Experimental Models of Impaired Hypoglycaemia-Associated Counter-Regulation

• Published in: Trends in endocrinology and metabolism Vol. 31; no. 9; pp. 691 - 703
• Main Authors: Sankar, Adhithya, Khodai, Tansi, McNeilly, Alison D., McCrimmon, Rory J., Luckman, Simon M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01-09-2020
• Subjects: counter-regulatory response; experimental model; hypoglycaemia; impaired awareness of hypoglycaemia; impaired awareness of hypoglycaemia; counter-regulatory response; experimental model; hypoglycaemia
• ISSN: 1043-2760; 1879-3061
• DOI: 10.1016/j.tem.2020.05.008

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.
Impaired awareness of hypoglycaemia (IAH) is a common and poorly understood complication of insulin-treated diabetes and evolves following repeated episodes of hypoglycaemia.An improved mechanistic understanding of IAH is required and necessitates a robust disease model with which to interrogate changes within the glucose-regulatory network.A large variety of experimental models have been outlined, leading to a lack of consensus among investigators in this field. Appreciating the influence of experimental parameters and physiological differences on findings can aid progress in the field.