Identifying novel mechanisms behind the development of impaired awareness of hypoglycaemia (IAH)

胰岛素引起的反复低血糖常见于接受胰岛素治疗的1型糖尿病患者和晚期2型糖尿病患者，患者对低血糖(IAH)的认识受损。意识受损削弱了检测急性低血糖发作的能力，因此极大地增加了严重低血糖的风险，这可能导致认知功能障碍2，甚至死亡3。这是由于神经激素反调节反应(CRR)的钝化导致的，这将触发症状意识并恢复血糖水平。意识受损被认为是通过一种称为习惯化的过程发生的，在这种过程中，重复应用同型应激源[复发性低血糖]会导致反应减弱[CRR]4，5。这项研究将通过观察大脑中关键的糖调节区域来阐述导致意识受损的中央机制，以及如何通过一种称为去习惯化的过程来恢复这些区域。这利用了一种新的急性应激源来恢复IAH。先前的研究已经证实，使用高强度运动或冷暴露能够成功地恢复有缺陷的反调节，从而恢复杆状5、6和T1D个体7的IAH。通过使用意识受损的在体啮齿动物模型来概括在人类中看到的情况，生化技术将识别参与IAH发育的新基因和蛋白质，以及这些基因和蛋白质是否对去居住性有反应。其他令人感兴趣的技术包括IDISCO，它使整个器官组织能够被清除，以便对我们感兴趣的蛋白质进行染色。这将使我们能够确定整个大脑如何对反复发生的低血糖做出反应，并确定可能参与IAH习惯性-去习惯性过程的其他新的感兴趣区域。通过识别促进IAH发展的新机制以及那些参与习惯化过程的机制，我们可以更好地了解为什么身体以这种方式适应反复低血糖，以及我们如何预防或恢复这种潜在威胁生命的疾病。如果确定了感兴趣的关键蛋白质并具有靶向性，这项研究可能会产生新的治疗方法。该项目提供跨学科技能培训。参考：1。Graveling A.J&Frier B.M(2010)。低血糖意识受损：一篇综述。糖尿病与新陈代谢。36(3)：S64-S74.2。Graveling等人。(2013年)。急性低血糖损害患有和不患有1型糖尿病的成年人的执行认知功能。糖尿病护理。36(10)：3240-3246.3。McCoy等人。(2012年)。报告严重低血糖的糖尿病患者死亡率增加。糖尿病护理。35(9)：1897-1901.4。Rankin等人。(2009)。习惯化：习惯化的行为特征的更新和修订的描述。神经生物学学习记忆。92(2)：135-138.5。麦克内利等人。(2017年)。高强度运动作为一种去习惯化刺激，可以恢复反复低血糖啮齿动物的反调节反应。糖尿病。66(6)：1696-1702.6。Vickenson等人的研究。(2021)在暴露于反复低血糖的啮齿动物中，寒冷诱导的去适应。糖尿病。7.Farrell等人。(2020)。一项随机对照研究，将高强度运动作为一种去除习惯的刺激，以改善1型糖尿病患者的低血糖意识：一项概念验证研究。糖尿病。63：853-863。

Impaired awareness of hypoglycaemia (IAH) occurs in response to recurrent insulin-induced hypoglycaemia which is frequently observed in individuals with type 1 diabetes and late stage type 2 diabetes who take insulin as a therapy1. Impaired awareness dampens the ability to detect the onset of an acute hypoglycaemic episode and therefore greatly increases the risk of severe hypoglycaemia, which can result in cognitive dysfunction2 and even death3. This occurs due to the blunting of the neurohormonal counter-regulatory response (CRR) which would trigger symptomatic awareness and restore blood glucose levels. Impaired awareness is thought to occur through a process known as habituation, in which repeated application of a homotypic stressor [recurrent hypoglycaemia] leads to a dampening of the response [CRR]4,5. This studentship will address the central mechanisms that result in impaired awareness by looking at key glucoregulatory regions in the brain, and how these can be restored via a process known as dishabituation. This utilises a novel acute stressor to restore IAH. Previous studies have confirmed that using either high intensity exercise or cold exposure were able to successfully restore defective counter-regulation and thus restore IAH in the rodent5,6 and in T1D individuals7. Through the use of in vivo rodent models of impaired awareness to recapitulate that seen in humans, biochemical techniques will identify novel genes and proteins that are involved in IAH development and if these respond to dishabituation. Other techniques of interest include iDISCO which enables whole organ tissue clearing for staining of our protein of interest. This will enable us to identify how the whole brain responds to recurrent hypoglycaemia and identify other novel regions of interest that might be involved in the habituation-dishabituation process of IAH. By identifying novel mechanisms that facilitate IAH development and also those involved in the dishabituation process, we can gain a better understanding behind why the body adapts in this manner to repeated hypoglycaemia and how we can prevent or restore this potentially life-threatening condition. Novel therapies may come out of this research if key proteins of interest are identified and are targetable. Project provides training in Interdisciplinary Skills.References:1. Graveling A.J & Frier B.M (2010). Impaired awareness of hypoglycaemia: a review. Diabetes & Metabolism. 36(3): S64-S74.2. Graveling et al. (2013). Acute hypoglycaemia impaires executive cognitive function in adults with and without Type 1 Diabetes. Diabetes Care. 36(10):3240-3246.3. McCoy et al. (2012). Increased mortality of patients with diabetes reporting severe hypoglycaemia. Diabetes Care. 35(9): 1897-1901.4. Rankin et al. (2009). Habituation revisited: an updated and revised description of the behavioural characteristics of habituation. Neurobiol Learn Mem. 92(2): 135-138.5. McNeilly et al. (2017). High intensity exercise as a dishabituating stimulus restores counter-regulatory responses in recurrently hypoglycaemic rodents. Diabetes. 66(6): 1696-1702.6. Vickneson et al. (2021) Cold-induced dishabituation in rodents exposed to recurrent hypoglycaemia. Diabetalogia. 7. Farrell et al. (2020). A randomised controlled study of high intensity exercise as a dishabituating stimulus to improve hypoglycaemia awareness in people with type 1 diabetes: a proof of concept study. Diabetalogia. 63: 853-863.