Received 15 April 2016; accepted 16 May 2016; published 20 May 2016
Step-by-step development of diabetic disorder proposed a schematic “Energy homeostasis diagram” and accordingly, we suggested that alteration in Na+-K+ pump structure/function might cause further modification towards diabetics. Diabetes mellitus is a disorder that involve whole metabolism of body  , glucose uptake strength is low in diabetic patients  . In these individuals’ energy charges, ATP/ADP is imbalance opposed to normal individuals  . Individuals that taken diabetes might have disordered in signal transduction  , mitochondrial dysfunction  , imbalance in calcium level in cytoplasm  or dysfunction in membrane proteins such as Na+-K+ pump  . The goal of this short-communication is to unveil the cross-talk between signaling which is involved in energy homeostasis and finds the initiate point of this pathway as well as citric acid cycle which determines oxaloacetate as a critical point of cycle. There are some evidences that identify Na+-K+ pump as a source of this impairment  . It is suggested that compensation of Na+-K+ pump activity in diabetic patients might improve illness status through increasing of calcium level in cytoplasm  ; activating of calcium signaling pathway proteins such as calmudulin-dependent kinase (CAMK) and calcineurine (a protein phosphates)  and these factors cause MEF2 (myocyte enhancer factor 2), NFAT (nuclear factor T-cell) activation   which is accompanied by overexpression of PGC-1α (peroxisome proliferators-activated receptor gamma coactivator-1 alpha)  , then up-regulation of NRF-1(nuclear respiratory factor A)  and ultimately mitochondrial biogenesis has been observed  . On the other hand, concomitant collaboration between PGC-1α with MEF2 leads to both up-regulation and transportation of GLUT4 (glucose transporter-4) toward cell membranes  . Furthermore, the interaction between PGC-1α and PPAR (peroxisome proliferator activated receptor-Alpha) in turn modulates the expression of PPRES (PPAR Response elements) which lead to increase of enzymes overexpression which is involved in glucose and fatty acid oxidation  . In this so called schematic view, a reversible equilibrium among Na+-K+ pump and mitochondrial biogenesis/activity is observed. In the absence of suitable function of this pump, the amount of Na+ is overloaded in cytoplasm and this results in calcium penetration from mitochondria and also deficiency of calcium availability of cytoplasm. It should be pointed out that many calcium-dependent enzymes are working in mitochondria and decrease of matrix calcium has deleterious effects on them   . On the other hand, harmful effects of lowering-calcium on intracellular energy production cause failure of Na+-K+ pump. It should be noted that about 4% - 50% of basal energy expenditure is used to maintain physiological intracellular sodium (Na+) and potassium (K+) concentrations  . Finally, we could found a series of related signals which cooperate altogether and result in cell energy homeostasis as it can be seen in Figure 1.
Figure 1. As it has been shown in the figure, there are some negative feedbacks such as NEFA (non-esterifies fatty acid), cabin1, HDACII and positive feedbacks like insulin, exercise, AMPK, P38, MAPK. According to the diagram the key point which can be considered as a starting and extending diabetes disease is disorder in Na+-K+ Pump. As it has been shown ,the activators can increase intracellular level of calcium concentration (inhibitors can act inversely), at the second step, temporal and prolong increase in calcium concentration can led to activation of CAMK and calcineurin, protein-protein interaction between the mentioned proteins can activate a series of signals such as MEF2, NFAT which in turn leading to increase in PGC-1α expression level, the role of the last factor is energy cell homeostasis and inducing NRF-1, NRF-2 activity/expression level. Also NRFs has a positive effect on nuclear genome which involved in expression of respiratory factors. Then, these factors will effect on mTFA (mithochondrial transcription factor), both factors can increase mitochondria biogenesis/activity. The backward arrow between Na-K pump and mitochondria at the top of figure reveals direct effect of increasing Na concentration on exiting Ca from mitochondria and inactivation of Ca-dependent mitochondorial enzymes.
The author of this manuscript is so grateful from Young Researchers and Elite Club, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran that financial support this study.
Conflict and Interest
We declare that there is not any conflict and interest from this study.
MEF2 (myocyte enhancer factor 2), CREB (cAMP response elements), NFAT (nuclear factor of activated T-cells), MAPK (mitogen-activated protein kinases), AMPK (5’ adenosine monophosphate-activated protein kinase), PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), CAMK (Ca2+/calmo- dulin-dependent protein kinase), Calcineurin (calcium and calmodulin dependent serine/threonine protein phosphatase), PPAR (peroxisome proliferator activated receptor-Alpha), GLUT4 (glucose transporter-4), NRF-1 (nuclear respiratory factor A), PPAR (peroxisome proliferator activated receptor-Alpha).