对全球55,000多人的DNA进行的一项研究，揭示了我们如何在进食后保持健康的血糖水平，这对我们了解2型糖尿病的病因具有重要意义。

A study of the DNA of more than 55,000 people worldwide has shed light on how we maintain healthy blood sugar levels after we have eaten, with implications for our understanding of how the process goes wrong in type 2 diabetes.

这项发表在《自然遗传学》(Nature Genetics) 上的研究结果可能有助于为未来的2型糖尿病治疗提供信息，该病影响英国约400 万人和全球超过4.6亿人。

The findings, published in Nature Genetics, could help inform future treatments of type 2 diabetes, which affects around 4 million people in the UK and over 460 million people worldwide.

有几个因素会增加患2型糖尿病的风险，例如年龄较大、超重或肥胖、缺乏运动和遗传易感性。如果不治疗，2型糖尿病会导致并发症，包括眼睛和足部问题、神经损伤以及心脏病发作和中风的风险增加。

Several factors contribute to an increased risk of type 2 diabetes, such as older age, being overweight or having obesity, physical inactivity, and genetic predisposition. If untreated, type 2 diabetes can lead to complications, including eye and foot problems, nerve damage, and increased risk of heart attack and stroke.

迄今为止，大多数关于胰岛素抵抗的研究都集中在空腹状态——即饭后数小时——此时胰岛素主要作用于肝脏。但是当胰岛素作用于我们的肌肉和脂肪组织时，我们大部分时间都处于进食状态。

Most studies to date of insulin resistance have focused on the fasting state – that is, several hours after a meal – when insulin is largely acting on the liver.  But we spend most of our time in the fed state, when insulin acts on our muscle and fat tissues.

人们认为，在所谓的“葡萄糖挑战”（例如含糖饮料或一顿饭）之后，胰岛素抵抗的分子机制在2型糖尿病的发展中起着关键作用。然而，人们对这些机制知之甚少。

It’s thought that the molecular mechanisms underlying insulin resistance after a so-called ‘glucose challenge’ – a sugary drink, or a meal, for example – play a key role in the development of type 2 diabetes. Yet these mechanisms are poorly-understood.

剑桥大学Wellcome-MRC代谢科学研究所联席主任Stephen O'Rahilly教授说：“我们知道有些患有特定罕见遗传病的人在空腹状态下胰岛素完全正常工作，它主要作用于肝脏，但在饭后效果很差，因为它主要作用于肌肉和脂肪。目前尚不清楚的是，这类问题是否在更广泛的人群中更常见，以及它是否与患2型糖尿病的风险有关。”

Professor Sir Stephen O’Rahilly, Co-Director of the Wellcome-MRC Institute of Metabolic Science at the University of Cambridge, said: “We know there are some people with specific rare genetic disorders in whom insulin works completely normally in the fasting state, where it’s acting mostly on the liver, but very poorly after a meal, when it’s acting mostly on muscle and fat. What has not been clear is whether this sort of problem occurs more commonly in the wider population, and whether it’s relevant to the risk of getting type 2 diabetes.”

该团队确定了10个新的基因位点——基因组区域——与含糖饮料后的胰岛素抵抗有关。其中8个区域也具有较高的2型糖尿病风险，凸显了它们的重要性。

The team identified new 10 loci – regions of the genome – associated with insulin resistance after the sugary drink. Eight of these regions were also shared with a higher risk of type 2 diabetes, highlighting their importance.

这些新发现的位点之一位于编码GLUT4的基因内，GLUT4 是负责在进食后将血液中的葡萄糖吸收到细胞中的关键蛋白质。该位点与肌肉组织中GLUT4的减少量有关。

One of these newly-identified loci was located within the gene that codes for GLUT4, the critical protein responsible for taking up glucose from the blood into cells after eating. This locus was associated with a reduced amount of GLUT4 in muscle tissue.

寻找可能在葡萄糖调节中发挥作用的其他基因，研究人员转向从小鼠身上提取的细胞系来研究这些位点内和周围的特定基因。由此发现了14个基因，这些基因在GLUT4运输和葡萄糖摄取中发挥了重要作用——其中9个以前从未认为与胰岛素调节相关。

To look for additional genes that may play a role in glucose regulation, the researchers turned to cell lines taken from mice to study specific genes in and around these loci. This led to the discovery of 14 genes that played a significant role in GLUT 4 trafficking and glucose uptake – with nine of these never previously linked to insulin regulation.

进一步的实验表明，这些基因影响了在细胞表面发现的GLUT4的数量，这可能是通过改变蛋白质从细胞内部移动到细胞表面的能力来实现的。到达细胞表面的GLUT4越少，细胞从血液中去除葡萄糖的能力就越差。

Further experiments showed that these genes influenced how much GLUT4 was found on the surface of the cells, likely by altering the ability of the protein to move from inside the cell to its surface. The less GLUT4 that makes its way to the surface of the cell, the poorer the cell’s ability to remove glucose from the blood.

Alice Williamson博士在Wellcome-MRC代谢科学研究所攻读博士学位时开展了这项工作，她说：“令人兴奋的是，它展示了我们如何从大规模的遗传研究转向理解我们身体如何运转的基本机制——尤其是当这些机制出现问题时，它们会如何导致常见疾病，例如 2 型糖尿病。”

Dr Alice Williamson, who carried out the work while a PhD student at the Wellcome-MRC Institute of Metabolic Science, said: “What’s exciting about this is that it shows how we can go from large scale genetic studies to understanding fundamental mechanisms of how our bodies work – and in particular how, when these mechanisms go wrong, they can lead to common diseases such as type 2 diabetes.”

伦敦玛丽女王大学精准医疗大学研究所 (PHURI) 主任、德国柏林健康研究所计算医学教授Claudia Langenberg教授说：“我们的研究结果为开发阻止2型糖尿病发展的治疗方法开辟了一条潜在的新途径。它还展示了动态挑战测试的遗传研究如何提供重要的思路，否则这些思路将无从发现。”

Professor Claudia Langenberg, Director of the Precision Healthcare University Research Institute (PHURI) at Queen Mary University of London and Professor of Computational Medicine at the Berlin Institute of Health, Germany, said: “Our findings open up a potential new avenue for the development of treatments to stop the development of type 2 diabetes. It also shows how genetic studies of dynamic challenge tests can provide important insights that would otherwise remain hidden.”

这项研究得到了Wellcome基金会、英国医学研究委员会和英国国家健康与护理研究所的支持。

The research was supported by Wellcome, the Medical Research Council and the National Institute for Health and Care Research.