Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
Diabet Med. 2009 Nov;26(11):1083-9. doi: 10.1111/j.1464-5491.2009.02860.x.
The study of rare monogenic forms of diabetes and pancreatic B-cell dysfunction provides an unrivalled opportunity to link a specific change in gene function with precise cellular consequences and clinical phenotype in humans. Over the past 20 years there has been considerable success in determining the genetic aetiology of a number of rare monogenic forms of diabetes, which has had a significant impact on both our understanding of normal physiology and on translational medicine. The impact of these discoveries has been substantial, with insights into both developmental biology and normal physiology. There are clear examples where determining the genetic aetiology for individuals with rare monogenic subtypes of diabetes has led to improved treatment. Although formerly in the shadow of the monogenic diabetes field, over the past 3 years there has been staggering progress in our understanding of the genetic basis of Type 2 diabetes. This has been largely as a result of genome-wide association studies and has seen the list of 'diabetes susceptibility genes' increase from three to close to 20. There is now encouraging evidence to support a potential role for genetics in determining the response of individuals with Type 2 diabetes to different therapeutic options. One of the challenges that lies ahead is determining how the non-coding genetic variants exert their pathogenicity. It is possible that parallels can be drawn from functional work on rare regulatory mutations causing monogenic forms of diabetes. However, it is more likely that comprehensive approaches will be necessary.
对罕见的单基因糖尿病形式和胰腺β细胞功能障碍的研究为我们提供了一个无与伦比的机会，使我们能够将基因功能的特定变化与人类中特定的细胞后果和临床表型联系起来。在过去的 20 年中，已经在确定多种罕见的单基因糖尿病的遗传病因方面取得了相当大的成功，这对我们对正常生理学和转化医学的理解都产生了重大影响。这些发现的影响是巨大的，为发育生物学和正常生理学提供了深刻的见解。有明确的例子表明，确定罕见单基因糖尿病亚型个体的遗传病因可以改善治疗效果。虽然以前单基因糖尿病领域处于阴影之下，但在过去的 3 年中，我们对 2 型糖尿病遗传基础的理解取得了惊人的进展。这主要是由于全基因组关联研究的结果，使“糖尿病易感基因”的列表从 3 个增加到接近 20 个。现在有令人鼓舞的证据支持遗传因素在决定 2 型糖尿病患者对不同治疗选择的反应方面的潜在作用。未来面临的挑战之一是确定非编码遗传变异如何发挥其致病性。从导致单基因糖尿病的罕见调节突变的功能研究中可以得出一些相似之处。然而，更有可能需要综合方法。
