Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver.
Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver.
复制标题
DOI：
--
复制
发表时间：
2006
期刊：
影响因子：
8.2
通讯作者：
G. Bryzgalova;H. Gao;B. Ahrén;J. Zierath;D. Galuska;T. Steiler;K. Dahlman-Wright;S. Nilsson;J-A Gustafsson;S. Efendic;A. Khan
中科院分区：
文献类型：
--
作者：
G. Bryzgalova;H. Gao;B. Ahrén;J. Zierath;D. Galuska;T. Steiler;K. Dahlman-Wright;S. Nilsson;J-A Gustafsson;S. Efendic;A. Khan
目的/假设我们使用雌激素受体α（ER α）基因敲除（ERKO）和受体β（ER β）基因敲除（BERKO）小鼠来研究雌激素对葡萄糖稳态影响的机制。方法采用正常血-高胰岛素钳夹法测定ERKO小鼠的内源性葡萄糖生成（EGP）。从分离的胰岛测定胰岛素分泌。在离体肌肉中，通过使用放射性标记的同位素测定葡萄糖摄取。通过高密度寡核苷酸芯片分析全基因组表达谱，并通过RT-PCR证实编码固醇-CoA去饱和酶和瘦素受体（分别为Scd 1和Lepr）的基因的表达。结果ERKO小鼠空腹血糖、血浆胰岛素水平和IGT均升高。ERKO小鼠血浆瘦素水平升高，脂联素浓度降低。在ERKO和野生型小鼠中，葡萄糖和精氨酸诱导的胰岛分泌水平相似。正常血-高胰岛素钳夹显示，ERKO小鼠中胰岛素水平升高对EGP的抑制作用减弱，这表明存在明显的肝脏胰岛素抵抗。微阵列分析显示，在ERKO小鼠中，参与肝脏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小鼠的肝脏Lepr表达降低。体外研究显示ERKO小鼠比目鱼肌和趾长伸肌（EDL）肌肉中胰岛素介导的葡萄糖摄取适度降低。BERKO小鼠表现出正常的葡萄糖耐量和胰岛素释放。结论/解释我们得出结论，雌激素，通过ER α，调节葡萄糖稳态主要是通过调节肝脏胰岛素敏感性，这可能是由于通过抑制Lepr表达的脂肪生成基因的上调。
AIMS/HYPOTHESIS We used oestrogen receptor-alpha (ERalpha) knockout (ERKO) and receptor-beta (ERbeta) 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 ERalpha, 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.