Oxidative Stress, Diabetes, and Its Complications

Oxidative Stress, Diabetes, and Its Complications

Antonio Ceriello, Ludovica Piconi
US Endocrine Disease 2007 - Issue 1
Published: October 2008
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Our evolution as complex aerobic organisms with high energy demands is tightly linked to the acquisition of mitochondria in our cells. This passage gave us the ability to use oxygen, harnessing its power in the respiratory chain, but also the fundamental function to compartmentalize this process, protecting the cytosol from its potentially harmful side effects.1 In fact, even being scarcely reactive this molecule has the tendency to ‘radicalize,’ forming incompletely reduced molecules characterized by an uncoupled electron. This highly reactive and short-living class of molecules is known as reactive oxygen species (ROS). ROS production is a side effect of the normal metabolism of the cell, which developed a series of enzymes able to disarm them. Superoxide dismutase, catalase, and glutathione peroxidase are powerful weapons that act together with antioxidant molecules introduced with diet to protect the organism. In healthy subjects there is a balance between ROS formation and elimination. Every time this balance is lost due to an augmented production of reactive species or due to a reduction in antioxidant production or activity there is a condition of oxidative stress. Losing control of ROS is very harmful and almost all the constituents of the cell can be targets of these molecules. DNA, proteins, and lipids can be involved in chain reactions that entail their modification and, in the worst case, the loss of their functionality. Genetic degeneration and physiological dysfunction can lead to cell death and aging of the organism.

On this basis it is not surprising that oxidative stress has been implicated in involved in diabetic complications entails the intracellular formation of AGEs. The augmented presence of glucose inside the cell originates reactive dicarbonyl molecules such as glyoxal, methylglyoxal, and 3- deoxyglucosone, which react with the aminic groups of proteins to form AGEs. The modification process does not require the presence of an enzyme and the two-step reaction is not reversible. Proteins with a very slow turnover rate, such as collagen and hemoglobin, exist in the body partly modified by glucose. These kind of modifications usually imply a loss of functionality and the denaturation of the target protein; moreover, the binding of the modified protein to AGE receptors on endothelial cells, mesangial cells, and macrophages induces the production of reactive oxygen species. AGEs are proved to be responsible for several aspects of diabetic complications involving vessels and kidneys.7,8

PKC is a family of at least 11 serin/treonin protein kinase isoenzymes involved in several cellular responses, such as growth, differentiation, genic expression, angiogenesis, and sorting of proteins inside the cell’s district. Based on their activating substances, the isoenzymes are classified in different families. The conventional PKCs require calcium and diacylglycerol (DAG) for activation, while the new PKCs require DAG but are calciumindependent.9 In diabetic patients, the augmented availability of glucose causes an augmented availability of DAG and a consequent activation of PKCs. Effects of this extra-activation are different and detrimental for vascular functionality with increased vascular permeability,10 deregulated nitric oxide generation via NADPH oxidase activation,11 stabilized vascular endothelial growth factor (VEGF) messenger ribonucleic acid (mRNA) expression through post-transcriptional mechanisms, increased leukocyte-endothelium interaction, and activating nuclear factor kappa Beta (NF-kB). 12

Last but not least, in diabetes there is an augmented flux through the hexosamine pathway (HP). In the healthy metabolism a relatively low amount of fructose-6P is diverted from glycolysis and directed to a cascade of reactions whose end-product is a series of amino-sugars, the building blocks of the glycosyl-side chains of proteins and lipids.13 Unlike AGE formation, the modification of proteins and lipids requires specific enzymes. Once again, the augmented availability of glucose in the diabetic patient causes an accumulation of end-products of this pathway. This was associated with the development of the complications of diabetes, basically due to the modification on serine/threonine residues of selected proteins.14-16 HP was involved in transforming growth factor beta-1 (TGF-β1) and fibronectin expression,17,18 and stimulates plasminogen activator inhibitor 1 (PAI-1) via modification of the transcription factor stimulatory protein 1 (Sp1).19 Augmented flux through the HP was also linked to insulin resistance and several authors proposed that flux through the hexosamine pathway may represent a cellular ‘sensor’ to monitor the flux of a nutrient, glucose, that can became toxic when in excess.20 This position ascribes to insulin resistance a sort of protective action to minimize glucose entrance.

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