Characterizing the evolution of impaired hypoglycemia awareness in people with type 1 diabetes and the impact of automated insulin delivery and exercise on restoring hypoglycemia awareness

University Of Melbourne, Melbourne

Investigators

Abstract

Abstract Impaired hypoglycemia awareness (IAH) affects 25% of adults with type 1 diabetes and is associated with a six-fold higher risk of severe hypoglycemia. Those severely affected have an estimated mortality of 3.4%. IAH is characterized by defects in adrenergic symptoms and the counter-regulatory hormone response to hypoglycemia. Only limited data are available regarding the evolution of IAH. To date, strategies to restore hypoglycemia awareness have focused upon minimizing hypoglycemia exposure. While islet-cell transplantation has met with success, this approach is reserved for only the most severely affected as it is invasive, has strict eligibility criteria, requires long-term immunosuppression and is resource-intensive. So far interventions incorporating education and technologies, including continuous glucose monitoring (CGM) and automated insulin delivery (AID), have had limited success, though studies have been small and of short duration. We hypothesize that IAH evolves over many years, promoted by recurrent hypoglycemia. In the absence of restoration of a glucagon response, IAH reversal may require an extended period of near-absolute hypoglycemia avoidance. We also hypothesize that high intensity interval exercise (HIIT), which elicits a counter-regulatory hormone response, even in those with severe IAH, may have an adjunctive role in the restoration of hypoglycemia awareness. We propose a randomized-controlled trial in a cohort of adults with type 1 diabetes with IAH using manual insulin dosing. All will be provided with hypoglycemia recognition and avoidance psycho-education. Participants (n=500 in total with 50 studied at our site) will be randomized to 2-years of insulin delivery using the most advanced AID system available with and without adjunctive support for an HIIT program, which will be compared with usual care. The primary outcome will be a composite of sympathetic symptoms and the endogenous glucose production (EGP) response during hypoglycemic clamp studies. Other outcomes are (i) counter-regulatory responses during clamp studies; (ii) percent time in CGM low- glucose ranges in real-world conditions; and (iii) person reported outcomes, including hypoglycemia awareness symptom scores. Type 1 diabetes cohorts without IAH and those who have had a successful islet-transplant will be studied at a single time-point to provide positive control data. In addition, we will follow a population-based pediatric cohort of over 1000 children, with 93% using CGM. Changes in CGM low glucose time will be related to changes in Gold and Clarke scores over 4-years, with potential to extend this with separate funding. Data from this program of research will substantially advance knowledge of IAH and guide practical and meaningful interventions.