一项新的研究显示：在胎儿发育时期，一个重要基因的活性降低有可能会增加以后2型糖尿病患病的可能性。
　　子宫内胎儿生长延迟(IUGR)可以造成新生儿体重的减低，现在已证实它同2型糖尿病以及其他儿童生长期疾病的形成有关。

胎儿期基因

　　如果在胎儿发育期间Pdx1基因活性降低的话，那么孩子以后患2型糖尿病的可能性就会增加。这个基因在胰腺β细胞的发育和发挥功能方面起着重要作用。胰腺β细胞的功能是分泌胰岛素，而胰岛素则可以将糖从血液转运到身体的细胞中以加以利用。糖尿病患者的身体并不能产生足够的胰岛素或是会对胰岛素的敏感性下降。

　　但是，Pdx1基因在患有子宫内胎儿生长延迟的动物体内并没有发生突变，这就让很多科学家感到困惑：如果基因没有突变的话，那么它为什么会发生这些永久性的变化呢？

　　发表于五月份《临床检查杂质》上的这篇文章的主要作者Rebecca A. Simmons博士接着问到：“子宫内的环境究竟发生了什么变化？为什么会导致以后产生糖尿病呢？”

　　宾夕法尼亚医学院的儿科助理教授Simmons又接着说：“到底是子宫内的什么因素使得胎儿即使在一个正常的环境中出生，他的β细胞还是不能正常工作？”

　　在通过对一个患有子宫内胎儿生长延迟的啮齿动物模型进行研究之后，研究人员发现是表观遗传学改变造成了基因的活性降低：基因的活性并不是完全消失了，而是被“标记降低“了，Simmons说。所谓的表观遗传学变化是指：在细胞分裂或是DNA被复制之后DNA结构发生的改变。她说，这些变化干扰了DNA的转录或是向身体的其他部位发送信息的功能。

　　以前，研究人员可以通过使用模拟肠促胰岛素(Exendin-4)来恢复患有糖尿病的新生的或是成人动物的Pdx1基因活性。但现在还不清楚这个药物是否可以扭转这些表观遗传学改变。

　　Simmons介绍说，这些药物均来自于希拉毒蜥蜴的唾液。

　　但是现在，要在人类身上验证这些发现，还面临着巨大的技术性障碍。

　　“我们知道这个过程（基因沉默）确实是可以发生在人类身上的，特别是那些具有肿瘤抑制基因的癌症的人身上，”Simmons解释道，“发育迟缓的孩子在成长过程中会出现很多与正常人不同的特点，我们不知道这个过程是否就是导致这些特点产生的主要原因。”

　　“我们很愿意这是真的（即这个人体中也存在这个过程），但现在还没有办法确定，“Simmons继续说。

　　如果在人体当中真的存在这种机制的话，那么Pdx1基因就有可能成为2型糖尿病新药开发的靶点了。

Fetal Gene May Contribute to Diabetes Risk

Reduced activity of an important gene during fetal development appears to increase vulnerability to type 2 diabetes later in life, new research suggests.

Intrauterine growth retardation (IUGR), which causes low birth weight in newborns, has been linked to the development of type 2 diabetes and other diseases when a child grows up.

And decreased activity of the Pdx1 gene during fetal development has been linked to susceptibility for type 2 diabetes later on. The gene plays an important role in the development and function of pancreatic beta cells, which produce the hormone insulin. Insulin is necessary to transport sugar from the blood stream to the body's cells for energy. People with diabetes either don't produce enough insulin or aren't sensitive enough to the insulin that is produced.

The Pdx1 gene, however, had no mutation in animals with IUGR, presenting a mystery to scientists: If there is no mutation, why is the gene permanently altered?

"What happens in the intra-uterine environment? Why does that lead to the development of diabetes later in life?" asked Dr. Rebecca A. Simmons, senior author of a paper published in the May issue of the Journal of Clinical Investigation.

"What in intra-uterine life makes that beta cell not work properly even after you've been born into a normal environment?" added Simmons, an associate professor of pediatrics at the University of Pennsylvania School of Medicine.

Using a rodent model of IUGR, the researchers found that "epigenetic" changes were responsible for the lowered activity -- the gene was not totally silenced but was "markedly reduced," Simmons said. Epigenetic changes are basically changes in the structure of the DNA that occur when the cell divides and the DNA is replicated. These changes interfere with the ability of DNA to be transcribed, or send messages out to the rest of the body, she said.

Researchers were previously able to normalize the activity of the Pdx1 gene in both newborn and adult animals with diabetes, using the drug Byetta (Exendin-4). It's not clear yet if the drug can also reverse epigenetic changes. The drug comes from Gila monster saliva, Simmons said.

But investigators face a huge technical hurdle trying to confirm these findings in humans.

"We do know this process [gene silencing] occurs in humans, particularly in cancer with tumor suppressor genes," Simmons explained. "What we don't know is if this process is responsible, in humans, for changes that we see in growth-retarded babies growing up."

"We'd like to think this is the case [that the same process is at work in humans], but we have no way right now to determine that," Simmons continued.

If the same mechanism is at work in humans, the Pdx1 gene may present a good target for drug therapy to prevent the development of type 2 diabetes, she said.

表观遗传学是 研究没有DNA 序列变化并且可以遗传的基因功能变化之学科