Glucose toxicity in the vascular complications of diabetes: The cellular perspective

Lorenzi, Mara

doi:10.1002/dmr.5610080202

Cited by 86 publications

(50 citation statements)

References 156 publications

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“…The observation that GFAT expression is increased in the mesangium of biopsies from patient with diabetic nephropathy [5] provides further support to the notion that individual rates of GFAT activity could participate in the susceptibility to the development and/or progression of nephropathy in people with diabetes. It is possible that increased rates of intracellular hexosamine production and/or accumulation represent one of the mechanisms of glucose toxicity for the diabetic glomerulus [24,25]. We found that activation of the diated p38-MAPK activation respectively by 75% and 50% (Fig.…”

Section: Discussionmentioning

confidence: 64%

“…High glucose enhances the effect of GFAT overexpression on UDP-NAG cellular concentrations, p38-MAPK activation, and TGFβ1 expression. Hexosamine accumulation could be one of the intracellular mechanisms for glucose toxicity and activation of the HBP is likely to play an important role in the pathophysiology of renal and possibly other vascular complications of diabetes [24,25].…”

Section: Discussionmentioning

confidence: 99%

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P38 mitogen-activated protein kinase mediates hexosamine-induced TGFβ1 mRNA expression in human mesangial cells

et al. 2003

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Aims/hypothesis. The hexosamine pathway has been implicated in the induction of TGFβ1 expression and in the pathophysiology of diabetic glomerulopathy. Glucose-induced TGFβ1 expression is mediated by p38 mitogen-activated-protein-kinase (p38-MAPK) and this kinase is activated in the diabetic glomeruli. We examined whether the p38-MAPK is implicated in hexosamine-induced TGFβ1 mRNA expression in human mesangial cells. Methods. The products of the hexosamine biosynthetic pathway were increased by the addition of glucosamine or by the overexpression of the rate-limiting enzyme of the hexosamine pathway, glutamine: fructose-6-phosphate amidotransferase (GFAT).Results. Glucosamine addition resulted in cell death. UDP-N-Acetylglucosamine, one of the major hexosamine end-products, was increased in normal (7 mmol/l) and high (25 mmol/l) glucose conditions in GFAT-transfected cells compared to control transfected cells by twofold and 1.7-fold respectively (p≤0.04) and this was accompanied by a 1.6-and 2.3-fold increase (p≤0.02) in TGFβ1 mRNA expression. Addition of the GFAT inhibitor azaserine (10 µmol/l) prevented the induction of TGFβ1 in GFAT transfected cells. GFAT overexpression induced an increase in p38-MAPK activation after 6 and 12 h incubation in normal glucose, and this was prevented by the GFAT inhibitor azaserine. Furthermore, high glucose enhanced p38-MAPK activation in GFAT tranfected cells (p≤0.04). P38-MAPK inhibition using SB202190 (1 µmol/l) reduced hexosamine-induced TGFβ1 expression in normal and high glucose. The activation of the p38-MAPK was dependent on protein kinase-C. Conclusion/interpretation. Overexpression of GFAT increases hexosamine accumulation which mediates TGFβ1 expression via a protein kinase-C and p38-MAPK dependent mechanism. Increased glucose concentrations magnify these effects. [Diabetologia (2003) 46:531-537]

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

P38 mitogen-activated protein kinase mediates hexosamine-induced TGFβ1 mRNA expression in human mesangial cells

et al. 2003

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“…Studies using longterm treatment of well-specified arsenic species are necessary for future conclusions. Arsenicinduced oxidative stress, mainly through the depletion of glutathione (Suzuki et al 2001), has been proposed to cause both insulin resistance and atherosclerosis (del Razo et al 2001), and the latter may be profound in hyperglycemia or diabetic states (Curcio and Ceriello 1992;Lorenzi 1992).…”

Section: Discussionmentioning

confidence: 99%

Prevalence of non-insulin-dependent diabetes mellitus and related vascular diseases in southwestern arseniasis-endemic and nonendemic areas in Taiwan.

Wang

Chiou

Chen

et al. 2003

Environ Health Perspect

138

111

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There is evidence indicating that ingestion of arsenic may predispose the development of diabetes mellitus in arsenic-endemic areas in Taiwan. However, the prevalence of diabetes and related vascular diseases in the entire southwestern arseniasis-endemic and nonendemic areas remains to be elucidated. We used the National Health Insurance Database for 1999-2000 to derive the prevalence of non-insulin-dependent diabetes and related vascular diseases by age and sex among residents in southwestern arseniasis-endemic and nonendemic areas in Taiwan. The study included 66,667 residents living in endemic areas and 639,667 in nonendemic areas, all ≥ 25 years of age. The status of diabetes and vascular diseases was ascertained through disease diagnosis and treatment prescription included in the reimbursement claims of clinics and hospitals. The prevalence of non-insulin-dependent diabetes, age-and gender-adjusted to the general population in Taiwan, was 7.5% (95% confidence interval, 7.4-7.7%) in the arseniasis-endemic areas and 3.5% (3.5-3.6%) in the nonendemic areas. Among both diabetics and nondiabetics, higher prevalence of microvascular and macrovascular diseases was observed in arseniasis-endemic than in the nonendemic areas. Age-and gender-adjusted prevalence of microvascular disease in endemic and nonendemic areas was 20.0% and 6.0%, respectively, for diabetics, and 8.6% and 1.0%, respectively, for nondiabetics. The corresponding prevalence of macrovascular disease was 25.3% and 13.7% for diabetics, and 12.3% and 5.5% for nondiabetics. Arsenic has been suggested to increase the risk of non-insulin-dependent diabetes mellitus and its related micro-and macrovascular diseases.

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“…High ambient glucose has been shown to affect endothelial and other vascular cells [6], such as is shown by the induction of apoptosis in cultured endothelial cells [7] and endothelial dysfunction in vivo [8]. Dysfunction of vascular smooth muscle cells (VSMC) is also known to occur in diabetes.…”

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confidence: 99%

The effects of glucose-induced oxidative stress on growth and extracellular matrix gene expression of vascular smooth muscle cells

et al. 1998

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Diabetes mellitus is a major risk factor for atherosclerosis. In population based studies diabetes is associated with an increased incidence of coronary heart disease [1], cerebrovascular disease and peripheral vascular disease [2]. The high prevalence of macrovascular disease is partly explained by the increased frequency of conventional risk factors and partly by risk factors specific for diabetes including hyperglycaemia, hyperinsulinaemia and dyslipidaemia. The view that diabetic vasculopathy is, at least in part, related to excess free radicals is supported by evidence such as increased lipid peroxidation [3] and reduced antioxidant reserve in patients with diabetes [4] and from studies showing a direct cytotoxic effect of free Diabetologia (1998) Summary Vascular smooth muscle cell (VSMC) dysfunction plays a role in diabetic macrovasculopathy and this may include abnormalities in growth characteristics and the extracellular matrix. As the actual mechanisms by which glucose induces VSMC dysfunction remain unclear, the aim of this study was to assess the potential role of glucose-induced oxidative stress. Porcine aortic VSMCs were cultured for 10 days in either 5 mmol/l normal glucose or 25 mmol/l D-glucose (high glucose). There was evidence of oxidative stress as indicated by a 50 % increase in intracellular malondialdehyde (p < 0.05), increased mRNA expression of CuZn superoxide dismutase and Mn superoxide dismutase (by 51 % and 37 % respectively, p < 0.01) and a 50 % decrease in glutathione in 25 mmol/l D-glucose (p < 0.001). Growth was increased by 25.0 % (p < 0.01). mRNA expression of extracellular matrix proteins (collagens I, III, IV and fibronectin) was not altered by high glucose in these experimental conditions. Repletion of glutathione with N-acetyl L-cysteine (1 mmol/l) in VSMC grown in high glucose was associated with reduction in malondialdehyde and restored growth to that of normal glucose. The water soluble analogue of vitamin E, Trolox (200 mmol/l), reduced malondialdehyde concentrations, but had no effect on glutathione depletion or the increased growth rate seen with high glucose. The addition of buthionine sulphoximine (10 mmol/l) to VSMC cultured in normal glucose reduced glutathione, increased malondialdehyde and increased growth to a similar extent as that found in high glucose alone. These results suggest that thiol status, rather than lipid peroxides, is a key factor in modulating VSMC growth and that mRNA expression of extracellular matrix proteins is not increased in VSMC under conditions of glucose-induced oxidative stress. [Diabetologia (1998

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Glucose toxicity in the vascular complications of diabetes: The cellular perspective

Cited by 86 publications

References 156 publications

P38 mitogen-activated protein kinase mediates hexosamine-induced TGFβ1 mRNA expression in human mesangial cells

P38 mitogen-activated protein kinase mediates hexosamine-induced TGFβ1 mRNA expression in human mesangial cells

Prevalence of non-insulin-dependent diabetes mellitus and related vascular diseases in southwestern arseniasis-endemic and nonendemic areas in Taiwan.

The effects of glucose-induced oxidative stress on growth and extracellular matrix gene expression of vascular smooth muscle cells

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