Roles of GWA genes in controlling pancreatic beta cell function and mass.

糖尿病影响着超过2000万欧洲人和全世界3亿人。该病的并发症，包括失明、肾衰竭、心血管疾病和癌症，大大降低了患者的生活质量，并消耗了大多数西方国家近10%的医疗费用。最常见的形式是2型糖尿病（T2D），有遗传和环境原因，在超重人群中尤为普遍。胰岛素是主要的“合成代谢”激素，负责在饭后恢复血糖水平，而胰岛素的缺乏——以及在t2dm中未能适当发挥作用——是这种疾病症状的基础。T2D的治疗方法过去依赖于增强胰岛素的作用，最近则依赖于刺激胰岛素分泌。然而，没有一种现有的治疗方法可以逆转功能性β细胞的逐渐丧失，从而使疾病症状逐渐恶化。因此，迫切需要新的策略来恢复足够数量的正常功能的β细胞。2000年完成的人类基因组计划使研究成为可能，随后对人类遗传变异（单核苷酸多态性）的绘制使得在过去四年中对T2D进行“全基因组关联研究”（GWAS）成为可能。他们已经确定了几种基因变异，其遗传与糖尿病风险增加有关。这些基因中的大多数影响胰岛素的产生，它们的识别不仅提高了预测的能力，而且令人兴奋的是，它们还为药物治疗提供了潜在的新分子靶点。我们提出的研究将涉及两个互补的领域，旨在更全面地了解T2D基因子集如何影响疾病风险。我们的第一个目标是详细研究在人类基因组中两个新的GWAS“位点”上鉴定的五个基因在胰腺β细胞中的作用。我们将使用一种新的小鼠模型，允许在胰腺β细胞中选择性地删除感兴趣的基因，以及经典的生化和小鼠遗传方法来检查相关基因产物的作用。其次，我们试图研究一种被称为LKB1的肿瘤抑制因子，它控制着β细胞的生长，可能被两个相对较好的研究过的T2D的GWA基因调节。男性LKB1的失活会导致一种罕见的癌症，称为Peutz-Jeghers综合征。值得注意的是，当β细胞中的LKB1基因被选择性删除时，突变小鼠的β细胞质量大幅增加，胰岛素产量增加，葡萄糖稳态改善。重要的是，胰岛素释放只发生在血糖水平高的时候，避免了血糖“过低”的危险（低血糖）。在这里，我们将剖析LKB1下游的信号通路，并探索GWA基因TCF7L2和SLC30A8的潜在作用。

Diabetes mellitus affects more than 20 m Europeans and 300 m individuals worldwide. The complications of the disease, including blindness, kidney failure, cardiovascular disease and cancer, drastically reduce the quality of life of sufferers, and consume almost 10 % of health care costs in most westernised nations. The most common form, Type 2 diabetes (T2D), has both genetic and environmental causes, and is particularly prevalent in the overweight. Insulin is the chief "anabolic" hormone responsible for restoring blood sugar levels after a meal and its absence - as well as a failure to act appropriately in T2D - underlies the symptoms of this disease. Therapeutic approaches towards T2D have relied in the past on enhancing the actions of insulin, and more recently on stimulating insulin secretion. However, none of the existing therapies reverse the progressive loss of functional beta cells and hence the gradual worsening of disease symptoms. New strategies aimed at restoring an adequate number of normally functioning beta-cells are thus urgently sought. Studies made possible by the human genome project, completed in 2000, and the subsequent mapping of genetic variants (single nucleotide polymorphisms) in man have permitted in the last four years "Genome wide association studies" (GWAS) for T2D. These have identified several genetic variants whose inheritance is associated with an increased risk of diabetes. The identification of these genes, most of which influence insulin production, provides both improved powers of prediction and, just as excitingly, potential new molecular targets for drug treatment. Our proposed studies will involve two complementary areas aimed at obtaining a fuller understanding of how a subset of T2D genes affect disease risk. Our first aim is to examine in detail the role in the pancreatic beta cell of five genes identified at two novel GWAS "loci" in the human genome. We shall use both a new mouse model engineered to allow genes of interest to be selectively deleted in the pancreatic beta cell, and classical biochemical and mouse genetic approaches to examine the roles of the implicated gene products. Secondly, we seek to examine the means through which a tumour suppressor termed LKB1, which controls beta cell growth, may be modulated by two relatively well-studied GWA genes for T2D. Inactivation of LKB1 in man leads to a rare form of cancer termed Peutz-Jeghers syndrome. Remarkably, when the LKB1 gene is deleted selectively in the beta cell, mutant mice experience a substantial expansion in beta cell mass and enjoy increased insulin production and improved glucose homeostasis. Importantly, insulin release only occurs when blood glucose levels are high, avoiding the risk of a dangerous "undershoot" in glucose (hypoglycaemia). Here, we shall dissect the signalling pathways lying downstream of LKB1, and explore the potential roles of the GWA genes TCF7L2 and SLC30A8.