Impairment of glutathione metabolism in erythrocytes from patients with diabetes mellitus

Murakami, Kazuhiro; Kondo, Takahito; Ohtsuka, Yoshinori; Fujiwara, Yutaka; Shimada, Michiro; Kawakami, Yoshikazu

doi:10.1016/0026-0495(89)90061-9

Cited by 245 publications

(140 citation statements)

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“…As previously shown by other authors, antioxidant defences were lower depending on the type of diabetes. For example, glutathione was lower in both types of diabetes (Murakami et al, 1989), but ascorbate was lower only in T2DM (Sinclair et al, 1991). Retinol and plasma total antioxidant capacity, which is predominantly determined by uric acid, were lower only in T1DM (Tsai et al, 1994).…”

Section: Discussionmentioning

confidence: 92%

“…Hyperglycaemia results in glucose auto-oxidation, nonenzymatic glycation and monocyte dysfunction, which lead to increased production of free radicals (Hiramatsu & Arimori, 1988;Hunt et al, 1990;Mullarkey et al, 1990;Brownlee, 1994). This is further aggravated by the decreased levels of antioxidants (Murakami et al, 1989;Jain et al, 1991;Sinclair et al, 1991) and leads to oxidative damage, illustrated by the high levels of lipid and DNA peroxidation products found in these patients (Griesmacher et al, 1995;Dandona et al, 1996). All these diabetes-related abnormalities can intensify the endothelial dysfunction, oxidation of LDL and foam cell formation, which ultimately lead to the formation of the atheroma plaque (Ross, 1993).…”

Section: Introductionmentioning

confidence: 99%

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Oxidative stress status in patients with diabetes mellitus: relationship to diet

et al. 2003

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Objective: To investigate the relationship between dietary intakes and in vivo oxidative stress (OS) status in diabetic patients. Design: Case-control study. Setting: Outpatient-Clinic and Laboratory Endocrinology, University Antwerp. Subjects and methods: A total of 30 patients (24 type 1 diabetes mellitus (T1DM)/6 type 2 diabetes mellitus (T2DM) were asked to complete a 2 weekdays+1weekend day food consumption questionnaire during the week preceding their yearly diabetes control consultation, when samples were collected for the assay of oxidative stress (OS) (blood levels of antioxidants, peroxides, malondialdehyde (MDA) and minerals). Blood samples were also collected from 25 age-and sex-matched healthy controls. Results: Diabetic patients had lower glutathione (5.8071.15 vs 6.7571.03 mmol/g Hb in the controls, P ¼ 0.002) and higher MDA (0.68770.212 vs 0.54570.101 mmol/l, P ¼ 0.002). Although the group average intakes were within the Belgian RDA, intakes of fat 435% energy, fibre o15 g/1000 kcal, fruit o2 portions and vitamin E o10 mg/day were seen in more than 20 patients. Blood antioxidants did not correlate with intakes of energy, fat, protein or fibres or of their respective antioxidant. Vitamins A and E correlated with serum lipids (r ¼ 0.58, P o0.0005 between serum a-tocopherol and cholesterol). Blood peroxide levels were only related to intakes of saturated fat and cholesterol (Po0.05). In diabetic subjects but not in controls (Po0.05) MDA was related to glutathione and uric acid. Conclusions: In diabetic patients, blood levels of antioxidants are not related to their dietary intakes but to serum lipids. Levels of oxidative damage products are only related to intakes of saturated fats and cholesterol and to levels of endogenous antioxidants.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Oxidative stress status in patients with diabetes mellitus: relationship to diet

et al. 2003

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“…We have also reported that decreasing intraislet GSH levels by the GCL inhibitor buthionine sulfoximine augments the adverse effects of ROS on beta cell function (6). These observations are clinically relevant because decreases in GSH levels or the ratio of reduced to oxidized glutathione (GSH/GSSG) measured in the red blood cells of type 2 diabetic patients correlate with worsening of the diabetic state (11)(12)(13).…”

mentioning

confidence: 87%

Adenoviral Overexpression of the Glutamylcysteine Ligase Catalytic Subunit Protects Pancreatic Islets against Oxidative Stress

Tran

Parker

Leroy

et al. 2004

Journal of Biological Chemistry

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The catalytic subunit of glutamylcysteine ligase (GCLC) primarily regulates de novo synthesis of glutathione (GSH) in mammalian cells and is central to the antioxidant capacity of the cell. However, GCLC expression in pancreatic islets has not been previously examined. We designed experiments to ascertain whether GCLC is normally expressed in islets and whether it is up-regulated by interleukin-1␤ (IL-1␤). GCLC expression levels were intermediate compared with other metabolic tissues (kidney, liver, muscle, fat, and lung). IL-1␤ up-regulated GCLC expression (10 ng/ml IL-1␤, 3.76 ؎ 0.86; 100 ng/ml IL-1␤, 4.22 ؎ 0.68-fold control) via the p38 form of mitogen-activated protein kinase and NF B and also increased reactive oxygen species levels (10 ng/ml IL-1␤, 5.41 ؎ 1.8-fold control). This was accompanied by an increase in intraislet GSH/GSSG ratio (control, 7.1 ؎ 0.1; 10 ng/ml IL-1␤, 8.0 ؎ 0.5; 100 ng/ml IL-1␤, 8.2 ؎ 0.5-fold control; p < 0.05). To determine whether overexpression of GCLC increases the antioxidant capacity of the islet and prevents the adverse effects of IL-1␤ on glucose-induced insulin secretion, islets were infected with an adenovirus encoding GCLC. IL-1␤ significantly decreased glucose-stimulated insulin secretion (control, 123.8 ؎ 17.7; IL-1␤, 40.2 ؎ 3.9 microunits/ml insulin/islet). GCLC overexpression increased intraislet GSH levels and partially prevented the decrease in glucose-stimulated insulin secretion caused by IL-1␤. These data provide the first report of GCLC expression in the islet and demonstrate that adenoviral overexpression of GCLC increases intracellular GSH levels and protects the beta cell from the adverse effects of IL-1␤.Glutamylcysteine ligase (GCL) 1 is the primary and ratelimiting enzyme responsible for de novo synthesis of intracellular glutathione (GSH). This enzyme catalyzes ATP-dependent ligation of L-glutamate and L-cysteine to form ␥-glutamyl-L-cysteine, which undergoes another ATP-dependent ligation with glycine catalyzed by glutathione synthetase to form the final GSH product (1, 2). GCL is a heterodimer, composed of a light regulatory subunit as well as a heavy catalytic subunit. Although both are required for optimal enzyme activity, overexpression of the catalytic subunit GCLC alone is sufficient to increase enzyme activity significantly over control levels (1). The regulation of GCL expression and activity has been studied in many other cell types, including mesangial and endothelial cells, but not the pancreatic islet. Long term exposure to high glucose levels decreases GCL expression in mesangial, retinal Muller, and endothelial cells, which results in a decrease in GSH levels (3-5). Long term exposure to high glucose conditions inhibits endothelial cells from responding to cytokine exposure with an increase in GCL expression and activity (3). That the pathogenesis of diabetes mellitus involves interactions with IL-1␤ and oxidative stress secondary to chronic hyperglycemia (6, 7) raises the questions of whether GCL is normally expressed in the islet and whe...

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“…As expected, studies of blood samples are the most commonly reported regarding the study of oxidative changes. Early reports described that glutathione metabolism was impaired in erythrocytes from patients with diabetes mellitus (Murakami et al, 1989). Decreased levels of GSH and increased levels of GSSG were found.…”

Section: S-glutathionylation In Diabetic Patientsmentioning

confidence: 99%

S-glutathionylation: relevance in diabetes and potential role as a biomarker

Sánchez‐Gómez

Espinosa‐Díez

Dubey

et al. 2013

Biological Chemistry

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Glutathione is considered the main regulator of redox balance in the cellular milieu due to its capacity for detoxifying deleterious molecules. The oxidative stress induced as a result of a variety of stimuli promotes protein oxidation, usually at cysteine residues, leading to changes in their activity. Mild oxidative stress, which may take place in physiological conditions, induces the reversible oxidation of cysteines to sulfenic acid form, while pathological conditions are associated with higher rates of reactive oxygen species production, inducing the irreversible oxidation of cysteines. Among these, neurodegenerative disorders, cardiovascular diseases and diabetes have been proposed to be pathogenetically linked to this state. In diabetes-associated vascular complications, lower levels of glutathione and increased oxidative stress have been reported. S-glutathionylation has been proposed as a posttranslational modification able to protect proteins from over-oxidizing environments. S-glutathionylation has been identified in proteins involved in diabetic models both in vitro and in vivo. In all of them, S-glutathionylation represents a mechanism that regulates the response to diabetic conditions, and has been described to occur in erythrocytes and neutrophils from diabetic patients. However, additional studies are necessary to discern whether this modification represents a biomarker for the early onset of diabetic vascular complications.

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Impairment of glutathione metabolism in erythrocytes from patients with diabetes mellitus

Cited by 245 publications

References 19 publications

Oxidative stress status in patients with diabetes mellitus: relationship to diet

Oxidative stress status in patients with diabetes mellitus: relationship to diet

Adenoviral Overexpression of the Glutamylcysteine Ligase Catalytic Subunit Protects Pancreatic Islets against Oxidative Stress

S-glutathionylation: relevance in diabetes and potential role as a biomarker

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