Experimental Models of Impaired Hypoglycaemia-Associated Counter-Regulation

Impaired awareness of hypoglycaemia (IAH) affects around a quarter of patients with diabetes who receive insulin treatment. This condition is characterised by a progressive reduction in symptomatic and behavioural responses to hypoglycaemia, increasing risk of deeper drops in blood glucose, unconsciousness, and collapse. Thus, patients with IAH experience severe hypoglycaemic episodes more frequently, resulting in significant morbidity and mortality. IAH is thought to develop as a consequence of whole-body adaptations to repeated insulin-induced hypoglycaemia (RH), with widespread deficits in the hypoglycaemia counter-regulatory response (CRR). Despite this important insight, the precise pathophysiology by which RH leads to an attenuated CRR is unknown. Studies into the underlying mechanisms of IAH have employed a variety of protocols in humans and experimental species. The use of animal models has many investigational benefits, including the unprecedented increase in the availability of transgenic strains. However, modelling impaired hypoglycaemia-associated counter-regulation remains challenging and appropriate interpretation of findings across species and protocols even more so. Here, we review the experimental modelling of IAH and impaired hypoglycaemia-associated counter-regulation, with a focus on understanding species-specific variation in glucose homeostasis. This review will aid investigators in interpreting outputs from different studies in IAH and aid progress in the field.