**4. Mitochondrial dehydrogenases under diabetic conditions**

A vast body of literature covers the functional modifications of mitochondria under diabetic conditions. Because cardiovascular insults remain the leading cause of death for diabetic patients [38], most of the attention has been focused on the modifications occurring in cardiac mitochondria to provide a better rationale for the morphological and functional modifications observed in diabetic hearts. Further, the incidence and severity of cardiovascular complications are markedly increased in both male and female diabetic patients, with the latter exhibiting a greater incidence than the diabetic male counterparts [39].

In humans, our understanding of the disease is complicated by the presence of two pathological conditions: diabetes type 1, in which insulin production is lacking, and diabetes type 2, in which insulin is still produced, sometimes to a greater extent than under normal conditions, and yet it is not functionally efficient in controlling the glycemic state of the patient. An additional confounding parameter is that to a large extent type 2 diabetic patients are overweight or obese, with an altered lipid status both in serum and within tissues (lipotoxicity).

This variety of conditions is also reflected in the heterogeneity of animal experimental models utilized to investigate the disease. Also here, models of type 1 diabetes are conceptually simpler in that animals are injected with agents that damage pancreatic beta-cells and abolish insulin secretion, fully mimicking the human condition. Models for type 2 diabetes are more heterogeneous, spanning from genetically conditioned animals (KO animals for specific proteins, receptors, or signaling molecules) to genetically inbred animals (e.g. Koletsky rats), to animals that develop diabetes spontaneously, to animals fed assorted high fat diets with or without sucrose, and injected with subliminal doses of beta-cell damaging agents that limit but not completely abolish the endogenous production of insulin, or treated with various oral antidiabetic agents [40]. Because of this plethora of models, it is not simple to determine to which extent modifications of mitochondrial dehydrogenase are a primary or secondary insult in the pathogenesis of the diabetic condition and its complications.

The development of diabetic cardiomyopathy has been etiologically attributed to several factors including metabolic [41], biochemical [42] and ultra-structural [43] modifications within the cardiac myocytes. Scrutiny of mitochondrial function in cardiac mitochondria from streptozotocin-treated rats has shown a decline in respiration and oxygen consumption, more pronounced for state 3 than state 4, which translates into a decrease in ATP production [44]. This energy deficiency has been considered a key factor in the development of diabetes-related cardiac dysfunctions, although changes in cardiac microvasculature [45], metabolic and hormonal disturbances [46] and concurring hyperglycemia [47] can certainly act as co-factors. Combining defective mitochondrial respiration with increased ROS formation, studies from our laboratory have indicated that succinate dehydrogenase [48] and pyruvate dehydrogenase [49] are highly sensitive to ROS-induced damage, forming stable, non-functional adducts within the mitochondrion of streptozotocin-treated rats. As mentioned in the previous section, the consequences of this dysfunction are three-fold: 1) the inability of the electron transport chain to operate properly is compromised, resulting in decreased ATP production; 2) the production of ROS is enhanced, further damaging macromolecules within the mitochondrion and its surroundings, and 3) forcing the cardiac myocytes to depend on glycolysis to produce ATP. Interestingly, these changes were observed predominantly in cardiac and liver tissue but not in the kidney of the diabetic animals [49], rising the intriguing question of which protective mechanism(s) may operate in the latter organ under diabetic conditions.
