美國阿拉巴馬大學(xué)（UAB）研究人員鑒定出與胰島素抵抗相關(guān)兩基因——NR4A3 和NR4A1,，從而為Ⅱ型糖尿病和其他代謝綜合征的治療提供了一條新途徑,。研究結(jié)果發(fā)表在10 月26 日J(rèn)ournal of Biological Chemistry上,。
胰島素通過將血糖從血管中移動(dòng)到骨骼肌用于能量代謝或者儲(chǔ)存下來隨后利用的方式，來降低血糖,。Ⅱ型糖尿病的發(fā)生源于胰島素缺乏,，或者是肌肉鈍化，不能響應(yīng)胰島素信號,，從而導(dǎo)致血液中葡萄糖含量的升高,。第二種情形，即不能對胰島素信號做出響應(yīng)稱之為胰島素抵抗（insulin resistance）,。
UAB 營養(yǎng)科學(xué)系主任,，論文作者W. Timothy Garvey 教授稱，這兩個(gè)蛋白可以促使肌肉對胰島素敏感,，加速葡萄糖的攝取,，從而維持正常的血糖水平,。研究同時(shí)發(fā)現(xiàn)，在動(dòng)物糖尿病模型中,，兩個(gè)基因表達(dá)下調(diào),，伴隨胰島素抵抗提高。
對糖尿病研究而言,，新的發(fā)現(xiàn)提示可以以提升NR4A3 和NR4A1 表達(dá)或活性進(jìn)行藥物研發(fā),。Garvey 表示，下一步工作將圍繞可以與兩個(gè)蛋白相互作用或者促進(jìn)其表達(dá)的分子的篩選,。
目前,，美國目前有2 千萬糖尿病患者，占總?cè)丝诘?%,。美國國立衛(wèi)生研究院（NIH）稱，隨著美國人口的老齡化和美國人群中肥胖的盛行,，糖尿病的發(fā)病率可能進(jìn)一步增加,。
王小理 編譯自http://www.sciencedaily.com/releases/2007/10/071027095416.htm
原始出處:
J. Biol. Chem., Vol. 282, Issue 43, 31525-31533, October 26, 2007
NR4A Orphan Nuclear Receptors Modulate Insulin Action and the Glucose Transport System
POTENTIAL ROLE IN INSULIN RESISTANCE*
Yuchang Fu1, Liehong Luo, Nanlan Luo, Xiaolin Zhu, and W. Timothy Garvey
From the Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama 35294-3360 and the Birmingham Veterans Affairs Medical Center, Birmingham, Alabama 35233
After observing that expression of two NR4A orphan nuclear receptors, NR4A3 and NR4A1, was altered by insulin in cDNA microarray analyses of human skeletal muscle, we studied whether these receptors could modulate insulin sensitivity. We found that both NR4A3 and NR4A1 were induced by insulin and by thiazolidinedione drugs (pioglitazone and troglitazone) in 3T3-L1 adipocytes. Furthermore, gene expression of NR4A3 and NR4A1 was reduced in skeletal muscles and adipose tissues from multiple rodent models of insulin resistance. To determine whether NR4A3 could modulate insulin sensitivity, 3T3-L1 adipocytes were stably transduced with NR4A3 or LacZ (control) lentiviral vectors. Compared with LacZ expressing cells, hyperexpression of NR4A3 increased the ability of insulin to augment glucose transport activity, and the mechanism involved increased recruitment of GLUT4 glucose transporters to the plasma membrane. NR4A3 hyperexpression also led to an increase in insulin-mediated tyrosine phosphorylation of insulin receptor substrate-1 as well as Akt phosphorylation. Suppression of NR4A3 using lentiviral short hairpin RNA constructs reduced the ability of insulin to stimulate glucose transport and phosphorylate Insulin receptor substrate-1 and Akt. Thus, NR4A3 and NR4A1 are attractive novel therapeutic targets for potential amelioration of insulin resistance, and treatment and prevention of type 2 diabetes and the metabolic syndrome.
