A multidisciplinary approach to validate the role of ATM in glycaemic response to metformin in type 2 diabetes

全世界有超过1亿人使用二甲双胍主要治疗糖尿病，但最近这种药物在癌症预防或治疗中的潜在益处正在实现。尽管二甲双胍已使用50多年，但其作用机制尚未完全确定。一项关于二甲双胍反应遗传学的创新研究显示，包括二甲双胍的基因组区域？癌症相关？ATM基因与二甲双胍如何降低糖尿病患者的血糖有关。我们建议关键的后续研究，以确认这是ATM基因是负责这一点？基因信号？我们将利用邓迪糖尿病研究中心的大量合作资源，以及邓迪和牛津威康人类遗传学信托中心的遗传学专业知识，通过对人类，小鼠和细胞的研究来解决这一关键步骤。遗传学研究将用于寻找与二甲双胍应答大幅变化相关的遗传变异（或DNA变化），因为这些可能在临床上有用，可预测谁将对二甲双胍治疗产生应答，谁将获胜？t.在小鼠研究中，我们将观察正常小鼠和缺乏Atm基因一个（或两个）拷贝的小鼠。我们将用高脂肪和高碳水化合物的饮食喂养他们，这将导致他们中的一些人患上糖尿病，然后我们将用二甲双胍治疗糖尿病患者，看看遗传差异是否会改变二甲双胍的反应。然后在细胞研究中（无论是标准实验室？细胞系或来自人献血者的细胞），我们将研究ATM变异改变二甲双胍反应的机制。本研究可能的关键结果是，我们将验证基因ATM是参与二甲双胍反应的关键基因，并深入了解其机制。这对二甲双胍治疗糖尿病患者有影响，特别是1%的人群有一个错误的ATM基因拷贝;可能对罕见的神经/癌症综合征患者有影响？共济失调-毛细血管扩张症？此外，这对癌症生物学家、对代谢感兴趣的生物学家和制药行业来说都是一个重要的结果，因为二甲双胍的这种意想不到的机制可能揭示药物开发的新途径。

Metformin is used by over 100 million people world wide primarily to treat diabetes, but more recently the potential benefits of this drug in cancer prevention or treatment are being realized. Despite its use for over 50 years the mechanism of action of metformin has not been fully determined. An innovative study on the genetics of response to metformin has revealed that an area of the genome that includes the ?cancer associated? gene ATM is involved in how metformin lowers blood sugar in people with diabetes. We propose key follow on studies to confirm that it is the ATM gene that is responsible for this ?genetic signal?. We will use the considerable collaborative resources within the Diabetes Research Centre in Dundee, and the genetics expertise both within Dundee and the Wellcome Trust Centre for Human Genetics in Oxford, to address this key step, using studies in humans, mice and cells. The genetic studies will be used to look for genetic variants (or changes in the DNA) that are associated with large changes in metformin response as these may be usefully clinically to predict who will respond to metformin treatment and who won?t. In the mouse studies, we will look at normal mice and mice that lack one (of two) copies of the Atm gene. We will feed them with a high fat and high carbohydrate diet, which will result in some of them developing diabetes, and we will then treat those with diabetes with metformin to see if the genetic difference alters metformin response. Then in studies of cells (either standard laboratory ?cell-lines? or cells from human blood donors) we will study the mechanism whereby ATM variation alters metformin response. The likely key outcome of this study is that we will have validated that the gene ATM is a key gene involved in metformin response and gained insight into the mechanism. This has implications for the treatment of diabetic patients with metformin, especially as 1% of the population has one faulty copy of the ATM gene; and may have implications for the rare group of patients who have the neurological/cancer syndrome ?ataxia-telangiectasia?. In addition, this will be an important result for both cancer biologists, biologists interested in metabolism, and the pharmaceutical industry as this unexpected mechanism for metformin may reveal novel pathways for drug development.