Oxygen metabolism is essential for sustaining aerobic life, and normal cellular homeostasis works on a fine balance between the formation and elimination of reactive oxygen species (ROS). Oxidative stress, a cytopathic consequence of excessive production of ROS and the suppression of ROS removal by antioxidant defense system, is implicated in the development of many diseases, including Alzheimer's disease, and diabetes and its complications. Retinopathy, a debilitating microvascular complication of diabetes, is the leading cause of acquired blindness in developed countries. Many diabetes-induced metabolic abnormalities are implicated in its development, and appear to be influenced by elevated oxidative stress; however the exact mechanism of its development remains elusive. Increased superoxide concentration is considered as a causal link between elevated glucose and the other metabolic abnormalities important in the pathogenesis of diabetic complications. Animal studies have shown that antioxidants have beneficial effects on the development of retinopathy, but the results from very limited clinical trials are somewhat ambiguous. Although antioxidants are being used for other chronic diseases, controlled clinical trials are warranted to investigate potential beneficial effects of antioxidants in the development of retinopathy in diabetic patients.

/pdf/oxidative-stress-and-diabetic-retinopathy-2g890l1tys.pdf

Oxidative Stress and Diabetic Retinopathy

Insulin resistance in skeletal muscle in obesity and T2DM is associated with reduced muscle oxidative capacity, reduced expression in nuclear genes responsible for oxidative metabolism, and reduced activity of mitochondrial electron transport chain. The presented study was undertaken to analyze mitochondrial content and mitochondrial enzyme profile in skeletal muscle of sedentary lean individuals and to compare that with our previous data on obese or obese T2DM group. Frozen skeletal muscle biopsies obtained from lean volunteers were used to estimate cardiolipin content, mtDNA (markers of mitochondrial mass), NADH oxidase activity of mitochondrial electron transport chain (ETC), and activity of citrate synthase and β-hydroxyacyl-CoA dehydrogenase (β-HAD), key enzymes of TCA cycle and β-oxidation pathway, respectively. Frozen biopsies collected from obese or T2DM individuals in our previous studies were used to estimate activity of β-HAD. The obtained data were complemented by data from our previous studies and statistically analyzed to compare mitochondrial content and mitochondrial enzyme profile in lean, obese, or T2DM cohort. The total activity of NADH oxidase was reduced significantly in obese or T2DM subjects. The cardiolipin content for lean or obese group was similar, and although for T2DM group cardiolipin showed a tendency to decline, it was statistically insignificant. The total activity of citrate synthase for lean and T2DM group was similar; however, it was increased significantly in the obese group. Activity of β-HAD and mtDNA content was similar for all three groups. We conclude that the total activity of NADH oxidase in biopsy for lean group is significantly higher than corresponding activity for obese or T2DM cohort. The specific activity of NADH oxidase (per mg cardiolipin) and NADH oxidase/citrate synthase and NADH oxidase/β-HAD ratios are reduced two- to threefold in both T2DM and obesity.

https://www.physiology.org/doi/pdf/10.1152/ajpendo.00317.2009

Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity

The formation and accumulation of methylglyoxal (MGO), a highly reactive dicarbonyl compound, has been implicated in the pathogenesis of type 2 diabetes, vascular complications of diabetes, and sev...

https://journals.physiology.org/doi/pdf/10.1152/physrev.00001.2019

Methylglyoxal, a highly reactive dicarbonyl compound, in diabetes, its vascular complications and other age-related diseases

Oxidative stress, a cytopathic outcome of excessive generation of ROS and the repression of antioxidant defense system for ROS elimination, is involved in the pathogenesis of multiple diseases, including diabetes and its complications. Retinopathy, a microvascular complication of diabetes, is the primary cause of acquired blindness in diabetic patients. Oxidative stress has been verified as one critical contributor to the pathogenesis of diabetic retinopathy. Oxidative stress can both contribute to and result from the metabolic abnormalities induced by hyperglycemia, mainly including the increased flux of the polyol pathway and hexosamine pathway, the hyper-activation of protein kinase C (PKC) isoforms, and the accumulation of advanced glycation end products (AGEs). Moreover, the repression of the antioxidant defense system by hyperglycemia-mediated epigenetic modification also leads to the imbalance between the scavenging and production of ROS. Excessive accumulation of ROS induces mitochondrial damage, cellular apoptosis, inflammation, lipid peroxidation, and structural and functional alterations in retina. Therefore, it is important to understand and elucidate the oxidative stress-related mechanisms underlying the progress of diabetic retinopathy. In addition, the abnormalities correlated with oxidative stress provide multiple potential therapeutic targets to develop safe and effective treatments for diabetic retinopathy. Here, we also summarized the main antioxidant therapeutic strategies to control this disease.

Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications.

Recently, the oxidoreductase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), has become a subject of interest as more and more studies reveal a surfeit of diverse GAPDH functions, extending beyond traditional aerobic metabolism of glucose. As a result of multiple isoforms and cellular locales, GAPDH is able to come in contact with a variety of small molecules, proteins, membranes, etc., that play important roles in normal and pathologic cell function. Specifically, GAPDH has been shown to interact with neurodegenerative disease-associated proteins, including the amyloid-beta protein precursor (AbetaPP). Studies from our laboratory have shown significant inhibition of GAPDH dehydrogenase activity in Alzheimer's disease (AD) brain due to oxidative modification. Although oxidative stress and damage is a common phenomenon in the AD brain, it would seem that inhibition of glycolytic enzyme activity is merely one avenue in which AD pathology affects neuronal cell development and survival, as oxidative modification can also impart a toxic gain-of-function to many proteins, including GAPDH. In this review, we examine the many functions of GAPDH with respect to AD brain; in particular, the apparent role(s) of GAPDH in AD-related apoptotic cell death is emphasized.

/pdf/oxidatively-modified-glyceraldehyde-3-phosphate-po65bhw8lk.pdf

Kenneth Smith

Papers

Glyceraldehyde-3-phosphate dehydrogenase activity as an independent modifier of methylglyoxal levels in diabetes.