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

采用多学科方法验证 ATM 在 2 型糖尿病二甲双胍血糖反应中的作用

• 批准号: G1100203/1
• 负责人: Ewan Pearson
• 金额: $ 12.67万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1100203%2F1
• 关键词: multidisciplinary; approach; validate; role; ATM

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.

全球有超过 1 亿人使用二甲双胍主要用于治疗糖尿病，但最近人们逐渐认识到这种药物在癌症预防或治疗方面的潜在益处。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表明，基因组中的一个区域包含“与癌症相关”的区域。基因 ATM 与二甲双胍如何降低糖尿病患者的血糖有关。我们建议进行关键的后续研究，以确认 ATM 基因负责这种“遗传信号”。我们将利用邓迪糖尿病研究中心内的大量合作资源，以及邓迪和牛津威康信托人类遗传学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反应的巨大变化相关的遗传变异（或 DNA 的变化），因为这些可能在临床上有用地预测谁会对二甲双胍治疗产生反应，谁不会。在小鼠研究中，我们将观察正常小鼠和缺乏一个（或两个）Atm 基因拷贝的小鼠。我们将为他们喂食高脂肪和高碳水化合物的饮食，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那些患有糖尿病的人，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（标准实验室“细胞系”或来自人类献血者的细胞）中，我们将研究 ATM 变异改变二甲双胍反应的机制。这项研究可能的关键结果是，我们将验证 ATM 基因是参与二甲双胍反应的关键基因，并深入了解该机制。这对于使用二甲双胍治疗糖尿病患者具有重要意义，特别是因为 1% 的人群有一个 ATM 基因的错误拷贝；并可能对极少数患有神经/癌症综合征“共济失调-毛细血管扩张”的患者产生影响。此外，这对于癌症生物学家、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会揭示药物开发的新途径。