The morbidity and mortality associated with diabetes is the result of the myriad complications related to the disease One of the most explored hypotheses to explain the onset of complications is a hyperglycemia-induced increase in oxidative stress Reactive oxygen species (ROS) are produced by oxidative phosphorylation, nicotinamide adenine dinucleotide phosphate oxidase (NADPH), xanthine oxidase, the uncoupling of lipoxygenases, cytochrome P450 monooxygenases, and glucose autoxidation Once formed, ROS deplete antioxidant defenses, rendering the affected cells and tissues more susceptible to oxidative damage Lipid, DNA, and protein are the cellular targets for oxidation, leading to changes in cellular structure and function Recent evidence suggests ROS are also important as second messengers in the regulation of intracellular signaling pathways and, ultimately, gene expression This review explores the production of ROS and the propagation and consequences of oxidative stress in diabetes

The role of oxidative stress in diabetic complications.

Preface Introduction The Chemistry of Non-Enzymic Browning Recent Advances Colour Formation in Non-Enzymic Browning Flavour and Off-Flavour Formation in Non-Enzymic Browning Toxicological Aspects Nutritional Aspects Other Physiological Aspects Other Consequences of Technological Significance Implications for Other Fields Non-Enzymic Browning Due Mainly to Ascorbic Acid Caramelisation Inhibition of Non-Enzymic Browning in Foods Inhibition of the Maillard Reaction in Vivo Subject Index

The Maillard reaction : chemistry, biochemistry and implications

Arterial stiffening is a progressive, ubiquitous and irreversible aging process that is interwoven with and accelerated by various diseases such as diabetes, atherosclerosis and hypertension. In large arteries, aging is characterized by decreased turnover of collagen and elastin and increased advanced glycation end-products (AGEs) and cross-links. Elastic fibers undergo lysis and disorganization subsequent to their replacement by collagen and other matrix components. These events cause the loss of elasticity and induce stiffening. Conceptual approaches to minimize AGE accumulation in arteries include caloric restriction, exercise, low dietary intake of AGEs, deglycation enzymes, increased clearance of AGEs, antagonists of AGE receptors and pharmaceutical interventions. Much optimism exists in the ability of ‘AGE breakers’ such as alagebrium (ALT-711) to cleave AGE cross-links and reverse the age-related stiffening of arteries. However, there is little evidence that these agents actually break pre-existing AGE cross-links in vivo. In contrast, many of these anti-AGE agents share in common the ability to chelate metals, thus acting as inhibitors of metal-catalyzed AGE and protein carbonyl formation. Future work on interventions into the causes of arterial stiffness in aging needs to address more rigorously the relationship between stochastic forms of damage, such a glycation and oxidation, and the changes in elastic fiber structure thought to contribute to loss of arterial elasticity.

Molecular basis of arterial stiffening: role of glycation - a mini-review.

The aging extracellular matrix is characterized by an age-related increase in insolubilization, yellowing, and stiffening, all of which can be mimicked by the Maillard reaction in vitro These phenomena are accelerated in metabolic diseases such as diabetes and end-stage renal disease, which have in common with physiological aging the accumulation of various glycation products and cross-links Eight years ago we concluded that the evidence favored oxidative cross-linking in experimental diabetes [Monnier, VM et al 1996 The mechanism of collagen cross-linking in diabetes: a puzzle nearing completion Diabetes 45(Suppl 3): 67-72] and proposed a major role for a putative non-UV active cross-link derived from glucose Below, we provide an update of the field that leads to the conclusion that, while oxidation might be important for Maillard reaction-mediated cross-linking via Strecker degradation and allysine formation, the single most important collagen cross-link known to date in diabetes and aging is glucosepane, a lysyl-arginine cross-link that forms under nonoxidative conditions

Cross‐Linking of the Extracellular Matrix by the Maillard Reaction in Aging and Diabetes: An Update on “a Puzzle Nearing Resolution”

The effects of the Maillard reaction on the physical properties and cell interactions of collagen.

The levels of alpha-aminoadipic-delta-semialdehyde residue, the oxidative deamination product of lysine residue, in plasma protein from streptozotocin-induced diabetic rats were evaluated. alpha-Aminoadipic-delta-semialdehyde was converted to a bisphenol derivative by acid hydrolysis in the presence of phenol, and determined by high performance liquid chromatography. Analysis of plasma proteins revealed three times higher levels of alpha-aminoadipic-delta-semialdehyde in diabetic subjects compared with normal controls. Furthermore, we explored the oxidative deamination via the Maillard reaction and demonstrated that the lysine residue of bovine serum albumin is oxidatively deaminated during the incubation with various carbohydrates in the presence of Cu2+ at a physiological pH and temperature. This experiment showed that 3-deoxyglucosone and methylglyoxal are the most efficient oxidants of the lysine residue. When the reaction was initiated from glucose, a significant amount of alpha-aminoadipic-delta-semialdehyde was also formed in the presence of Cu2+. The reaction was significantly inhibited by deoxygenation, catalase, and a hydroxyl radical scavenger. The mechanism we propose for the oxidative deamination is the Strecker-type reaction and the reactive oxygen species-mediated oxidation. Based on these findings, we propose a novel mechanism for the oxidative modification of proteins in diabetes, namely the oxidative deamination of the lysine residue via the Maillard reaction.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1046/j.1432-1033.2002.03243.x

Oxidative deamination of lysine residue in plasma protein of diabetic rats. Novel mechanism via the Maillard reaction.

Oxidative deamination of benzylamine by glycoxidation.

The lysine residue of bovine serum albumin was deaminated to allysine (α-aminoadipic-δ-semialdehyde) during the incubation with glucose, 3-deoxyglucosone (3-DG), and methylglyoxal (MG) in the presence of Cu2+ at a physiological pH and temperature but not with glyoxal. Further, glucose, 3-DG, and MG oxidatively deaminated benzylamine to benzaldehyde in the presence of Cu2+. The formation of benzaldehyde was greatest with Cu2+, and was accelerated in the presence of oxygen. EDTA, catalase, and dimethyl sulfoxide (DMSO) significantly inhibited the oxidation. Analysis of plasma proteins revealed significantly higher levels of allysine in streptozotocin (STZ)-induced diabetic rats compared with normal controls. From these findings, we propose a novel mechanism for the oxidative modification of proteins in diabetes via the Maillard reaction.

Takeshi Sasaki

Papers

Oxidative deamination of lysine residue in plasma protein of diabetic rats. Novel mechanism via the Maillard reaction.

Oxidative deamination of benzylamine by glycoxidation.

Oxidative deamination of lysine residue in plasma protein from diabetic rat: α-dicarbonyl-mediated mechanism