Medicine (St Vincent's) - Theses
Permanent URI for this collection
Search Results
1 - 1 of 1
-
ItemImpaired awareness of hypoglycaemia in type 1 diabetes: Challenges to achieving metabolic control and advances in therapeutic options to replace beta cell function( 2021)Impaired awareness of hypoglycaemia (IAH) affects an estimated 20% of people living with type 1 diabetes and increases the risk of severe hypoglycaemia six-fold. The increased susceptibility to hypoglycaemia results from defective physiological defences in response to a fall in blood glucose levels, leading to IAH and a self-perpetuating cycle of recurrent hypoglycaemia. People with IAH and recurrent severe hypoglycaemia have high morbidity and mortality, though this remains to be fully defined. The management of individuals with IAH is complex. A staged clinical approach has been proposed which includes educational, technological and transplantation interventions, aiming to avoid hypoglycaemia. Novel diabetes therapies and technologies, in particular closed-loop insulin delivery systems, also known as the ‘artificial pancreas’, may be a viable alternative therapeutic option to manage these high-risk individuals. This thesis focuses on IAH in adults with type 1 diabetes, aiming to better define mortality risk in people living with IAH and recurrent severe hypoglycaemia, and to better understand strategies to address challenges to achieving optimal glycaemic control. The original research conducted in this thesis also investigates the efficacy of hybrid closed-loop technology and a novel insulin formulation to optimise overall glucose control, and specifically, for individuals with IAH, to minimise hypoglycaemia and potentially ameliorate hypoglycaemia awareness. The first study of this thesis explored mortality rates and cause of death in adults with IAH and recurrent severe hypoglycaemia who were considered for islet transplantation. This study found that hypoglycaemia-related mortality was high in those who did not undergo islet transplantation, which is considered gold standard for this vulnerable group. These findings highlight the importance of seeking alternative technology-based therapeutic options for those who are deemed not suitable for transplantation or for those awaiting transplantation. The findings from this study also justify the importance of the subsequent studies of this thesis. The following two studies of this thesis investigated whether novel technology, specifically advanced hybrid closed-loop algorithms and faster-acting insulin formulations, which are two important components critical to the success of a closed-loop system, can improve glucose control further in a well-controlled general adult population with type 1 diabetes. Overall high glucose time-in-range, high time spent in closed-loop, positive user acceptability with no major safety concerns demonstrated promising progression in the evolution of these technologies, and warrants broader evaluation in a group with IAH. The fourth randomised crossover study investigated glucose control and counterregulatory responses using a hybrid closed-loop system in adults with IAH when undertaking moderate- and high-intensity exercise. This is a particularly challenging area for people with IAH due to the risk of exercise-associated hypoglycaemia. Closed-loop use during exercise was safe and effective with minimal hypoglycaemia, despite an overall attenuated counterregulatory response to exercise, though the cortisol response to high-intensity exercise was preserved. The final study brought together elements of the preceding studies to comprehensively evaluate adults with IAH and recurrent severe hypoglycaemia, comparable to those who meet criteria for islet transplantation. Findings demonstrated that a hybrid closed-loop system improved overall glucose control without an increase in hypoglycaemia, reduced glucose variability, reduced quantitative composite hypoglycaemia scores, and partially improved glucose counterregulatory responses without restoration of hypoglycaemia awareness compared with standard diabetes therapy. This thesis adds a substantial body of knowledge towards the current understanding of IAH and its associated burden, and the strengths and limitations of hybrid closed-loop insulin delivery for the management of adults with IAH. This work contributes added knowledge towards better delineating and improving decision algorithms to allocate closed-loop systems or transplantation to the most appropriate recipients. Until a biological cure is achieved, ongoing advances in both automated insulin delivery systems and beta cell replacement with transplantation will continue to improve biological and psychosocial outcomes for this vulnerable group of people living with type 1 diabetes.