**Abstract**

Diabetes mellitus can induce substantial damage to the conduction system of the heart, especially the sinoatrial node. This is due to hyperglycemia leading to bradyarrhythmia. DM, via the elevation of HG, generates the production of a number of insulting agents in the myocardium known as reactive oxygen species and reactive carbonyl species, which elicit direct damage to neuro-filament-M and β2-adrenergic receptors in the conducting system as well as a number of cardiac contractile, cation transporting and channel proteins. One cation channel protein is the hyperpolarization-activated cyclic nucleotide-gated potassium channel. It encodes the protein responsible for the hyperpolarizing-activated current or the "funny current" that participates in spontaneous diastolic membrane depolarization in sinoatrial node cells. Gene expression of these proteins and their physiological functions are decreased in the diabetic heart, which affects the generation of electrical impulses or action potentials resulting in increases in RR and PR intervals and QRS complex duration of the electrocardiogram. The heart rate and force of contraction of the myocardium are decreased leading to bradyarrhythmia and sudden cardiac death. This review attempts to explain the cellular mechanism(s) involved in diabetes-induced bradyarrhythmia with emphasis on cation-transporting proteins, especially the hyperpolarization-activated cyclic nucleotide-gated channels pacemaker current channels.

**Keywords:** diabetes mellitus, sinoatrial node (SAN), heart, cardiac conduction system, arrhythmias

## **1. Introduction**

Diabetes mellitus (DM) is a serious global disease that currently affects more than 480 million people, and its number is growing rapidly. DM results from hyperglycemia (HG) and it is responsible for many long-term complications [1]. Cardiovascular

diseases (CVDs) account for more than half of the observed mortality in the diabetic population [2]. Nodal myocytes spontaneously generate APs in the absence of hormonal and neural stimulation [3]. Decreased heart rate (HR) is a common finding in patients with type 1 diabetes mellitus (T1DM) [4] indicating that many of these patients are likely to have impaired pacemaker function [5]. Cardiovascular defects are the major cause of morbidity and mortality in diabetic patients [6]. The cause of cardiac conduction disorders (CCDs) in DM patients is not fully understood. It remains unclear whether autonomic neuropathy or CVDs play a role [7]. This review addresses the effects of DM on the cardiac conduction system (CCS) which in turn can lead to arrhythmias and subsequently, sudden cardiac death (SCD). But first, it is important to understand the normal physiology of the conduction system before considering the mechanism(s) that might underlie the pathophysiology of DM-induced electrical conduction defects in the heart and its treatment.
