Reduction of oxidative stress by oral N-acetyl-L-cysteine treatment decreases plasma soluble vascular cell adhesion molecule-1 concentrations in non-obese, non-dyslipidaemic, normotensive, patients with non-insulin-dependent diabetes

Mattia, G. De; Bravi, M.; Laurenti, O.; Cassone-Faldetta, M.; Proietti, A.; Luca, Ottavia De; Armiento, A.; Ferri, Claudio

doi:10.1007/s001250051082

Cited by 89 publications

(58 citation statements)

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“…The risk increase did not vary with time. In accordance with previous studies, we showed sVCAM-1 levels to be significantly associated with male sex, age, fasting insulin levels, vWF level, the presence of type 2 diabetes, hypertension, and microalbuminuria, and, inversely, with levels of total, LDL, and HDL cholesterol and estimates of glomerular filtration rate (18,(20)(21)(22)27,37). These variables, however, did not materially affect the association between sVCAM-1 levels and risk of cardiovascular mortality (Ta b l e 3).…”

Section: Discussionsupporting

confidence: 92%

Increased levels of soluble vascular cell adhesion molecule 1 are associated with risk of cardiovascular mortality in type 2 diabetes: the Hoorn study.

et al. 2000

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Membrane-bound vascular cell adhesion molecule 1 (VCAM-1) allows the tethering and rolling of monocytes and lymphocytes as well as firm attachment and transendothelial migration of leukocytes. Soluble forms of VCAM (sVCAM-1) may serve as monitors of increased expression of membrane-bound VCAM-1 and thus may reflect progressive formation of atherosclerotic lesions. Levels of sVCAM-1 have been found to be increased among type 2 diabetic as compared with nondiabetic subjects. To study the association of plasma sVCAM-1 concentration and risk of cardiovascular and all-cause mortality among nondiabetic and diabetic subjects, we investigated an age-, sex-, and glucose-tolerance-stratified sample (n = 631) of a populationbased cohort aged 50-75 years that was followed p r o s p e c t i v e l y. Plasma levels of sVCAM-1 were determined in frozen -70°C baseline samples. After 7.4 years (mean) of follow-up, 107 (17%) subjects had died ( 4 2 of cardiovascular causes). In the entire group, increased sVCAM-1 levels were significantly associated with increased risk of cardiovascular mortality (relative risks [RRs] per 100 ng/ml sVCAM-1 increase, 1.10 [1.05-1.15] after adjustment for age, sex, and glucose tolerance status). This RR was somewhat diminished by further adjustment for the presence of hypertension and cardiovascular disease; levels of total, HDL, and LDL cholesterol and homocysteine; the presence of microalbuminuria (a putative marker of endothelial dysfunction); levels of von Willebrand factor (a marker of endothelial dysfunction) and C-reactive protein (a marker of low-grade inflammation); and estimates of glomerular filtration rate. However, the RR remained statistically significant. The RR among type 2 diabetic subjects was 1.13 (1.07-1.20) per 100 ng/ml sVCAM-1 increase after adjustment for age and sex, which was somewhat higher but not significantly different from the RR in nondiabetic subjects (P value for interaction term, 0.12). Further adjustment for other risk factors gave similar results. In conclusion, levels of sVCAM-1 are independently associated with the risk of cardiovascular mortality in type 2 diabetic subjects and therefore might be useful for identifying subjects at increased cardiovascular risk. Increased plasma sVCAM-1 levels may reflect progressive formation of atherosclerotic lesions, or sVCAM-1 itself may have bioactive properties related to cardiovascular risk. Our data, however, argue against the hypotheses of sVCAM-1 levels simply being a marker of endothelial dysfunction, of low-grade inflammation, or of an impaired renal function. D i a b e t e s 4 9 :4 8 5-491, 2000

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Section: Discussionsupporting

confidence: 92%

Increased levels of soluble vascular cell adhesion molecule 1 are associated with risk of cardiovascular mortality in type 2 diabetes: the Hoorn study.

et al. 2000

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“…Further, plasma soluble VCAM-1 negatively correlated with intraerythrocytic glutathione concentrations and decreased after N-acetyl-l-cysteine was given orally [8]. Therefore, the current findings support the previous hypothesis [8] that an early up regulation of VCAM-1 is present in non-insulin-dependent diabetic patients due to increased oxidative stress rather than hyperinsulinaemia.…”

Section: Discussionsupporting

confidence: 87%

“…Consistent with this interpretation, increased plasma soluble VCAM-1 concentrations, that were unrelated to fasting insulin concentrations, have already been described in noninsulin-dependent [8] and insulin-dependent diabetic patients [9]. Further, plasma soluble VCAM-1 negatively correlated with intraerythrocytic glutathione concentrations and decreased after N-acetyl-l-cysteine was given orally [8]. Therefore, the current findings support the previous hypothesis [8] that an early up regulation of VCAM-1 is present in non-insulin-dependent diabetic patients due to increased oxidative stress rather than hyperinsulinaemia.…”

Section: Discussionsupporting

confidence: 78%

“…Despite these latter patients being greatly hyperinsulinaemic, insulin was not responsible for the observed endothelial activation, as indicated by the lack of effects of insulin infusion on plasma soluble VCAM-1 concentrations. Consistent with this interpretation, increased plasma soluble VCAM-1 concentrations, that were unrelated to fasting insulin concentrations, have already been described in noninsulin-dependent [8] and insulin-dependent diabetic patients [9]. Further, plasma soluble VCAM-1 negatively correlated with intraerythrocytic glutathione concentrations and decreased after N-acetyl-l-cysteine was given orally [8].…”

Section: Discussionsupporting

confidence: 73%

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Effects of insulin on in vitro vascular cell adhesion molecule-1 expression and in vivo soluble VCAM-1 release

et al. 1999

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Although hyperinsulinaemia is an independent risk factor for the development of atherosclerotic lesions [1], mechanisms underlying the atherogenetic actions of insulin are largely unclear. Recent studies have shown that insulin exerts various endothelial effects, such as an increase of endothelin-1 and nitric oxide production [2]. These findings are of particular relevance and suggest insulin might also exert other endothelial effects which, in turn, could trigger and maintain the atherogenetic process.In this context, vascular cell adhesion molecule(VCAM)-1 is an endothelial adhesin whose up regulation is the most important initiating event in atheroma formation [3]. In spite of this, whether or not insulin might influence VCAM-1 expression by the human vascular endothelium is notknown. Diabetologia (1999) Methods. Human vascular endothelial cells derived from umbilical cord veins were incubated with either insulin (from 10 ±6 to 10 ±9 mol/l) or tumour necrosis factor-a (5 ng/ml) for 6 to 24 h. Plasma soluble vascular cell adhesion molecule-1 concentrations were evaluated in 12 non-insulin-dependent diabetic patients (8 men, 4 women, mean age 47.1 ± 7.7 years) and 12 healthy volunteers matched for age, sex and weight (7 men, 5 women, mean age 42.2 ± 7.2 years) before and after a 2-h euglycaemic hyperinsulinaemic clamp. Results. Transcriptional activities of nuclear factor-kB luciferase and vascular adhesion molecule-1 luciferase statistically significantly increased after incubation with tumour necrosis factor-a. By contrast, a slight increment of nuclear factor-kB luciferase (mean: 1.8 ± 0.3 fold) but not of vascular cell adhesion molecule-1 luciferase transcriptional activities were detected in cells stimulated with insulin. Soluble vascular cell adhesion molecule-1 concentrations in cell supernatants increased after tumour necrosis factor-a but not insulin stimulation. In vivo, baseline plasma soluble vascular cell adhesion molecule-1 concentrations were higher (p = 0.03) in non-insulin-dependent patients (708.7 ± 97.4 mg/l) than controls (632.1 ± 65.2 mg/l) but were not related to fasting insulin concentrations and did not change during insulin infusion. Conclusion/interpretation. The increased concentrations of circulating soluble vascular cell adhesion molecule-1 indicates that the vascular endothelium is activated in non-insulin dependent diabetic patients. Our in vitro and in vivo findings show that vascular cell adhesion molecule-1 activation cannot be due to hyperinsulinaemia. [Diabetologia (1999

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“…Glycosylated hemoglobin concentrations are associated with reduced total plasma antioxidant trapping capacity in patients with type 2 diabetes (23), a finding consistent with the concept that clinically relevant hyperglycemia increases oxidative stress. However, antioxidant treatment (N-acetyl-L-cysteine) has decreased sVCAM-1 levels in one study (28), although it has not been possible to decrease sE-selectin or sVCAM-1 levels by tomato juice (29), ␣-tocopherol (29), or gliclazide (30). Because treatment of hyperglycemia has reduced sE-selectin levels in three studies (7,10; present study), it could be considered a better tool than antioxidants to lower sE-selectin concentrations in type 2 diabetes.…”

Section: Resultsmentioning

confidence: 88%

Improvement of Glycemic Control by 1 Year of Insulin Therapy Leads to a Sustained Decrease in sE-Selectin Concentrations in Type 2 Diabetes

Ryysy

Yki‐Järvinen

2001

Diabetes Care

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OBJECTIVE -To examine whether and how improvement of glycemic control by long-term insulin therapy decreases endothelial activation as measured by serum levels of the soluble adhesion molecules sE-selectin and vascular cell adhesion molecule (VCAM-1) and whether the drug used to lower blood glucose in addition to insulin influences such a response.RESEARCH DESIGN AND METHODS -Circulating adhesion molecules were measured before and after 3 and 12 months of therapy in 81 patients with type 2 diabetes and 41 subjects without diabetes. The patients were treated with bedtime administration of NPH insulin combined with either glibenclamide (n ϭ 19), metformin (n ϭ 17), glibenclamide and metformin (n ϭ 17), or morning administration of NPH insulin (n ϭ 23).RESULTS -Before insulin therapy, serum sE-selectin level was 71% higher in the patients with type 2 diabetes (77 Ϯ 4 ng/ml) than in the normal subjects (45 Ϯ 3 ng/ml, P Ͻ 0.001), whereas levels of sVCAM-1 were comparable (420 Ϯ 25 vs. 400 Ϯ 11 ng/ml, respectively). Glycemic control in all patients improved as judged from a decrease in HbA 1c from 9.7 Ϯ 0.2 to 7.6 Ϯ 0.1% (P Ͻ 0.001). sE-selectin decreased to 67 Ϯ 4 ng/ml by 3 months (P Ͻ 0.001 vs. 0 months) and then remained unchanged until 12 months (70 Ϯ 4 ng/ml, P Ͻ 0.001 vs. 0 months). sVCAM-1 levels at 12 months was similar to those at 0 months (416 Ϯ 25 ng/ml). The change in glycemic control, measured by HbA 1c , but not in other parameters, was correlated with the change of sE-selectin (r ϭ 0.41, P Ͻ 0.001) within the patients with type 2 diabetes. The decreases in sE-selectin were not different between the various treatment groups.CONCLUSIONS -We conclude that improvement in glycemic control by administration of insulin alone or insulin combined with either glibenclamide, metformin, or both agents induces a sustained decrease in sE-selectin, the magnitude of which seems to be dependent on the degree of improvement in glycemia. These data suggest that sE-selectin might provide a marker of effects of treatment of chronic hyperglycemia on endothelial activation. Diabetes Care 24:549 -554, 2001H yperglycemia promotes leukocyte adhesion to endothelial cells through upregulation of cell-surface expression of E-selectin, intercellular adhesion molecule (ICAM-1), and vascular cell adhesion molecule (VCAM-1) (1). Stimulation of endothelial cells with glycated albumin (advanced glycation end product/bovine serum albumin) also increases expression of these adhesion molecules (1,2), which can be detected in soluble (3) forms (sE-selectin, sICAM-1, and sVCAM-1) in the circulation (4,5). In patients with type 2 diabetes, concentrations of serum sE-selectin, which is expressed exclusively on endothelial cells, have been increased in most (3,6 -11) but not all (12,13) comparisons and have correlated with glycemia in five studies (6 -10). Serum sICAM-1 concentrations have been increased in most comparisons between groups of patients with type 2 diabetes and normal subjects (8,9,(11)(12)(13)(14). A positive correlation with gly...

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Reduction of oxidative stress by oral N-acetyl-L-cysteine treatment decreases plasma soluble vascular cell adhesion molecule-1 concentrations in non-obese, non-dyslipidaemic, normotensive, patients with non-insulin-dependent diabetes

Cited by 89 publications

References 20 publications

Increased levels of soluble vascular cell adhesion molecule 1 are associated with risk of cardiovascular mortality in type 2 diabetes: the Hoorn study.

Increased levels of soluble vascular cell adhesion molecule 1 are associated with risk of cardiovascular mortality in type 2 diabetes: the Hoorn study.

Effects of insulin on in vitro vascular cell adhesion molecule-1 expression and in vivo soluble VCAM-1 release

Improvement of Glycemic Control by 1 Year of Insulin Therapy Leads to a Sustained Decrease in sE-Selectin Concentrations in Type 2 Diabetes

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