Role of oxidative stress in diabetic complications: a new perspective on an old paradigm.

Baynes, John W.; Thorpe, Suzanne R.

doi:10.2337/diabetes.48.1.1

Cited by 2,171 publications

(1,559 citation statements)

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“…The recognition of NEG as a molecular mechanism that contributes to the development of OA provides new opportunities for therapies directed at the prevention of OA by inhibiting or reversing AGE formation. Inhibition of AGE formation by prophylactic treatment with compounds such as aminoguanidine, pyridoxamine, tenilsetam, or simple amino acids (e.g., lysine or arginine) has been shown to prevent AGErelated pathologies such as vascular stiffening, heart collagen accumulation, and protein crosslinking (59)(60)(61)(62)(63). Alternatively, AGE-directed therapy can consist of so-called AGE-breakers (64).…”

Section: Discussionmentioning

confidence: 99%

Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis

DeGroot¹,

Verzijl²,

Wijk

et al. 2004

Arthritis & Rheumatism

182

114

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Objective. Osteoarthritis (OA) is one of the most prevalent and disabling chronic conditions affecting the elderly. Its etiology is largely unknown, but age is the most prominent risk factor. The current study was designed to test whether accumulation of advanced glycation end products (AGEs), which are known to adversely affect cartilage turnover and mechanical properties, provides a molecular mechanism by which aging contributes to the development of OA.Methods. The hypothesis that elevated AGE levels predispose to the development of OA was tested in the canine anterior cruciate ligament transection (ACLT) model of experimental OA. Cartilage AGE levels were enhanced in young dogs by intraarticular injections of ribose. This mimics the accumulation of AGEs without the interference of other age-related changes. The severity of OA was then assessed 7 weeks after ACLT surgery in dogs with normal versus enhanced AGE levels.Results. Intraarticular injections of ribose enhanced cartilage AGE levels ϳ5-fold, which is similar to the normal increase that is observed in old dogs. ACLT surgery resulted in more-pronounced OA in dogs with enhanced AGE levels. This was observed as increased collagen damage and enhanced release of proteoglycans. The attempt to repair the matrix damage was impaired; proteoglycan synthesis and retention were decreased at enhanced AGE levels. Mankin grading of histology sections also revealed more-severe OA in animals with enhanced AGE levels.Conclusion. These findings demonstrate increased severity of OA at higher cartilage AGE levels and provide the first in vivo experimental evidence for a molecular mechanism by which aging may predispose to the development of OA.The population of Western society is aging rapidly. Consequently, age-related diseases will increase greatly over the coming decades and will have a great impact on the quality of life of the elderly. Osteoarthritis (OA) is one of the most prevalent and disabling chronic conditions affecting the elderly and poses a significant public health problem (1). The most prominent feature of OA is the progressive destruction of articular cartilage, resulting in impaired joint motion, severe pain, and, ultimately, disability (2). As yet, the etiology of OA remains largely unknown. The incidence of OA increases with age: Ͼ50% of the population over 60 years of age is affected (3,4). Although age is identified as the main risk factor for the development of OA, the mechanism by which aging is involved remains unclear. Age-related changes in the articular cartilage are expected to play an important role in the susceptibility of cartilage to OA.Articular cartilage derives its mechanical properties from its extracellular matrix. This matrix is composed of type II collagen, which forms a 3-dimensional network that provides the cartilage with resistance to tensile forces (5).

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Section: Discussionmentioning

confidence: 99%

Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis

DeGroot¹,

Verzijl²,

Wijk

et al. 2004

Arthritis & Rheumatism

182

114

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“…The accumulation of AGE on tissue proteins has been implicated in the ageing of proteins and the progression of chronic, age-related diseases [1], such as atherosclerosis [2], chronic renal failure [3], Alzheimer's disease [4] and diabetes mellitus [5,6,7,8]. Glucose initially reacts with proteins to form reversible early glycation products.…”

Section: Introductionmentioning

confidence: 99%

“…In diabetes mellitus, AGE accumulation in skin collagen is correlated both with the duration and severity of hyperglycaemia, and with the presence of long-term complications [6,7,8,12,13,14,15]. In a DCCT substudy, skin AGE levels explained 19 to 36% of the variance in the incidence of long-term diabetic complications in intensively treated patients, and 14 to 51% in conventionally treated patients [8].…”

Section: Introductionmentioning

confidence: 99%

Simple non-invasive assessment of advanced glycation endproduct accumulation

Meerwaldt¹,

Graaff

Oomen³

et al. 2004

Diabetologia

654

815

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Aims/hypothesis. The accumulation of AGE is thought to play a role in the pathogenesis of chronic complications of diabetes mellitus and renal failure. All current measurements of AGE accumulation require invasive sampling. We exploited the fact that several AGE exhibit autofluorescence to develop a non-invasive tool for measuring skin AGE accumulation, the Autofluorescence Reader (AFR). We validated its use by comparing the values obtained using the AFR with the AGE content measured in extracts from skin biopsies of diabetic and control subjects. Methods. Using the AFR with an excitation light source of 300-420 nm, fluorescence of the skin was measured at the arm and lower leg in 46 patients with diabetes (Type 1 and 2) and in 46 age-and sexmatched control subjects, the majority of whom were Caucasian. Autofluorescence was defined as the average fluorescence per nm over the entire emission spectrum (420-600 nm) as ratio of the average fluorescence per nm over the 300-420-nm range. Skin biopsies were obtained from the same site of the arm, and analysed for collagen-linked fluorescence (CLF) and specific AGE: pentosidine, N ε -(carboxymethyl)-lysine (CML) and N ε -(carboxyethyl)lysine (CEL).Results. Autofluorescence correlated with CLF, pentosidine, CML, and CEL (r=0.47-0.62, p≤0.002). In 32 of 46 diabetic patients (70%), autofluorescence values were above the 95% CI of the mean value in control subjects, and correlated with age, diabetes duration, mean HbA 1 c of the previous year and creatinine levels. Conclusions/interpretation. The AFR offers a simple alternative to invasive measurement of AGE accumulation and, to date, has been validated in non-pigmented skin. The AFR may prove to be a useful clinical tool for rapid risk assessment of AGE-related long-term complications in diabetes mellitus and in other conditions associated with AGE accumulation.

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“…Protein glycation, as well as protein oxidation and nitration, is thought to contribute to vascular cell dysfunction and the development of microvascular diabetic complications (retinopathy, nephropathy and neuropathy) [2][3][4]. Recent research has shown that protein glycation, oxidation and nitration are increased in cellular and ex-tracellular proteins in diabetes [5].…”

Section: Introductionmentioning

confidence: 99%

Degradation products of proteins damaged by glycation, oxidation and nitration in clinical type 1 diabetes

et al. 2005

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Aims/hypothesis: Hyperglycaemia in diabetes is associated with increased glycation, oxidative stress and nitrosative stress. Proteins modified consequently contain glycation, oxidation and nitration adduct residues, and undergo cellular proteolysis with release of corresponding free adducts. These free adducts leak into blood plasma for eventual renal excretion. The aim of this study was to perform a comprehensive quantitative analysis of protein glycation, oxidation and nitration adduct residues in plasma protein and haemoglobin as well as of free adducts in plasma and urine to quantify increased protein damage and flux of proteolytic degradation products in diabetes. Methods: Type 1 diabetic patients (n=21) and normal healthy control subjects (n=12) were studied. Venous blood samples, with heparin anticoagulant, and 24-h urine samples were taken. Samples were analysed for protein glycation, oxidation and nitration adducts by a quantitative comprehensive screening method using liquid chromatography with triple quadrupole mass spectrometric detection. Results: In type 1 diabetic patients, the concentrations of protein glycation, oxidation and nitration adduct residues increased up to three-fold in plasma protein and up to one-fold in haemoglobin, except for decreases in pentosidine and 3-nitrotyrosine residues in haemoglobin when compared with normal control subjects. In contrast, the concentrations of protein glycation and oxidation free adducts increased up to ten-fold in blood plasma, and urinary excretion increased up to 15-fold in diabetic patients. Conclusions/interpretation: We conclude that there are profound increases in proteolytic products of glycated and oxidised proteins in diabetic patients, concurrent with much lower increases in protein glycation and oxidation adduct residues.

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Role of oxidative stress in diabetic complications: a new perspective on an old paradigm.

Cited by 2,171 publications

References 46 publications

Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis

Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis

Simple non-invasive assessment of advanced glycation endproduct accumulation

Degradation products of proteins damaged by glycation, oxidation and nitration in clinical type 1 diabetes

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