Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Skåne, Malmö, Sweden; Glostrup Research Institute, Glostrup University Hospital, Glostrup, Denmark.
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Skåne, Malmö, Sweden; Glostrup Research Institute, Glostrup University Hospital, Glostrup, Denmark.
Mol Cell Endocrinol. 2014 Jan 25;382(1):726-739. doi: 10.1016/j.mce.2013.04.002. Epub 2013 Apr 13.
Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the beta-cells of the pancreas with consequent insulin deficiency to abnormalities that result in resistance to insulin action (American Diabetes Association, 2011). The vast majority of cases of diabetes fall into two broad categories. In type 1 diabetes (T1D), the cause is an absolute deficiency of insulin secretion, whereas in type 2 diabetes (T2D), the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. However, the subdivision into two main categories represents a simplification of the real situation, and research during the recent years has shown that the disease is much more heterogeneous than a simple subdivision into two major subtypes assumes. Worldwide prevalence figures estimate that there are 280 million diabetic patients in 2011 and more than 500 million in 2030 (http://www.diabetesatlas.org/). In Europe, about 6-8% of the population suffer from diabetes, of them about 90% has T2D and 10% T1D, thereby making T2D to the fastest increasing disease in Europe and worldwide. This epidemic has been ascribed to a collision between the genes and the environment. While our knowledge about the genes is clearly better for T1D than for T2D given the strong contribution of variation in the HLA region to the risk of T1D, the opposite is the case for T2D, where our knowledge about the environmental triggers (obesity, lack of exercise) is much better than the understanding of the underlying genetic causes. This lack of knowledge about the underlying genetic causes of diabetes is often referred to as missing heritability (Manolio et al., 2009) which exceeds 80% for T2D but less than 25% for T1D. In the following review, we will discuss potential sources of this missing heritability which also includes the possibility that our definition of diabetes and its subgroups is imprecise and thereby making the identification of genetic causes difficult.
糖尿病是一组以高血糖为特征的代谢性疾病，由胰岛素分泌缺陷或胰岛素作用缺陷或两者共同引起。糖尿病的慢性高血糖与不同器官，尤其是眼睛、肾脏、神经、心脏和血管的长期损伤、功能障碍和衰竭有关。几种致病过程参与了糖尿病的发展。这些过程范围从胰腺β细胞的自身免疫性破坏导致胰岛素缺乏到导致胰岛素作用抵抗的异常（美国糖尿病协会，2011 年）。绝大多数糖尿病病例分为两大类。在 1 型糖尿病（T1D）中，病因是胰岛素分泌绝对缺乏，而在 2 型糖尿病（T2D）中，病因是胰岛素作用抵抗和代偿性胰岛素分泌反应不足的结合。然而，将其分为两大类只是对实际情况的简化，近年来的研究表明，这种疾病比简单地分为两个主要亚型复杂得多。全球患病率估计，2011 年有 2.8 亿糖尿病患者，2030 年将超过 5 亿（http://www.diabetesatlas.org/）。在欧洲，约有 6-8%的人口患有糖尿病，其中约 90%为 T2D，10%为 T1D，因此 T2D 是欧洲和全球增长最快的疾病。这种流行归因于基因与环境的碰撞。虽然我们对 T1D 的基因知识显然比 T2D 要好，因为 HLA 区域的变异对 T1D 的风险有很强的贡献，但对于 T2D 来说，情况正好相反，我们对环境触发因素（肥胖、缺乏运动）的了解远远超过对潜在遗传原因的理解。这种对糖尿病潜在遗传原因的认识不足通常被称为遗传缺失（Manolio 等人，2009 年），对于 T2D 来说，遗传缺失超过 80%，而对于 T1D 来说，遗传缺失不到 25%。在下面的综述中，我们将讨论这种遗传缺失的潜在来源，其中包括我们对糖尿病及其亚组的定义不精确的可能性，从而使遗传原因的识别变得困难。
