Role of PFK2/FBPase-2 in regulating hepatic glucokinase

2型糖尿病是一种非常常见的代谢性疾病，其原因是复杂的遗传和环境因素。它表现为血糖（葡萄糖）水平的增加，如果不适当地纠正，由于血管和神经的长期损伤以及随后的器官衰竭而导致慢性发病率和死亡率。目前2型糖尿病的治疗不能充分控制血糖水平，迫切需要更好的口服疗法。针对葡萄糖激酶蛋白的药物目前被认为是治疗2型糖尿病的非常有希望的候选药物。据报道，葡萄糖激酶基因的几种突变在人类中引起了一种罕见的糖尿病，称为年轻人的成熟型糖尿病。虽然葡萄糖激酶基因的缺陷本身并不是2型糖尿病的常见原因，但有迹象表明，打开或关闭葡萄糖激酶基因的机制中的缺陷可能非常重要。我们现在知道，有一个复杂的网络？上？然后呢？关闭？由不同基因编码的机制解释了葡萄糖激酶功能的微调。我们实验室最近的工作已经确定了一种新的机制，涉及一种名为PFK 2/FDP 2的蛋白质，该蛋白质对维持葡萄糖激酶功能至关重要。本研究旨在详细探讨PFK 2/FDP 2调控肝脏葡萄糖激酶活性的机制基础。这在两个方面很重要：首先，因为这种或相关机制在2型糖尿病中可能存在缺陷;其次，了解激活葡萄糖激酶的生理机制对于更全面地评估靶向葡萄糖激酶的药物的长期益处至关重要。该项目的成果将通过以下方式传播：（i）研究出版物;（ii）在地方、国家和国际会议上的演讲;（iii）为英国糖尿病协会和其他组织的专业和非专业成员举办的公开讲座和非正式会谈以及讨论小组。

Type-2 diabetes is a very common metabolic disease that is due to complex genetic and environmental factors. It manifests as an increase in blood sugar (glucose) level which if not adequately corrected leads to chronic morbidity and mortality as a result of long-term damage to blood vessels and nerves with consequent organ failure. Current therapy for Type-2 diabetes does not achieve adequate control of blood sugar levels and there is an urgent need for better oral therapeutics. Drugs that target a protein called glucokinase are currently considered to be very promising candidates for treatment for Type-2 diabetes.Several mutations in the glucokinase gene have been reported in man which cause a somewhat rare form of Diabetes described as Maturity Onset Diabetes of the Young. Whilst defects in the glucokinase gene are not in themselves a common cause of Type 2 diabetes, nonetheless there are indications that defects in the mechanism(s) that switch ON or OFF the glucokinase gene may be very important. We now know that there are complex networks of ?on? and ?off? mechanisms encoded by different genes that account for the fine tuning of glucokinase function. Recent work from our laboratory has identified a novel mechanism involving a protein called PFK2/FDP2 that is critical for maintaining glucokinase functional. This proposal is to explore in detail the mechanistic basis by which PFK2/FDP2 regulates glucokinase activity in the liver. This is important on two accounts: first, because this or related mechanisms may be defective in Type-2 diabetes; second, understanding the physiological mechanisms that activate glucokinase is essential for a more complete evaluation of the long-term benefits of drugs targeting glucokinase. The results of the project will be disseminated through: (i) Research Publications; (ii) Presentations at local, national and international meetings; (iii) Public Lectures and Informal Talks and discussion groups to both Professional and Lay members of Diabetes UK and other organisations.