Selenium Controlled Diabetic Cardiomyopathy Complications

Secondary complications of diabetes develop gradually in longer terms. The longer you have diabetes the higher the risk and severity of the complications. Sooner or later, diabetes induced complications may result in the paucity of the physiological functions of the body which in turn give rise to life-threatening situations.Although we need small quantities still selenium plays a key role in the body metabolism. Indeed, having an antioxidant characteristic, it protects many cell types from damage especially during chronic diseases.


INTRODUCTION
Diabetes mellitus is a metabolic disorder caused either by the deficiency in the production of insulin (type 1), or by the ineffectiveness of it (type 2). Presence of the different entities of diabetes was first stated by Sir Harold Percival Himsworth in 1936. In any of these entities uncontrolled blood glucose is a common end point, which in turn affects the vital functions of the body's systems.
Secondary complications of diabetes develop gradually in longer terms. The longer you have diabetes the higher the risk and severity of the complications. Sooner or later, diabetes induced complications may result in the paucity of the physiological functions of the body which in turn give rise to life-threatening situations. Among many other complications cardiomyopathy, neuropathy, nephropathy and retinopathy are the most principal ones that increase patient's morbidity and mortality.
The biological systems are continuously exposed to oxidants which are generated either by deliberately or as byproducts. These oxidants are able to initiate many enzyme-and genedependent reactions in both physiological and pathophysiological conditions. Having paramagnetic free radicals these oxidants can be classified as reactive oxygen species (ROS) and reactive nitrogen species (RNS). Indeed, deficiencies or overproduction of ROS and/or RNS can result in pathological state through impaired homeostasis.
Selenium -trace element from soilnaturally appears in water and some foods. Although we need small quantities still it plays a key role in the body metabolism. Indeed, having an antioxidant characteristic, it protects many cell types from damage especially during chronic diseases.
This review covers current knowledge of the role of selenium in the diabetic cardiomyopathy. We describe, in depth, selenium as an antioxidant either protects or restores the diabetes induced electrical remodeling of the hearth tissue.

Diabetic Cardiomyopathy
Diabetic cardiomyopathy is the latest complications of diabetes -is one of the most fundamental causes of diabetes induced deaths and poor quality of life 1 . Type independently; it is characterized by the dysfunctions in the early-onset diastolic and the late-onset systolic periods. 2 In experimental models studies of diabetes, this type of cardiomyopathy is characterized by the mechanical, biochemical and morphological abnormalities in the heart tissue. 1 Although the disease at first characterized by the left ventricular expansion and restrained of systolic function but later the diastolic left ventricular dysfunction was also identified. 3,4 In longer terms of diabetes, significant changes in the heart tissue such as impaired lipid metabolism and increase in oxidative stress causes an electrical remodeling. As a result of these changes have been observed that in AP and contraction period are dysfunctions as a consequence of ionic current impairments. 1,5,6 These implies the relationship between the action potential and muscle contraction parameters which known as excitation contraction coupling.It is well known fact that the excitation and contraction processes are strictly connected especially for the heart tissue i.e alteration in one concomitantly affects the other.

Abnormalities in Contraction Parameters
Diabetic cardiomyopathy includes alterations in intracellular free Ca 2+ ([Ca 2+ ] i ) homeostasis which in turn leads to contractile malfunctions. 7 Researches dealing with the left ventricular papillary muscles isolated from streptozotocine (STZ)-induced diabetic rats and rabbits have shown that the prolonged contraction and relaxation periods 5,8 associated with the down regulation of Ca 2+ uptake by the sarcoplasmic reticulum (SR). 9 In accordance with the uptake results of fluorometric ([Ca 2+ ] i measurements of showed a prolongation in the contraction and relaxation periods of diabetic myocytes 10,11 . These effects which occur in the sarcoplasmic reticulum are mostly attributed to the reduction in the amount of ryanodine receptor protein (RyR2), SR Ca 2+ -ATPase protein content, and SR Ca 2+ storage capacity. However, L-type Ca 2+ currents (I CaL ) and channel protein content remained same 9,10,12 . Fauconnier J et al. has been reported that I to decreases as a consequence of increased diastolic calcium content following RyR2 changes, which it explains that diabetes exhibits some similarities with heart failure. 12 These changes in the contraction parameters as a consequence of cardiomyopathy are summarized on the table 1.

Abnormalities in AP Parameters
Fein et al. (1980), for the first time, demonstrated the effects of diabetes mellitus on the duration of action potential and ionic currents with experimental diabetic animal model studies. 1 In his pioneer work, it was reported that the diabetes results in an increase in the action potential (AP) duration and a decrease in ventricular AP amplitude. 1 Researches focused on the underling mechanism of this prolonged repolarization phase of the AP ended up with the down regulated potassium currents. Indeed, deep patch clamped studies have shown that there was a tremendous decrease in transient outward potassium current (I to ) and steady state outward K + current (I ss ) but invert rectifier (I K1 )on the other hand remained same. 6 Furthermore, it is well known that the prolongation in AP duration is due to by not only the inhibition of K + currents but also the reduction of Na + -Ca 2+ exchanger current. 13 Taken together, the present data indicate that [Na + ] i is an important modulator of excitationcontraction coupling by regulating Ca 2+ efflux / influx. Bilginoglu et al. have shown that the less Na + influx during contraction in diabetic rat heart tissue reduces Ca 2+ influx in diabetic cardiomyopathy. 14 These changes in the action potential parameters as a consequence of diabetic cardiomyopathy are summarized on the table 2.

Oxidative Stress
The effective usage of input is a very significant step in evolution. Thus oxidative phosphorylation has the greatest importance due to its high energy yield. It is a series of oxidationredox reactions in which the molecular oxygen is an electron donor but the reaction has reactive intermediates. The oxidation is the major drawback since it is called as one of the main causal in many disorders including diabetes mellitus.
In an atomic order of magnitude, oxidation can be explained as an increase in electron spin resonance, which is a result of unpaired electrons. By using the definition of the "nearsightedness of electrons" in many atomic systems, it is easier to visualize the effects of the oxidation. The definition posits that in the absence of the long-range ionic interaction large molecules can be studied one neighborhood at a time, so it is not necessary to study the whole system at once 15 . In this point of view, the effect of a reactive molecule in the entire system -in the body-can be ignored easily, but the local effect on the other hand can be as destructive as a category 4 hurricane.
The fine tuned balance in the oxidative system (oxidant and antioxidant) is essential for sustaining life properly. If the balance shifts in the favor of the former the oxidative stress occurs, that leads a potential damage in its vicinity 16 . Since oxidation, the production of the reactive oxygen species such as superoxide and hydrogen peroxide, is inevitable, it is wise to find ways to reinforce the endogenous antioxidant defense mechanisms in the body by adding antioxidant supplements to the daily diets, which helps to scavenge free radicals. In the light of the animal model studies, a wide variety of substances are recommended as supplements -spans from tungsten 17 , a transition metal, to resveratrol 18,19 , vitamin E 20 , curcumin 21 , and selenium-that 22 , have positive effects on the diabetes mellitus related complications. Among the others, selenium needs more attention because selenium, an essential trace element, functions as a cofactor for glutathione peroxidases and a key parameter in selenoproteins such as thioredoxin reductase 23 .

Selenium intake and Diabetes
Diabetic milieu, the main reason of the diabetic cardiomyopathy, alters protein kinase C, causes abnormalities in lipid metabolism, action potential duration, calcium ion homeostasis, and antioxidant defense, which causes an electrical remodeling in the heart 24 . The electrical remodeling in diabetes is well known and the electrophysiological studies reveal the underlying ionic mechanism. It is known that potassium ion channels are responsible not only for the repolarization of the action potential but also for maintaining the resting membrane potential in the heart. The modulation of the potassium channels are the primarily reason of the electrical remodeling of cardiac action potential 25 . Thus, one must restore the alteration in the potassium ion channels to cure or decelerate the complications of diabetic cardiomyopathy. The reason of downregulaton in potassium currents is not well known yet, but it is found that oxidative stress and hyperglycemia are involved in this remodeling 26 . The studies about glutathione have promising results on potassium channels. The oxidative stress results in a decrease in reduced glutathione (GSH) and an increase in oxidized glutathione (GSSG). The accumulation of GSSG results the oxidation of protein thiol groups of cysteine residues.
Moreover, it is stated that along with its antioxidant property insulin like characteristics brings selenium one more step further. The main issue in diabetes mellitus is the impairment in glucose transport mechanisms; selenium, like insulin, translocates the glucose transporters on the cell membrane. Furthermore, it stimulates the activity of CAMP phosphodiesterase, and phosphorylation of ribosomal S6 protein. Since, in the absence of insulin, selenium failed to stimulate insulin receptor kinase activity it is probable that effect of the selenium is on other tyrosine kinase. Interestingly, in the presence of insulin, selenium enhances insulin receptor kinase activity and phosphorylations of insulin-stimulated tyrosylphosphoproteins 27 .
It is well known that calcium is the most important ion in regulating contraction in the heart. Diabetic milieu and oxidative stress also affect contracting channel proteins and causes hyperphosphorlation of PyR2 which causes a leakage from SR 28 , moreover the abnormalities in Ca 2+ transients 29 , and an increase in basal intracellular calcium concentration is observed 30 . The selenium application has restored the observed abnormalities 31 , but since the selenium effects in a dose dependent manner, the reverse -no significantly alter the contraction related parametersis also proposed in some studies 26,32 .
S i n c e t h e e f f e c t s o f s e l e n i u m supplementation can be seen in metabolism through various pathways, in the literature the different effects of it are reported. It is stated that the combination of insulin and selenium suppresses the cardiomyocyte apoptosis through inhibiting the p38MAPK/CBP pathway 33 . Fur thermore, selenium restores depressed Beta-adrenergic responses of the heart in diabetic rats 34 . Besides its antioxidant and hypolipidemic effects 35 , due to its anti-inflammatory activity, it has a beneficial effect on the regulation of the leukotriene pathway in diabetic cardiac hypertrophy heart 36 . Not only diabetes mellitus but also cardiovascular diseases are also linked to low plasma selenium levels 37 . It is reported that supplementation is beneficial in patients with type 2 diabetes and coronary heart disease and significantly reduces the mortality 38,39 , and it protects the heart against ischemia/reperfusion (I/R) injury due to its action on cellular redox state and deactivation of NF-kB in I/R hearts 40 .
Recent and promising results are from the studies on the selenium nanoparticles. It is stated that insulin loaded selenium nanoparticles may overcome the oral insulin delivery problem and increase the comfort of the patients. Insulin loaded selenium nanoparticles could alleviate oxidative stress, improve pancreatic islet function, and promote glucose utilization 41 . By same token, elemental selenium nanoparticles delivered in liposomes has higher absorption than dietary selenium which may be explained by different absorption mechanisms and metabolic pathways42. The promising results of selenium studies conclude that it is wise to include selenium in treatment approaches for diabetes.

ACKNOWLEDGEMENT
We would like to thank Kazim Bugra Sekerci for technical assistance and Kevin Tugra Kalkan for assistance with manuscript editing.