Cellular Mechanisms and Physiological Roles of GLUT12 Mediated Glucose Transport in Glucose Homeostasis

近100万澳大利亚人患有糖尿病，尽管只有50%的人知道自己患有这种疾病。2型糖尿病约占糖尿病的90%，通常发生在40岁以后。作为导致死亡、成人失明、下肢截肢、肾衰竭、中风和心脏病发作的主要原因，糖尿病具有巨大的经济和社会后果，已被指定为澳大利亚国家卫生优先事项。2型糖尿病的一个临床特征是高血糖。这是因为胰岛素不能有效地刺激葡萄糖从血液转移到肌肉和脂肪中。造成这种情况的原因尚不完全清楚。胰岛素的作用通常是将葡萄糖转运蛋白（GLUT）转移到肌肉和脂肪细胞的表面。在肌肉和脂肪中被广泛研究的一种GLUT是GLUT4。GLUT4在胰岛素的作用下移动到细胞表面，这种反应是已知发生在2型糖尿病中的缺陷之一。然后葡萄糖在血液中积累，导致糖尿病的许多并发症。我们发现了一种新的葡萄糖转运蛋白，GLUT12，它也存在于肌肉和脂肪中。我们已经证明GLUT12和GLUT4一样对胰岛素有反应。因此，GLUT12可能是GLUT4的关键备份。我们还发现GLUT12对葡萄糖本身有反应，这表明它在控制血糖水平方面具有独特的作用。我们将探讨GLUT12如何在肌肉和脂肪细胞中起作用，以确定GLUT12是否可以作为GLUT4的备份。我们还将研究正常动物和具有2型糖尿病特征的动物组织中的GLUT12。为了确定GLUT12在维持正常血糖水平中的作用，我们将生产具有不活跃GLUT12基因的小鼠。我们的研究可以确定增加GLUT12活性的新方法。最终的目标是找到一种药物化合物，可以改善葡萄糖向肌肉的转运，降低高血糖水平，从而减少2型糖尿病的并发症。

Diabetes affects almost one million Australians, although only 50% are aware they have the disease. Type 2 diabetes accounts for about 90% of diabetes and usually occurs after the age of 40. As a leading cause of death, adult blindness, lower limb amputation, kidney failure, stroke and heart attack, diabetes has huge economic and social consequences and has been designated an Australian National Health priority. A clinical feature of Type 2 diabetes is high blood glucose levels. This occurs because insulin does not effectively stimulate the transfer of glucose from the blood into muscle and fat. The reasons for this are not fully understood. Insulin normally works to move glucose transporter (GLUT) proteins to the surface of muscle and fat cells. One GLUT that has been studied extensively in muscle and fat is GLUT4. GLUT4 moves to the cell surface in response to insulin and this response is one of the defects that is known to occur in Type 2 diabetes. Glucose then accumulates in the blood, leading to many of the complications of diabetes. We have discovered a novel glucose transporter, GLUT12, that is also present in muscle and fat. We have shown that GLUT12, like GLUT4, responds to insulin. GLUT12 could therefore be a critical backup for GLUT4. We have also found that GLUT12 responds to glucose itself, suggesting a unique role in controlling blood glucose levels. We will explore how GLUT12 acts in muscle and fat cells to find whether GLUT12 can act as a backup for GLUT4. We will also study GLUT12 in tissue from normal animals and in animals with features of Type 2 diabetes. To determine the role of GLUT12 in maintaining normal blood glucose levels, we will produce mice with an inactive GLUT12 gene. Our research could identify novel ways of increasing GLUT12 activity. The eventual goal will be to find a pharmaceutical compound that can improve glucose transport into muscle, reduce high blood glucose levels and thus the complications of Type 2 diabetes.