Hypoglycaemia combined with mild hypokalaemia reduces the heart rate and causes abnormal pacemaker activity in a computational model of a human sinoatrial cell.

Alan Bernjak,Ahmed Iqbal,Simon R Heller,Richard H Clayton

doi:10.1098/rsif.2021.0612

Abstract

Low blood glucose, hypoglycaemia, has been implicated as a possible contributing factor to sudden cardiac death (SCD) in people with diabetes but it is challenging to investigate in clinical studies. We hypothesized the effects of hypoglycaemia on the sinoatrial node (SAN) in the heart to be a candidate mechanism and adapted a computational model of the human SAN action potential developed by Fabbri et al., to investigate the effects of hypoglycaemia on the pacemaker rate. Using Latin hypercube sampling, we combined the effects of low glucose (LG) on the human ether-a-go-go-related gene channel with reduced blood potassium, hypokalaemia, and added sympathetic and parasympathetic stimulus. We showed that hypoglycaemia on its own causes a small decrease in heart rate but there was also a marked decrease in heart rate when combined with hypokalaemia. The effect of the sympathetic stimulus was diminished, causing a smaller increase in heart rate, with LG and hypokalaemia compared to normoglycaemia. By contrast, the effect of the parasympathetic stimulus was enhanced, causing a greater decrease in heart rate. We therefore demonstrate a potential mechanistic explanation for hypoglycaemia-induced bradycardia and show that sinus arrest is a plausible mechanism for SCD in people with diabetes.

Highlights

Blood glucose levels are elevated in both type 1 and type 2 diabetes
Insulin is used to therapeutically lower high glucose in individuals with type 1 and long-standing type 2 diabetes; this commonly results in iatrogenic hypoglycaemia, one major barrier in achieving and maintaining normal glucose control in diabetes [1]
Hypoglycaemia combined with sympathetic activity enhances the effect of sympathetic activity by further increasing the heart rate compared to NG

Summary

Introduction

Blood glucose levels are elevated in both type 1 and type 2 diabetes. Insulin is used to therapeutically lower high glucose in individuals with type 1 and long-standing type 2 diabetes; this commonly results in iatrogenic hypoglycaemia, one major barrier in achieving and maintaining normal glucose control in diabetes [1]. Insulin causes glucose to fall, but in individuals with diabetes, insulin levels are reduced due to auto-immune damage to the pancreatic β cells (type 1 diabetes) or a combination of impaired insulin secretion and action (type 2 diabetes). In both types of diabetes, exogenous insulin is used to lower glucose therapeutically but due to the limitations of current insulin delivery, insulin replacement is unphysiological. In one of the trials, intensive glucose therapy resulted in a sixfold increase in severe hypoglycaemia [2]. Over one-third of deaths were attributed to sudden cardiac death (SCD), raising the possible link between hypoglycaemia and cardiac arrhythmias

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