牛津大学的研究团队发现了第一个可增加胰岛素敏感性的单个基因。
和胰岛素敏感性增加相反的情形是胰岛素抵抗，这是2型糖尿病的常见特征，所以找到胰岛素敏感的原因可以为糖尿病新疗法的研发提供机遇。
尽管PTEN基因的突变会增加一种罕见癌症的风险，这个基因参与的生物通路可以为新药提供有前途的靶标。
这项研究由牛津大学、英国剑桥的巴布拉汉研究所(Babraham Institute)和英国牛津的丘吉尔医院（Churchill Hospital）合作完成，结果被发表在了《新英格兰医学杂志》（New England Journal of Medicine）上。
牛津大学糖尿病、内分泌学和代谢中心的安娜•格罗伊（Anna Gloyn）博士领导了这项研究。她说：“胰岛素抵抗是2型糖尿病的主要特征。胰腺中产生胰岛素的细胞在拼命排出胰岛素，但是身体里的细胞对此没有反应。”
“胰岛素敏感性是与此相反的过程，找到它的遗传原因如同打开了一扇窗口，让我们了解其中的生物过程。理解了过程对研可以发保持胰岛素敏感的2型糖尿病新药十分重要。”
PTEN基因编码一个参与胰岛素信号通路的酶。这个基因参与控制身体的代谢，对细胞增长也很重要。牛津的研究团队对深入了解该基因的两个作用很感兴趣。
PTEN基因失常会导致遗传疾病多发性错构瘤综合征(Cowden's syndrome)。这种疾病非常罕见，被认为会在每20万人中影响1人。英国大约有300名患者。PTEN在细胞生长中的作用导致多发性错构瘤综合征患者的皮肤、嘴部和肠道长出很多良性的息肉，并且还有比常人更高的风险患有乳房癌、甲状腺癌和子宫癌。
多发性错构瘤综合征(Cowden's syndrome)患者。（图片来源：Wikipedia）
“PTEN基因对细胞生长和代谢都具有重要的作用，”论文的第一作者、牛津大学的阿帕那•帕尔（Aparna Pal）博士说，“既然PTEN有两个作用，我们对理解多发性错构瘤综合征患者的代谢图谱很感兴趣。PTEN的突变有可能会改进代谢。”
研究团队测试了15名多发性错构瘤综合征患者对葡萄糖的耐受性，对应的对照组也有15人。多发性错构瘤综合征患者的胰岛素敏感度有显著提高。通过和巴布拉汉研究所的同事合作，研究团队发现，这是因为胰岛素信号通路的活性提高了。
研究人员还注意到，多发性错构瘤综合征患者的体重指数也比对照组要大。他们还用大得多的对照组进行了比较，新对照组包括了2000多个人。这些人的情况是从牛津的Biobank中获得的，Biobank是由弗雷德里克•卡普（Fredrik Karpe）教授创建的数据和身体组织研究资源。
这一结果验证了发性错构瘤综合征患者比对照组肥胖更严重的事实。多余的体重来自多余的脂类。但是和对照组相比，发性错构瘤综合征患者储存脂类的部位没有不同。
“这很让人惊讶，一般来说胰岛素敏感会让人变瘦，” 弗雷德里克•卡普教授说。格罗伊博士总结道：“我们知道PTEN基因突变失活会提升患癌风险，并导致肥胖，但也会增加胰岛素的敏感性，很可能可以预防2型糖尿病。”
“这项研究表明，生物通路对细胞生长和代谢的控制联系得非常紧密。我们需要彻底地理解这些通路以找到那些基因可以作为新药的靶标。”
她补充说：“尽管这项研究很有前途。但是就现在来说，预防糖尿病的最好手段是好好锻炼，控制饮食。”
本文编译自牛津大学通过EurekAlert!发布的新闻稿。
PTEN Mutations as a Cause of Constitutive Insulin Sensitivity and Obesity
Aparna Pal, M.R.C.P., Thomas M. Barber, D.Phil., M.R.C.P., Martijn Van de Bunt, M.D., Simon A. Rudge, Ph.D., Qifeng Zhang, Ph.D., Katherine L. Lachlan, M.R.C.P.C.H., Nicola S. Cooper, M.R.C.P., Helen Linden, M.R.C.P., Jonathan C. Levy, M.D., F.R.C.P., Michael J.O. Wakelam, Ph.D., Lisa Walker, D.Phil., M.R.C.P.C.H., Fredrik Karpe, Ph.D., F.R.C.P., and Anna L. Gloyn, D.Phil.
BACKGROUND Epidemiologic and genetic evidence links type 2 diabetes, obesity, and cancer. The tumor-suppressor phosphatase and tensin homologue (PTEN) has roles in both cellular growth and metabolic signaling. Germline PTEN mutations cause a cancer-predisposition syndrome, providing an opportunity to study the effect of PTEN haploinsufficiency in humans.
METHODS We measured insulin sensitivity and beta-cell function in 15 PTEN mutation carriers and 15 matched controls. Insulin signaling was measured in muscle and adipose-tissue biopsy specimens from 5 mutation carriers and 5 well-matched controls. We also assessed the effect of PTEN haploinsufficiency on obesity by comparing anthropometric indexes between the 15 patients and 2097 controls from a population-based study of healthy adults. Body composition was evaluated by means of dual-emission x-ray absorptiometry and skinfold thickness.
RESULTS Measures of insulin resistance were lower in the patients with a PTEN mutation than in controls (e.g., mean fasting plasma insulin level, 29 pmol per liter [range, 9 to 99] vs. 74 pmol per liter [range, 22 to 185]; P=0.001). This finding was confirmed with the use of hyperinsulinemic euglycemic clamping, showing a glucose infusion rate among carriers 2 times that among controls (P=0.009). The patients' insulin sensitivity could be explained by the presence of enhanced insulin signaling through the PI3K-AKT pathway, as evidenced by increased AKT phosphorylation. The PTEN mutation carriers were obese as compared with population-based controls (mean body-mass index [the weight in kilograms divided by the square of the height in meters], 32 [range, 23 to 42] vs. 26 [range, 15 to 48]; P<0.001). This increased body mass in the patients was due to augmented adiposity without corresponding changes in fat distribution.
CONCLUSIONS PTEN haploinsufficiency is a monogenic cause of profound constitutive insulin sensitization that is apparently obesogenic. We demonstrate an apparently divergent effect of PTEN mutations: increased risks of obesity and cancer but a decreased risk of type 2 diabetes owing to enhanced insulin sensitivity. (Funded by the Wellcome Trust and others.)
Supported by grants from the Wellcome Trust (095101/Z/10Z, to Dr. Gloyn), the Medical Research Council (G0700222, to Dr. Gloyn; and G0800467, to Drs. Pal and Gloyn), the National Institute for Health Research Oxford Biomedical Research Centre (to Drs. Pal, Karpe, and Gloyn), the Biotechnology and Biological Sciences Research Council (to Drs. Rudge, Zhang, and Wakelam), and the European Union Seventh Framework Program LipodomicNet (202272, for adipocyte signaling work, to Drs. Wakelam and Karpe).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the clinicians Trevor R.P. Cole, Louise Izatt, Carole McKeown, Eamonn R. Maher, and Mary Porteous for referring patients for this study; the research nurses Beryl Barrow and Jane Cheeseman for assistance with collecting clinical data; Amy Barrett for analysis of PTEN expression; Sandy Humphries for analysis of apolipoprotein B; Tim James and colleagues at the John Radcliffe Hospital, Oxford, for analysis of glucose and insulin; the NIHR Cambridge Biomedical Research Centre Core Biochemical Assay Laboratory for analysis of leptin and adiponectin; Leanne Hodson and Barbara Fielding for access to control dual-emission x-ray absorptiometry scans and phenotypic data on postmenopausal controls; and Jonathan Clark and Izabella Niewczas for providing lipid standards for the mass-spectrometry analysis.
文献链接：PTEN Mutations as a Cause of Constitutive Insulin Sensitivity and Obesity
