Insulin-induced hypoglycaemia in healthy and streptozotocin-induced diabetic Göttingen Minipigs

PhD student : Mille Kronborg Lyhne

Hypoglycaemia (low blood sugar) is the most common adverse effect of insulin treatment in people with diabetes. Severe hypoglycaemia has been associated with increased risk of cardiovascular events and deaths, however, no direct mechanistic link between cardiovascular disease and hypoglycaemia has yet been identified. While small animal models, such as rats and mice, have been commonly used to investigate the effects of hypoglycaemia, only few studies have investigated the cardiovascular effects.

The hearts of rats and mice are not very comparable to humans in regard to size and heart rate and large animal models are needed to investigate the cardiovascular effects of hypoglycaemia. The pig, and in particular the Göttingen Minipig, is increasingly used in preclinical research and have some advantageous comparative features, however, no studies have investigated the cardiovascular effects of hypoglycaemia using the Göttingen Minipig.

The aim of this project was to investigate healthy and streptozotocin-induced diabetic Göttingen Minipigs as a translational model of insulin-induced hypoglycaemia. The studies investigated the normal minipig electrocardiogram, electrocardiographic changes and endocrine counter-regulation during hypoglycaemia.

Study 1 of the project investigated the electrocardiographic features of healthy and diabetic minipigs and showed diurnal variation in both morphology and heart rate variability, lead differences in morphology and change in parameters over time, but could only detect minor changes after diabetes induction. 

Study 2 investigated healthy and diabetic minipigs to demonstrate a human-like hormonal counterregulatory response to insulin-induced hypoglycaemia, with increases in plasma glucagon and adrenaline. Hyperinsulinaemic hypoglycaemic clamping also induced QTc-interval prolongation in diabetic minipigs and a general increase in arrhythmic events was seen in both healthy and diabetic minipigs, changes also reported in humans experiencing hypoglycaemia. No changes in heart rate variability were found. 

Study 3 investigated the effects of recurrent hypoglycaemic episodes on the counterregulatory response and heart in healthy and diabetic minipigs during hyperinsulinaemic hypoglycaemic clamping. The study demonstrated a diminished glucagon response in groups preconditioned with three consecutive days of hypoglycaemic clamping, with no effect of diabetes status. There was no significant difference in the adrenaline response between hypoglycaemia preconditioned groups and controls. Analysis of electrocardiographic recordings are pending. 

Detailed methods and results are available in the two papers published during this project.

The Göttingen Minipig model of insulin-induced hypoglycaemia demonstrated translational value in counterregulatory responses and electrocardiographic changes of the heart. The model shows potential for future studies of biology, pharmacological interventions and development of devices and monitors for detection and prevention of hypoglycaemia with perspectives to better clinical management of people living with diabetes.