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

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.

Suspected congenital hyperinsulinism in a Shiba Inu dog.

A 3-month-old male intact Shiba Inu dog was evaluated for a seizure disorder initially deemed idiopathic in origin. Seizure frequency remained unchanged despite therapeutic serum phenobarbital concentration and use of levetiracetam. The dog was documented to be markedly hypoglycemic during a seizure episode on reevaluation at 6 months of age. Serum insulin concentrations during hypoglycemia were 41 U/µL (reference range, 10-29 U/µL). The dog was transitioned to 4 times per day feeding, diazoxide was started at 3.5 mg/kg PO q8h, and antiepileptic drugs were discontinued. No clinically relevant abnormalities were identified on bicavitary arterial and venous phase contrast computed tomographic imaging. The dog remained seizure-free and clinically normal at 3 years of age while receiving 5.5 mg/kg diazoxide PO q12h and twice daily feeding. Seizures later occurred approximately twice per year and after exertion, with or without vomiting of a diazoxide dose. Blood glucose curves and interstitial glucose monitoring were used to titrate diazoxide dose and dosing interval. Congenital hyperinsulinism is well recognized in people but has not been reported in veterinary medicine.