Regulation of glucose homeostasis and insulin signalling by Grb10 and Grb14.

胰岛素荷尔蒙是血糖水平的关键调节剂。胰岛素作用缺陷，也称为胰岛素抵抗，是2型糖尿病发展的基础，2型糖尿病是全球主要的健康问题。了解胰岛素的作用是如何调节的，可能会导致这种疾病的新疗法。胰岛素通过与细胞表面的受体结合来调节其作用，该受体将信号传递到细胞内部。根据细胞类型的不同，这些信号可以指示细胞从血液中摄取葡萄糖(肌肉和脂肪)或减少葡萄糖的产生(肝脏)。我们已经确定了细胞中一种新的胰岛素信号调节因子，一种名为Grb14的蛋白质。这是通过产生Grb14基因被移除的小鼠来实现的，这样动物就不再产生Grb14。这些动物对胰岛素的反应更好，这表明Grb14通常会抑制胰岛素的作用。然而，另一种密切相关的蛋白质Grb10很可能与Grb14一起发挥调节胰岛素信号的功能。因此，我们将使用Grb10和Grb14基因被单独和联合移除的小鼠，以确定这两种蛋白质在调节血糖水平和细胞内胰岛素信号方面的作用。我们还将使用从小鼠身上分离的细胞来分析Grb10和Grb14对胰岛素信号转导的潜在分子事件。这些研究的意义在于，明确Grb10和Grb14的功能作用和作用模式可能导致旨在阻断其功能的新的治疗方法。这种方法可以用来克服与2型糖尿病相关的胰岛素抵抗。

The hormone insulin is a critical regulator of blood glucose levels. Defective insulin action, also known as insulin resistance, underlies the development of Type 2 Diabetes, which is major health problem worldwide. Understanding how insulin action is regulated may lead to new treatments for this disease. Insulin mediates its effects by binding to a receptor on the cell surface that transmits signals to the interior of the cell. Depending on the cell type, these signals can instruct the cells to take up glucose from the bloodstream (muscle and fat) or decrease glucose production (liver). We have identified a new regulator of insulin signalling in cells, a protein termed Grb14. This was accomplished by generating mice in which the Grb14 gene was removed, so that the animals no longer produced Grb14. These animals responded better to insulin, indicating that Grb14 normally inhibits insulin action. However, it is likely that another closely related protein, Grb10, functions alongside Grb14 to regulate insulin signalling. Therefore, we will use mice in which the Grb10 and Grb14 genes have been removed, singly and in combination, to define the roles of these two proteins in regulating blood glucose levels and insulin signals inside the cell. We will also use cells isolated from the mice to analyse the molecular events underlying the effects of Grb10 and Grb14 on insulin signalling. The significance of these studies is that defining the functional role and mode of action of Grb10 and Grb14 may lead to novel therapeutic approaches aimed at blocking their function. Such approaches could be used to overcome the insulin resistance associated with Type 2 Diabetes.