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

Abstract

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

Insulin enhances vascular cell adhesion molecule-1 expression in human cultured endothelial cells through a pro-atherogenic pathway mediated by p38 mitogen-activated protein-kinase

“…Previous reports have shown that insulin can increase rolling and adhesion of monocytes to endothelial cells when pretreated with the PI3′-kinase inhibitor wortmannin, but the dependence of this on VCAM-1 had not been tested [8]. One report also described activation of the transcription factor nuclear factor-κB by insulin (consistent with our findings), but not the transcriptional activation of VCAM-1 in endothelial cells exposed to insulin [10], the latter possibly because lower-sensitivity techniques were used. Using a rotational adhesion assay we found that insulin per se (or even more together with PI3′-kinase inhibition by wortmannin) increases monocytoid cell adhesion, an effect related to the increase in VCAM-1 since largely inhibited by the blocking anti-VCAM-1 E1/6 antibody.…”

Relation Between Soluble Adhesion Molecules and Insulin Sensitivity in Type 2 Diabetic Individuals

“…This notion raises the possibility that the increased plasma levels of adhesion molecules found in obesity, dyslipidemia, hypertension, and type 2 diabetes are somehow related to insulin resistance and/or compensatory hyperinsulinemia. However, acute insulin infusion does not change plasma levels of adhesion molecules in both healthy subjects (9,10) and type 2 diabetic patients (11). This finding supports the conclusion that insulin resistance, rather than hyperinsulinemia, may be a factor contributing to the increased plasma levels of adhesion molecules in the clinical conditions mentioned above (12).…”

The change of serum tumor necrosis factor alpha in patients with type 1 diabetes mellitus: A systematic review and meta-analysis

“…TNF-α, through increasing the activities of the NF-κB transcriptional factor [56, 57], protein kinase C [58], amino terminal kinase and inhibitor kinase, could cause serine/threonine phosphorylation of the insulin receptor substrate, interfere with normal phosphorylation of tyrosine, and weaken signal transduction of insulin, resulting in insulin resistance [36], otherwise, TNF-α may be result in the destruction of pancreatic beta cells and lead to the development of T1DM [59]. …”