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

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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.