2012年9月13日 電 /生物谷BIOON/ --近日,，英國牛津大學(xué)研究人員發(fā)現(xiàn)導(dǎo)致胰島素敏感性增加的起始單個(gè)基因。胰島素抵抗是2型糖尿病一個(gè)共同的特點(diǎn),，找到胰島素抵抗的原因以降低胰島素的敏感性對(duì)開發(fā)新的治療糖尿病方法非常有必要,。
英國牛津大學(xué)的研究人員、劍橋Babraham研究所以及牛津丘吉爾醫(yī)院同事在New England Journal of Medicine醫(yī)學(xué)雜志上發(fā)表了他們的最新發(fā)現(xiàn),。這項(xiàng)研究是由威康信托基金會(huì),、美國國立衛(wèi)生研究院、牛津大學(xué)生物醫(yī)學(xué)研究中心以及生物科學(xué)研究理事會(huì)等資助
牛津大學(xué)Anna Gloyn博士說：胰島素抵抗是2型糖尿病的一大特色,，胰腺中產(chǎn)生胰島素的細(xì)胞必須更加努力工作以泵出大量的胰島素,，但體內(nèi)的細(xì)胞卻不再回應(yīng)。
從相反的角度出發(fā),，尋找一個(gè)能增加胰島素的敏感性遺傳因素為我們提供了治療糖尿病的新的窗口,。PTEN基因編碼的酶是體內(nèi)胰島素信號(hào)轉(zhuǎn)導(dǎo)通路的一部分。據(jù)了解,，PTEN基因在控制人體的新陳代謝有一定的作用,，并在細(xì)胞生長中扮演重要角色,。PTEN基因的突變會(huì)導(dǎo)致一種罕見的疾病如增加患癌癥的風(fēng)險(xiǎn)，參與PTEN生物信號(hào)途徑的基因?yàn)樾滤幬锏拈_發(fā)提供了廣泛的目標(biāo),。
牛津大學(xué)博士Aparna Pal說：PTEN基因積極參與細(xì)胞生長和代謝過程,。由于PTEN的雙重角色，我們非常有興趣了解患Cowden綜合征的人體內(nèi)的代謝情況,。研究人員認(rèn)為PTEN的突變可能提高新陳代謝,。該小組對(duì)15名Cowden綜合征患者和15名對(duì)照健康者進(jìn)行葡萄糖耐量試驗(yàn)。 Cowden綜合征者有顯著較高的胰島素敏感性,。研究小組發(fā)現(xiàn),，這是由于在胰島素信號(hào)轉(zhuǎn)導(dǎo)通路的活動(dòng)增加導(dǎo)致的。研究人員還注意到,，Cowden綜合征患者的身體質(zhì)量指數(shù)大于對(duì)照組,。 相關(guān)研究數(shù)據(jù)證實(shí)Cowden綜合征與對(duì)照組相比有較高水平的肥胖率。額外的體重似乎是多余的脂肪引發(fā)的,，但研究數(shù)據(jù)并未證實(shí)兩組人員的脂肪儲(chǔ)存部位有任何顯著性差異,。
博士Gloyn得出結(jié)論：我們現(xiàn)在知道，導(dǎo)致抑癌基因PTEN失活的基因突變?cè)黾影┌Y的風(fēng)險(xiǎn),，并會(huì)導(dǎo)致肥胖,，同時(shí)也增加胰島素的敏感性，明確這一點(diǎn)對(duì)開發(fā)以這些基因?yàn)榘悬c(diǎn)在新藥物對(duì)防止2型糖尿病有重要意義,。但她補(bǔ)充說：雖然有將來的研究會(huì)進(jìn)一步揭示糖尿病的發(fā)病機(jī)制,，但在此期間，最好的避免糖尿病的方式仍然是多運(yùn)動(dòng),，少吃,。（生物谷：Bioon.com）
doi:10.1056/NEJMoa1113966
PMC:
PMID:
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.)
