Abstract
The potentially fatal cardiovascular effects of hypoglycaemia are not well understood and large animal models of the counter-regulatory responses and cardiovascular consequences of insulin-induced hypoglycaemia are needed to understand the mechanisms in humans. The aim of this study was to develop a human-like minipig model of hypoglycaemia including healthy and diabetic pigs to investigate endocrine, electrocardiographic and platelet effects. Hypoglycaemia was induced using a hyperinsulinaemic, hypoglycaemic clamp and an insulin bolus protocol. Plasma glucose, glucagon, C-peptide, insulin, epinephrine and platelet aggregation responses were measured before, during and after hypoglycaemia. Continuous electrocardiographic recordings were obtained. Hypoglycaemia at a plasma glucose concentration of 0.8–1.0 mM in the clamp induced 25-fold increase in epinephrine and sixfold and threefold increase in glucagon for healthy and diabetic pigs, respectively. The hypoglycaemic clamp induced QTc-interval prolongation and increase in cardiac arrhythmias. In the bolus approach, the non-diabetic group reached plasma glucose target of 1.5 mM and QTc-interval was prolonged after insulin injection, but before glucose nadir. The diabetic group did not reach hypoglycaemic target, but still demonstrated QTc-interval prolongation. These results demonstrate effects of hyperinsulinaemic hypoglycaemia closely resembling human physiology, indicating the minipig as a translational animal model of counter-regulatory endocrine and myocardial effects of hypoglycaemia.
Highlights
Hypoglycaemia is a common adverse effect of insulin treatment in type 1 and type 2 diabetes with serious clinical implications for the p atient[1]
Severe hypoglycaemia induces fatal arrhythmias seemingly mediated by the para- and sympathetic nervous s ystem[14, 15], but the effects of hypoglycaemia has not been well investigated in a large animal model with more human-like anatomy and physiology
In the CLAMP, total insulin exposure did not differ between groups (CON 891 pM (721–1319), DIA 1630 pM (1235–2110)), temporal differences were seen between groups
Summary
Hypoglycaemia is a common adverse effect of insulin treatment in type 1 and type 2 diabetes with serious clinical implications for the p atient[1]. The majority of data linking diabetes to cardiovascular risk have been generated in type 2 diabetes patients, potentially due to large cardiovascular outcome trials in this populations, type 1 diabetes patients have an increased cardiovascular risk compared to the non-diabetic population, including higher risk of cardiovascular death[6]. The mechanisms underlying this association remains poorly understood, but is thought to include an acute proarrhythmic effect of hypoglycaemia and more long-lasting effects promoting inflammation, coagulation and atherosclerosis[7]. The aim of this study was to develop a human-like minipig model of hypoglycaemia in non-anaesthetized healthy and streptozotocin-induced diabetic Göttingen minipigs using two different protocols of insulin-induced hypoglycaemia, hypothesizing that hypoglycaemia induces a human-like counter-regulatory hormonal response, cardiac arrhythmias, electrocardiographic T-wave, QT interval and ST-segment changes, heart rate variability and increased platelet aggregation response, as has previously been shown in human clinical s tudies[9, 20,21,22]
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