**12. Impaired calcium and potassium homeostasis and sudden cardiac death**

Calcium (Ca2+) is a major trigger, a modulator, a second messenger and a regulator of cardiac contractility [24, 68, 69]. It is well known that most of the Ca2+ that activates contraction is released from sarcoplasmic reticulum (SR) through ryanodine receptors (RyRs). RyRs are themselves activated by Ca2+ which enters the myocyte via voltage-dependent L- type Ca2+ channels and this mechanism is known as Ca2+-induced Ca2+ release (CICR) [68]. The cytosolic Ca2+ in turn interacts with cardiac contractile proteins. By binding to troponin C, the Ca2+ triggers the sliding of thin and thick filaments, which results in cardiac contraction. Ca2+ then returns to diastolic levels mainly by the uptake of Ca2+ into the SR via the SR Ca2+ pump (SERCA2a) and extrusion of Ca2+ from the cell via the sarcolemmal Na+ -Ca2+ exchanger and the sarcolemma Ca2+-ATPase pump [24]. DM leads to mitochondrial dysfunction which contributes to the development of DC by altering ATP generation and Ca2+ mobilization [69]. A previous study has shown that diabetes-induced HG plays an integral role in altering the expression and function of RyRs, Na<sup>+</sup> -Ca2+ exchanger and SERCA. Failure of these three major calcium transporting proteins to function efficiently in cardiac muscles is the pivotal factor which is responsible the impairment of myocardial systolic and diastolic functions [30]. In such situations, Ca2+ homeostasis is altered during DC thereby affecting the ability of SR to take up Ca2+ and the Na+ -Ca2+ exchanger, and the sarcolemma Ca2+ ATPase to move Ca2+ out of the cell leading to elevated diastolic [Ca2+]i. Second, in diabetes, channel proteins within RyRs undergo carbonylation leading to asynchronous release of calcium into the cytoplasm from the SR [57]; (see **Figure 4**).

Like cellular calcium, potassium homeostasis is of crucial importance for normal cellular function and it is regulated by ion-exchange pumps, co–transporters and channels. Normal plasma potassium values range between 3.8 to5.1 mmol/l [70]. The deviations to both extremes (hypo- and hyperkalaemia) are associated with increased risk of arrhythmias and SCD especially in diabetes-induced chronic kidney failure. Moreover, diabetic patients are at high risks when the failing kidneys are unable to remove potassium from the plasma and as such it builds up in the body leading to hyperkalaemia. Potassium levels below 3.0 mmol/l cause significant Q-T interval prolongation with subsequent risk of torsade des pointes, ventricular fibrillation and SCD. Potassium levels above 6.0 mmol/l cause peaked T waves, wider QRS komplexes and may result in bradycardia, asystole and SCD [70]. Tight regulation of serum potassium levels is necessary for many physiologic processes, including normal cardiac conduction and function [71].
