Determining the role of arcuate nucleus glucokinase in the regulation of glucose homeostasis

确定弓状核葡萄糖激酶在葡萄糖稳态调节中的作用

• 批准号: MR/N020472/1
• 负责人: Risheka Ratnasabapathy
• 金额: $ 36.51万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN020472%2F1
• 关键词: Determining; role; arcuate; nucleus; glucokinase

Diabetes affects 382 million people worldwide including 3.2 million people in the UK alone. Hence most people will know a friend or relative living with this condition. It is the commonest cause of end stage kidney failure and lower limb amputation and diabetics are 10-20 times more likely to go blind than those without diabetes. Management of diabetes costs the National Health Service a staggering 1 million pounds per hour. Sadly no cure has been found and, despite advancements in treatment, diabetes remains a major cause of disability and death. Diabetes is caused by the inability of the body to respond appropriately to high blood glucose (or sugar) levels. Historically, the pancreas, an organ which lies within the abdomen and produces the hormone insulin, was believed to be the main controller of glucose balance. Insulin is a hormone which lowers blood glucose levels. Most treatments to date have been directed at the level of the pancreas. However, there is increasing evidence that certain areas within the brain, particularly an area known as the arcuate nucleus, play a key role. Within the arcuate nucleus there is an increased concentration of glucokinase. Glucokinase is an enzyme which senses and breaks down glucose thereby preventing high glucose levels building up in the bloodstream and therefore preventing the development of diabetes. However, the specific function and mechanism of action of glucokinase within the arcuate nucleus itself is not known. I aim to determine the exact role and function of glucokinase within the arcuate nucleus of rats. Rats have very similar mechanisms of appetite and glucose control to humans and therefore provide excellent models for study. Within my laboratory at Imperial College, I have worked alongside experts in this field to collect pilot data in rat models to determine whether there is any scope in exploring this avenue further. My preliminary work is very promising and shows that increased activity of the glucokinase enzyme within the arcuate nucleus area of the brain improves blood sugar levels and hence should, in theory, protect against the development of diabetes. In understanding this novel pathway within the brain I aim to investigate this area further and establish if there are new undiscovered mechanisms within the brain (rather than pancreas alone) which are involved in blood sugar control and therefore development of diabetes. Once identified, these pathways may provide targets for more optimal treatment of diabetes.

仅在英国，糖尿病就会影响全球3.82亿人。因此，大多数人会认识一个有这种情况的朋友或亲戚。它是终末期肾衰竭的最常见原因，下肢截肢和糖尿病患者比没有糖尿病的糖尿病患者失明的可能性高10-20倍。糖尿病的管理使国家卫生服务局每小时惊人的100万英镑。可悲的是，没有发现任何治愈方法，尽管治疗方面的进步，糖尿病仍然是残疾和死亡的主要原因。糖尿病是由于人体无法对高血糖（或糖）水平做出适当反应而引起的。从历史上看，胰腺是腹部内部并产生激素胰岛素的器官，被认为是葡萄糖平衡的主要控制器。胰岛素是一种降低血糖水平的激素。迄今为止，大多数治疗方法都是针对胰腺水平的。但是，有越来越多的证据表明，大脑内的某些区域，特别是称为弧形核的区域，起着关键作用。在弧形核中，葡萄糖酶浓度增加。葡萄糖酶是一种酶，可感知并分解葡萄糖，从而防止血液中升高的高葡萄糖水平，从而防止糖尿病的发展。然而，尚不清楚峰值核中葡萄糖酶的特定功能和作用机理。我的目标是确定葡萄糖酶在大鼠弧形核中的确切作用和功能。大鼠对人类具有非常相似的食欲和葡萄糖控制机制，因此为研究提供了出色的模型。在帝国学院的实验室内，我与该领域的专家一起工作，以收集Rat Models中的试点数据，以确定进一步探索这一途径是否存在范围。我的初步工作非常有前途，表明大脑弧形核区域内葡萄糖激酶酶的活性增加，可以改善血糖水平，因此，从理论上讲，应该预防糖尿病的发展。在理解大脑内的这一新型途径时，我旨在进一步研究该区域，并确定与血糖控制有关的大脑中是否存在新的未发现机制（而不是胰腺），从而涉及糖尿病。一旦确定，这些途径可能会为糖尿病的最佳治疗提供目标。

项目成果

Ligand-Specific Factors Influencing GLP-1 Receptor Post-Endocytic Trafficking and Degradation in Pancreatic Beta Cells.

• DOI: 10.3390/ijms21218404
• 发表时间: 2020-11-09
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Fang Z;Chen S;Manchanda Y;Bitsi S;Pickford P;David A;Shchepinova MM;Corrêa IR Jr;Hodson DJ;Broichhagen J;Tate EW;Reimann F;Salem V;Rutter GA;Tan T;Bloom SR;Tomas A;Jones B
• 通讯作者: Jones B

Reply: Clinical trial registry alone is not adequate: on the perception of possible endpoint switching and P-hacking.

答复：仅凭临床试验注册是不够的：对可能的终点切换和 P-hacking 的看法。

• DOI: 10.1093/humrep/dex360
• 发表时间: 2018
• 期刊: Human reproduction (Oxford, England)
• 作者: Abbara A