Role of methylglyoxal adducts in the development of vascular complications in diabetes mellitus

Bourajjaj, Meriem; Stehouwer, C.D.A.; Hinsbergh, Victor W.M. van; Schalkwijk, Casper G.

doi:10.1042/bst0311400

Cited by 99 publications

(64 citation statements)

References 18 publications

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“…A direct role for methylglyoxal in telomeric attrition has not been observed so far. However, methylglyoxal induces an increase of free radicals (ROS) (28), and ROS might, albeit indirectly, accelerate telomere attrition (29). Furthermore, methylglyoxal causes stable modification of DNA bases, which in turn induces chromosomal aberrations, sister chromatid exchanges, and micronuclei in human lymphocytes treated in vitro (30).…”

Section: Discussionmentioning

confidence: 99%

Lymphocytes of Type 2 Diabetic Women Carry a High Load of Stable Chromosomal Aberrations

Boehm

Möller²,

Högel³

et al. 2008

Diabetes

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OBJECTIVE-Diabetes is associated with an increased risk of death in women. Oxidative stress due to chronic hyperglycemia leads to the generation of reactive oxygen species and loss of chromosomal integrity. To clarify whether diabetes is a premature aging syndrome, we determined telomere erosion dynamics and occurrence of structural chromosomal aberrations in women of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study.RESEARCH DESIGN AND METHODS-Telomere lengths and karyotypes were examined in peripheral blood mononuclear cells. Regarding these parameters, surviving and deceased type 2 diabetic women of the LURIC study were compared with nondiabetic LURIC women with or without coronary heart disease and with healthy female control subjects.RESULTS-Significantly enhanced telomere attrition was seen in all LURIC subjects compared with healthy control subjects. Although the average telomere-length loss is equivalent to well Ͼ10 years of healthy aging, telomere erosion was not associated with outcome within the LURIC cohort. However, strikingly high numbers of stable chromosomal aberrations were found in type 2 diabetic women but not in LURIC disease control subjects or in healthy individuals. Furthermore, within the younger agegroups, deceased type 2 diabetes patients had significantly more marker chromosomes than the surviving type 2 diabetic patients.CONCLUSIONS-All women at high risk for cardiovascular death have accelerated telomere erosion, not caused by type 2 diabetes per se but likely linked to other risk factors, including dyslipidemia. By contrast, the occurrence of marker chromosomes is associated with type 2 diabetes and is a novel risk factor for type 2 diabetes-related early death. Diabetes 57:2950-2957, 2008 T ype 2 diabetes is characterized by increased morbidity and all-cause mortality (1,2). The combination of excess caloric intake and reduced physical activity leading to obesity, dyslipidemia, and hypertension increases the risk for diabetes and coronary heart disease (CHD). Recent data show that among diabetic men, the mortality rate has decreased significantly, whereas in diabetic women, no such trend was found (3). The all-cause mortality rate difference between diabetic and nondiabetic women is considerable. Therefore, the combination of diabetes with multiple risk factors identifies women at particularly high risk (2,4).The relative risk for morbidity and mortality in women with diabetes is increased compared with nondiabetic control subjects (2,5). Diabetes may therefore be regarded as a premature aging syndrome in which the overall metabolic shift leads to genotoxic stress that results in loss of chromosomal integrity (rev. in 6). Oxidative stress plays a crucial role in the pathogenesis of type 2 diabetes and in diabetes-associated complications. The generation of reactive oxygen species (ROS) is a common downstream mechanism whereby multiple by-products of glucose and (pro)inflammatory molecules exert adverse effects (7-11). DNA damage and telomere attrition can serve as marke...

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Section: Discussionmentioning

confidence: 99%

Lymphocytes of Type 2 Diabetic Women Carry a High Load of Stable Chromosomal Aberrations

Boehm

Möller²,

Högel³

et al. 2008

Diabetes

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“…AGE-modified proteins are antigenic and provoke cellular injury responses upon endocytosis by cell-surface receptors. Several MG-derived AGEs have been identified, including N e -(carboxyethyl)-lysine (CEL), MG-lysine dimer (MOLD), argpyrimidine, and 5-methylimidazolone (Bourajjaj et al 2003). Cysteine modification results in the formation of a highly unstable hemithioacetal, which then may be transformed to irreversible AGE-like adducts, a reaction mediated by phosphorylated GLO1 (Van Herreweghe et al 2002).…”

Section: Mg Modification Of Cellular Proteinsmentioning

confidence: 99%

“…Model predications for reversibly bound MG were the sum of cysteine and the initial modification steps for arginine and lysine. Secondary reactions at arginine and lysine residues are effectively irreversible based on the available rate constant data and described secondary structures (Bourajjaj et al 2003).…”

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confidence: 99%

Analysis of Methylglyoxal Metabolism in CHO Cells Grown in Culture

Kingkeohoi

Chaplen

2005

Cytotechnology

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Recent evidence suggests that several unknown or ill-characterized factors strongly influence cell growth and function in culture. Isolating these factors is necessary in order to maximize culture productivities. Methylglyoxal (MG), a potent protein and nucleic acid modifying agent, has been identified as a player in the signaling pathways associated with cell death and is known to be detrimental to cultured cells. This compound is produced in all mammalian systems by spontaneous phosphate elimination from glycolytic pathway intermediates. A kinetic model that qualitatively describes the cellular distribution of proteinassociated MG in the absence of enzymatic adduct formation predicted far lower levels of reversibly bound MG than measured in cultured CHO cells. This suggests that the targeted modification of proteins through enzymatically mediated mechanisms is a significant sink for cellular methylglyoxal. The model was validated with measurements of carbon flux through the glyoxalase pathway to D-lactic acid, a unique end product of MG metabolism in mammalian systems. Fluxes to D-lactic acid of up to 16.8 mmol ml-packed cells À1 day À1 were measured with CHO cells grown in batch culture or 100-fold more than found in normal tissues.

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“…MG is often found at high levels in the blood of diabetic patients, where it covalently depletes glutathione (GSH), leading to serious toxicological effects. In comparison to the parent sugar, MG is more likely to cross-link with the amino groups of various proteins, forming stable end products called advanced glycation end products (AGEs) [1,2] . In addition, MG may modify cross-linked lysine and arginine residues, leading to alterations in the protein characteristics [3] .…”

Section: Introductionmentioning

confidence: 99%

Protective effects of curcumin on methylglyoxal-induced oxidative DNA damage and cell injury in human mononuclear cells

Chan

2006

Acta Pharmacologica Sinica

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Aim: To examine the effect of curcumin on oxidative DNA damage and cell apoptosis and injury caused by the reaction of methylglyoxal(MG) with amino acids. Methods: We used DNA strand breaks to examine the effect of curcumin on oxidative DNA damage. In addition, reactive oxygen species(ROS) formation occurs in MG‐treated mononuclear cells, so the effect of curcumin on ROS generation was measured using 2′,7′‐dichlorofluorescin diacetate(DCF‐DA) as the detection reagent. Moreover, the impact effects of curcumin on MG‐induced cell apoptosis and ROS injury were analyzed by TUNEL and ELISA assay. The collagen I attachment ability of mononuclear cells was examined by trypan blue staining. Results: Our results revealed that curcumin prevented MG/lysine‐induced oxidative stress and DNA damage. Curcumin also inhibited MG‐induced apoptosis and generation of ROS in mononuclear cells. MG‐treated mononuclear cells displayed a lower degree of attachment to collagen (the major component of the vessel wall subendothelium), whereas cells pretreated with curcumin before MG treatment exhibited restored affinities for collagen. Conclusion: These results demonstrated that oxidative stress plays a role in MG‐induced cell injury and alterations in attachment ability, and that curcumin blocks these effects by virtue of its antioxidant properties.

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Role of methylglyoxal adducts in the development of vascular complications in diabetes mellitus

Cited by 99 publications

References 18 publications

Lymphocytes of Type 2 Diabetic Women Carry a High Load of Stable Chromosomal Aberrations

Lymphocytes of Type 2 Diabetic Women Carry a High Load of Stable Chromosomal Aberrations

Analysis of Methylglyoxal Metabolism in CHO Cells Grown in Culture

Protective effects of curcumin on methylglyoxal-induced oxidative DNA damage and cell injury in human mononuclear cells

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