Association of Glycemic Indices (Hyperglycemia, Glucose Variability, and Hypoglycemia) with Oxidative Stress and Diabetic Complications

Abstract

Oxidative stress (OS) is defined as a disturbance in the prooxidant-antioxidant balance of the cell, in favor of the former, which results in the antioxidant capacity of the cell to be overpowered. Excess reactive oxygen species (ROS) production is very harmful to cell constituents, especially proteins, lipids, and DNA, thus causing damage to the cell. Oxidative stress has been associated with a variety of pathologic conditions, including diabetes mellitus (DM), cancer, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and accelerated aging. Regarding DM specifically, previous experimental and clinical studies have pointed to the fact that oxidative stress probably plays a major role in the pathogenesis and development of diabetic complications. It is postulated that hyperglycemia induces free radicals and impairs endogenous antioxidant defense systems through several different mechanisms. In particular, hyperglycemia promotes the creation of advanced glycation end-products (AGEs), the activation of protein kinase C (PKC), and the hyperactivity of hexosamine and sorbitol pathways, leading to the development of insulin resistance, impaired insulin secretion, and endothelial dysfunction, by inducing excessive ROS production and OS. Furthermore, glucose variability has been associated with OS as well, and recent evidence suggests that also hypoglycemia may be playing an important role in favoring diabetic vascular complications through OS, inflammation, prothrombotic events, and endothelial dysfunction. The association of these diabetic parameters (i.e., hyperglycemia, glucose variability, and hypoglycemia) with oxidative stress will be reviewed here.

Figure 1

Reactive oxygen species- (ROS-) mediated inhibition of glycolysis reroutes flux into the oxidative arm of the pentose phosphate pathway. The enzymes inhibited by ROS are shown. ROS inhibits phosphofructokinase 1 (PFK1) and inactivates glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and the pyruvate kinase isoform PKM2 by directly targeting cysteine residues. Thus, this glycolytic inhibition promotes flux into the oxidative pentose phosphate pathway (PPP) to produce NADPH and fuel cellular antioxidant systems (for example NADPH is consumed by glutathione reductase (GSR) to recycle oxidized glutathione (GSSG)). PKM2 inhibition is unique in that it allows for a diversion of flux into the serine synthesis pathway. Serine not only contributes to the synthesis of macromolecules but is also a precursor for glutathione (GSH). Serine synthesis is activated by a buildup of 2-phosphoglycerate (2PG), which prevents 3-phosphoglycerate- (3PG-) induced inhibition of the oxidative pentose phosphate arm. PPP: pentose phosphate pathway; HK: hexokinase; G6PD: glucose-6 phosphate dehydrogenase; PGD: phosphogluconate dehydrogenase; G6P: glucose-6-phosphate; Ru5P: ribulose-5-phosphate; F6P: fructose-6-phosphate; NADPH: nicotinamide adenine dinucleotide phosphate; PFK1: phosphofructokinase 1; F1,6 BP: fructose 1,6 bisphosphate; DHAP: dihydroxyacetone phosphate, TPI: tirose phosphate isomerase; G3P: glyceraldehyde-3-Phosphate; GAPDH: glyceraldehyde-3 phosphate dehydrogenase; 1,3 BPG: 1,3-bisphosphoglycerate; 3 PG: 3-phosphoglycerate; 2-PG: 2-phosphoglycerate; PEP: phosphoenolpyruvate; PYR: pyruvate; PKM2: pyruvate kinase isoform M2; PHGDH: 3-phosphoglycerate dehydrogenase; ROS: reactive oxygen species; GSSG: glutathione disulfide (oxidized glutathione); GSR: glutathione reductase; GSH: glutathione (reduced glutathione); SER: serine.

Figure 2

Mitochondrial overproduction of superoxide during hyperglycemic conditions activates four major pathways of hyperglycemic damage by inhibiting GAPDH. NADPH: nicotinamide adenine dinucleotide phosphate; NADH: nicotinamide adenine dinucleotide; GAPDH: glyceraldehyde-3 phosphate dehydrogenase; PARP: poly-ADP-ribose polymerase; GFAT: glutamine:fructose-6-phosphate amidotransferase; UDP-GlcNAc: UDP-N-acetylglucosamine; DAG: diacylglycerol; AGE: advanced glycation end-product.