Hyperinsulinaemic hypoglycaemia in non-anaesthetized Göttingen minipigs induces a counter-regulatory endocrine response and electrocardiographic changes

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.

The Non-Human Primate in Safety Assessment of a Bifunctional Long-Acting Insulin Analogue

“…In cynomolgus monkeys, the normal serum/ plasma glucose level is about 3-4 mmol/L, 6,8,9,12 as compared to about 3.5-5 mmol/L in Göttingen minipigs, 4-6 mmol/L in Beagle dogs, 8-10 mmol/L in rats and 3.9-5.6 mmol/L in humans. [13][14][15][16][17][18] Therefore, relatively small absolute decrements in blood glucose level will correspond to a high percentage decrease; here, for instance, the fall in blood glucose level by 1.4 mM seen in the female after the first dose corresponded to a 36% decrease. In addition, the NHP was shown to have a higher basal insulin secretion, measured by C-peptide, compared to humans.…”