGP）。用离体胰岛测定胰岛素分泌。在离体肌肉中，用放射性标记同位素测定葡萄糖摄取。采用高密度寡核苷酸芯片分析全基因组表达谱，RT-PCR检测编码甾醇辅酶a去饱和酶和瘦素受体（分别为Scd1和Lepr）基因的表达。结果：ERKO小鼠有较高的空腹血糖、血浆胰岛素水平和IGT。ERKO小鼠血浆瘦素水平升高，脂联素浓度降低。葡萄糖和精氨酸诱导的胰岛胰岛素分泌水平在ERKO和野生型小鼠中是相似的。血糖-高胰岛素钳夹显示，胰岛素水平升高对EGP的抑制在ERKO小鼠中被减弱，这表明肝脏胰岛素抵抗明显。芯片分析显示，在ERKO小鼠中，参与肝脂质生物合成的基因上调，而参与脂质转运的基因下调。值得注意的是，ERKO小鼠肝脏Lepr表达降低。体外研究显示ERKO小鼠比目鱼肌和指长伸肌（EDL）胰岛素介导的葡萄糖摄取适度减少。BERKO小鼠表现出正常的葡萄糖耐量和胰岛素释放。结论/解释：我们得出的结论是，雌激素通过内质酰胺α发挥作用，主要通过调节肝脏胰岛素敏感性来调节葡萄糖稳态，这可能是由于通过抑制Lepr表达来上调脂质基因。
Aims/hypothesis: We used oestrogen receptor-alpha (ER alpha) knockout (ERKO) and receptor-beta (ER beta) knockout (BERKO) mice to investigate the mechanism(s) behind the effects of oestrogens on glucose homeostasis. Methods: Endogenous glucose production (EGP) was measured in ERKO mice using a euglycaemic-hyperinsulinaemic clamp. Insulin secretion was determined from isolated islets. In isolated muscles, glucose uptake was assayed by using radiolabelled isotopes. Genome-wide expression profiles were analysed by high-density oligonucleotide microarray assay, and the expression of the genes encoding steroyl-CoA desaturase and the Leptin receptor (Scd1 and Lepr, respectively) was confirmed by RT-PCR. Results: ERKO mice had higher fasting blood glucose, plasma insulin levels and IGT. The plasma leptin level was increased, while the adiponectin concentration was decreased in ERKO mice. Levels of both glucose- and arginine-induced insulin secretion from isolated islets were similar in ERKO and wild-type mice. The euglycaemic-hyperinsulinaemic clamp revealed that suppression of EGP by increased insulin levels was blunted in ERKO mice, which suggests a pronounced hepatic insulin resistance. Microarray analysis revealed that in ERKO mice, the genes involved in hepatic lipid biosynthesis were upregulated, while genes involved in lipid transport were downregulated. Notably, hepatic Lepr expression was decreased in ERKO mice. In vitro studies showed a modest decrease in insulin-mediated glucose uptake in soleus and extensor digitorum longus (EDL) muscles of ERKO mice. BERKO mice demonstrated normal glucose tolerance and insulin release. Conclusions/interpretation: We conclude that oestrogens, acting via ER alpha, regulate glucose homeostasis mainly by modulating hepatic insulin sensitivity, which can be due to the upregulation of lipogenic genes via the suppression of Lepr expression.