Genetic and functional studies of novel type 2 diabetes susceptibility genes

糖尿病是一种复杂的代谢性疾病，既有遗传原因，也有环境原因，其中身体？维持正常血糖水平的能力受到损害。近年来，糖尿病已发展成为流行病比例的全球健康问题，消耗了许多西方国家高达10%的卫生保健预算。血糖浓度的增加对健康有非常严重的影响，并可能导致失明、心脏病、肾功能障碍和神经损伤。糖尿病有两种主要的临床亚型：1型糖尿病的特征在于调节血糖水平的胰岛素分泌胰腺细胞的破坏; 2型糖尿病（T2 D）的特征在于胰岛素抵抗和胰岛素分泌功能障碍。在这两种亚型中，T2 D是糖尿病的主要形式，占糖尿病总患病率的90%。我们的研究集中在识别的基因，使个人发展T2 D和阐明的分子机制，这些T2 D的产品？易感基因？影响一个人？T2 D的风险。我们最近完成了首次对所有46条人类染色体进行T2 D易感基因的遗传扫描（这项研究的结果将于2007年晚些时候发表在顶级期刊《自然》上）。我们的研究结果证实了先前已知的10号染色体上的易感基因（称为TCF 7 L2），并确定了新的T2 D易感基因，包括锌转运蛋白基因称为ZnT-8。锌是非常重要的调节胰腺分泌的激素胰岛素的作用，以控制血糖水平。拟议的项目旨在通过以下方式跟进我们的遗传扫描：a）对欧洲人群中的这些新遗传位点进行详尽的遗传分析，以及B）阐明关键基因TCF 7 L2和ZnT-8导致T2 D风险的分子机制。

Diabetes is a complex metabolic disease, with both genetic and environmental causes, in which the body?s ability to maintain normal blood glucose levels is compromised. In recent years, diabetes has developed into a global health problem of epidemic proportions, consuming as much as 10 % of the health care budgets of many westernised countries. Increases in blood glucose concentrations have very serious health implications, and can lead to blindness, heart disease, kidney malfunction and nerve damage. There are two main clinical subtypes of diabetes: type 1 diabetes is characterised by the destruction of the insulin-secreting pancreatic cells that regulate blood glucose levels; and type 2 diabetes (T2D) is characterised by insulin resistance and dysfunctional insulin secretion. Of the two subtypes, T2D is by far the predominant form of diabetes, accounting for up to 90% of the total diabetes prevalence. Our research is focussed on the identification of the genes that predispose an individual to develop T2D and on elucidating the molecular mechanisms by which the products of these T2D ?susceptibility genes? influence an individual?s risk of T2D. We have recently completed the first ever genetic scan of all 46 human chromosomes for T2D susceptibility genes (the results of this research will be published in a top journal, Nature, later in 2007). Our results confirmed a previously known susceptibility gene on chromosome 10 (called TCF7L2) and identified novel T2D susceptibility genes, including a zinc transporter gene called ZnT-8. Zinc is very important for regulating the pancreatic secretion of the hormone insulin that acts to control blood glucose levels. The proposed project aims to follow up on our genetic scan by: a) carrying out an exhaustive genetic analysis of these novel genetic loci in the European population and b) elucidating the molecular mechanisms by which the key genes, TCF7L2 and ZnT-8, contribute to T2D risk.