Experimentally Induced Hypoglycemia-associated Autonomic Failure in Humans: Determinants, Designs, and Drawbacks

Abstract

Introduction Iatrogenic hypoglycemia remains one of the leading hindrances of optimal glycemic management in insulin-treated diabetes. Recurring hypoglycemia leads to a condition of hypoglycemia-associated autonomic failure (HAAF). HAAF refers to a combination of (i) impaired hormonal counter regulatory responses and (ii) hypoglycemia unawareness to subsequent hypoglycemia, substantially increasing the risk of severe hypoglycemia. Several studies since the 1990ies have experimentally induced HAAF yielding variable results. The aim of this review is to assess the varying designs, clinical outcomes, potential assets and drawbacks related to these studies. Method A systemic literature search was conducted on PubMed and Embase in the winter 2021 to include all human studies which attempting to experimentally induce HAAF. In different combinations, the search terms used were “hypoglycemia-associated autonomic failure", “HAAF”, “hypoglycemia” “recurring”, “recurrent”, “repeated”, “consecutive”, and “unawareness” yielding 1,565 publications. Inclusion criteria were studies who had aimed at experimentally inducing HAAF and measuring outcomes of hormonal counter regulation and awareness of hypoglycemia. Results The literature search yielded 27 eligible publications of which 20 were successful in inducing HAAF with statistical significantly impairing both hormonal counter regulation and impairing awareness of hypoglycemia to subsequent hypoglycemia. Several factors were of significance as regards inducing HAAF; foremost, the duration of antecedent hypoglycemia should be at least 90 minutes and blood glucose should be maintained below 3.4 mmol/L. Other important factors to consider are the type of participants, insulin dosage, and the risk of unintended hypoglycemia prior to the study. Conclusion Here we have outlined the most important factors to take into consideration when designing a study aimed at inducing HAAF including to take into consideration other disease states susceptible to hypoglycemia thus hopefully clarifying the field and allowing qualified studies in the future.

Role of the Adrenal Medulla in Hypoglycaemia-Associated Autonomic Failure—A Diabetic Perspective

“…The importance of this is highlighted in patients with insulinomas which cause hyperinsulinemia since surgical removal of insulinomas has been shown to restore some parameters of the counterregulatory response to hypoglycaemia [38]. Yet, these patients do not show restoration of normal insulin sensitivity and even present with hypoglycaemic unawareness, a feature of HAAF [19,38,39].…”

“…In diabetic rats, the glucose production and plasma adrenaline response to hypoglycaemia were lower than the normal rats and recurrent hyperinsulinemia restored these responses to hypoglycaemia [84]. Regardless of the mode of glucose deprivation used, great difficulty has been seen in mimicking HAAF in not only healthy, but also type 1 diabetic patients [19]. Given their unique advantages and disadvantages, 2DG can be a great tool in investigating the mechanisms of glucose counterregulatory and feeding responses without the interference of insulin signalling, while insulin-induced hypoglycaemia can be used in elucidating the clinically relevant condition.…”

“…Progress in the field is further hindered by the sparsity of studies of the HAAF phenomenon in humans. A recent review has assessed experimentally induced HAAF in humans and outlined the important factors to consider when designing HAAF experiments, and thus may facilitate future studies in humans [19]. Rodent models, as well as clinical studies, of insulinomas are also encouraged as these would provide valuable insight into the complex mechanisms involved in HAAF.…”

“…Interestingly, it has been shown that type 2 diabetics in the early phase of the disease show exaggerated sympathoadrenal responses and symptomatic responses to hypoglycaemic episodes, likely due to them not yet being in a state of pancreatic insulin insufficiency [18]. Spontaneous hypoglycaemic events as a result of insulinomas are also known to disrupt counterregulatory responses and result in HAAF [19]. Currently, avoidance of hypoglycaemic episodes by relaxing intensive insulin treatment for several weeks is one of the approaches to restore sympathoadrenal responses, hypoglycaemia awareness or both [20,21].…”