肿瘤抑制物可能影响妊娠糖尿病

Tumor Suppressor May Also Affect Gestational Diabetes
Jennifer Couzin
肿瘤抑制基因可能也影响妊娠糖尿病

Stanford University's Seung Kim was treating cancer patients when he first encountered a clue about the biology of diabetes. The patients suffered from a rare inherited syndrome called MEN1, or multiple endocrine neoplasia type 1, which triggers tumors in endocrine glands. In some cases, beta cells in the pancreas multiply and overproduce insulin.
斯坦福大学的Seung Kim治疗肿瘤患者时首次意外发现了一条关于糖尿病生物学的线索。这些患者都身患一种罕见的名为多发性内分泌腺瘤病1型（MEN1）的遗传性综合征，该病可诱发内分泌腺肿瘤。在一些患者中，胰腺中的B细胞增多并产生过度胰岛素。

This reminded Kim of a very different state: pregnancy. There, placental signals and the burden of a fetus lead to insulin resistance and a demand for more hormone. An unlucky 4% of women cannot produce enough and are diagnosed with gestational diabetes.
这使Kim想到一种很不同的情况：妊娠。怀孕时的胎盘信号和孕育胎儿的负担导致妇女身体产生了胰岛素抵抗，因而需要更多的胰岛素。而4%的孕妇不能产生足够的胰岛素并被诊断为妊娠糖尿病。

On page 806, Kim, a developmental biologist, and his Stanford colleagues describe a connection in mice between menin, the protein encoded by the MEN1 gene, and gestational diabetes. Menin had long been known as a tumor suppressor; MEN1 occurs when the protein is lacking. Now, Kim and his colleagues report that in healthy animals, menin inhibits the replication of beta cells. Dialing it down allows beta cells to proliferate, increasing insulin supply. It's a clever insight, says Robert Sorenson of the University of Minnesota, Minneapolis, who studies how these cells adapt to pregnancy: \"I knew about multiple endocrine neoplasia, for years and years, but I never thought about linking it to pregnancy.\" If its role holds up in humans, menin may offer clues about gestational diabetes and the ways beta cells regenerate.
在806页，发育生物学家Kim和他斯坦福的同仁们描述了老鼠身上多发性内分泌腺瘤蛋白（menin）和妊娠糖尿病的关系，menin是由MEN1基因编码的蛋白。Menin是一种早已知的肿瘤抑制基因；当该蛋白缺如时发生MEN1。现在Kim和他的同仁们报道了在健康动物中，menin抑制B细胞的复制。“这是一个聪明的观察。” Minneapolis明尼苏达州大学的Robert Sorenson说，他研究了这些细胞如何适应妊娠，“我知道关于内分泌腺肿瘤形成的知识很多年了… …但是从来没有想过把它和妊娠联系起来。”如果把它的作用应用于人类，menin可能提供妊娠糖尿病的线索和B细胞再生的途径。

Kim's group first examined what happens to menin during pregnancy. In normal mice, menin levels drop and climb back up after the animal gives birth. To test whether this was driving beta cell expansion, Kim and his colleagues created transgenic mice whose menin production didn't decline during pregnancy. When these mice became pregnant, their glucose rose to levels comparable to those in gestational diabetes. Autopsies confirmed that when menin didn't fade in pregnancy, beta cell proliferation was impaired, and the animals didn't produce the insulin they needed.
Kim的小组首次验证了妊娠时menin的变化。在正常老鼠，妊娠时menin的水平下降并在分娩后回升。为了验证menin下降是否能导致B细胞增生，Kim和他的同仁制作了转基因老鼠，妊娠时menin产量不下降。这些老鼠怀孕后血糖水平升高到妊娠糖尿病老鼠的水平。尸检证实妊娠时menin水平没有下降，B细胞增殖受损以致动物不能产生所需的胰岛素。

In mouse and human cells, Kim's team found that prolactin, a hormone that rises during pregnancy and that Sorenson had found triggers beta cell proliferation in rodents, was what caused menin levels to fall. This, says Sorenson, suggests a distinct chain of events: A boost in prolactin causes a drop in menin, which increases beta cell mass. The discovery is \"quite different than the tumor story,\" because here the normal functions of menin take center stage, says Stephen Marx of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, who helped lead the team that cloned the MEN1 gene. Still, because the work is in mice, \"it's hard to extrapolate too much,\" Kim cautions.
Kim小组在老鼠和人身上发现催乳素导致menin水平下降，催乳素是一种在妊娠时升高的激素，Sorenson已经在啮齿类动物中发现催乳素能致B细胞增殖。Sorenson说，这表明了一个清晰的事件链：催乳素的升高导致了menin的降低。马里兰州Bethesda国立糖尿病、消化和肾脏疾病研究所的Stephen Marx，他协助领导了克隆MEN1基因的小组，指出这个发现是“与肿瘤史话大不相同的”，因为在该发现中menin的正常功能处于中心地位。因为这个工作仍然处于老鼠试验阶段，“很难更多地做出推论”，Kim谨慎地评价。

The work suggests that menin might become a tool for developing beta cells in diabetes patients who lack them. \"Up until about 2004, everybody said that you can't get new beta cells from replication; if you lose your beta cells, too bad,\" says Andrew Stewart, an endocrinologist at the University of Pittsburgh in Pennsylvania. The find that suppressing menin induces beta cell expansion is \"one small step in a long quest\" to understand beta cell replication, says Yuval Dor, a developmental biologist at the Hebrew University-Hadassah Medical School in Jerusalem, Israel. Admittedly, devising a menin-based therapy could be complex, because it might interfere with menin's role as a tumor suppressor.
这项工作意味着menin也许能成为那些B细胞缺乏的糖尿病患者B细胞增殖的工具。“直到2004年，人人都说你不能通过复制得到更多的B细胞；如果你失去了B细胞，那就太糟了。” 宾夕法尼亚州匹兹堡大学的内分泌学家Andrew Stewart说道。发现menin降低导致B细胞增生是了解B细胞增生“长期探索过程中的一小步”，以色列耶路撒冷希伯莱大学Hadassah医学院发育生物学家Yuval Dor 说。大家一致公认设计一种基于menin的治疗方法是复杂的，因为受到menin作为肿瘤抑制基因作用的干扰。

Menin's relevance to gestational diabetes remains unclear. Some studies suggest that women who are diagnosed with gestational diabetes may have had insulin deficits before pregnancy. \"You happen to intercept them\" once they're pregnant, says Thomas Buchanan, an endocrinologist at the University of Southern California in Los Angeles, who doubts that menin is \"an important contributor\" in human gestational diabetes. Still, that's something scientists won't know until they assess menin in people.
Menin与妊娠糖尿病的关系不清楚。一些研究表明患妊娠糖尿病的妇女可能怀孕之前就有胰岛素分泌不足。一旦她们怀孕就“恰好发现”，洛杉矶南加利福尼亚州大学内分泌学家Thomas Buchanan说，他怀疑menin在人妊娠糖尿病中是一个“重要的贡献者”。有些事情科学家们也要等在人体中评估了menin的作用后才能知道。