Evidence for an Independent and Cumulative Effect of Postprandial Hypertriglyceridemia and Hyperglycemia on Endothelial Dysfunction and Oxidative Stress Generation

Abstract

Background-Postprandial hypertriglyceridemia and hyperglycemia are considered risk factors for cardiovascular disease.Evidence suggests that postprandial hypertriglyceridemia and hyperglycemia induce endothelial dysfunction through oxidative stress; however, the distinct role of these two factors is a matter of debate. Methods and Results-Thirty type 2 diabetic patients and 20 normal subjects ate 3 different meals: a high-fat meal; 75 g glucose alone; and high-fat meal plus glucose. Glycemia, triglyceridemia, nitrotyrosine, and endothelial function were assayed during the tests. Subsequently, diabetics took 40 mg/d simvastatin or placebo for 12 weeks. The 3 tests were performed again at baseline, between 3 to 6 days after the start, and at the end of each study. High-fat load and glucose alone produced a decrease of endothelial function and an increase of nitrotyrosine in normal and diabetic subjects. These effects were more pronounced when high fat and glucose were combined. Short-term simvastatin treatment had no effect on lipid parameters but reduced the effect on endothelial function and nitrotyrosine observed during each different test. Long-term simvastatin treatment was accompanied by a lower increase in postprandial triglycerides, which was followed by smaller variations of endothelial function and nitrotyrosine during the tests. Conclusions-This study shows an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial function, suggesting oxidative stress as common mediator of such effect. Simvastatin shows a beneficial effect on oxidative stress and endothelial dysfunction, which may be ascribed to a direct effect as well as the lipid-lowering action of the drug.

Effects of S21403 (mitiglinide) on postprandial generation of oxidative stress and inflammation in type 2 diabetic patients

“…However, the effect of the postprandial state, particularly postprandial hyperglycaemia, on CVD is still a matter of debate [21,22]; studies show that postprandial hyperglycaemia is accompanied by an increase of both oxidative stress and inflammatory markers [11][12][13][14][15]. This evidence is supported by findings showing an increase in vivo, during postprandial hyperglycaemia, of both protein kinase C and nuclear factor kappa B, two factors which regulate the generation of oxidative stress and inflammation [23,24].…”

“…the imbalance between free-radical production and antioxidant defence [8,9], and inflammation [10] are involved in the pathogenesis of CVD in diabetes mellitus. Postprandial generation of both oxidative stress [11][12][13] and inflammation [13][14][15] has been demonstrated in type 2 diabetic patients. However, it is still unclear whether this phenomenon can be controlled in clinical practice by modulating postprandial hyperglycaemia.…”

Effects of glucose tolerance on the changes provoked by glucose ingestion in microvascular function

“…The well-established tenet that acute hyperglycaemia impairs endothelial function is mainly based on in vitro studies using pharmacological (22 mmol/l or higher) concentrations of glucose [12,13] without insulin or on ex vivo studies using experimental animal models characterised by severe hyperglycaemia [14,15,37,38]. In humans, support for this notion derives mostly from studies using the OGTT as the stimulus, and flow-mediated dilatation of large arteries as the index of endothelial function [23][24][25]. Rather surprisingly, the results of these studies are not consistent [17,19] despite the fact that hyperinsulinaemia itself has been claimed to have a selective, major negative effect on this segment of the vascular tree [39,40].…”

“…With regard to the acute effect of hyperglycaemia on endothelium-dependent vasodilatation (EDV), conflicting results have been reported in vivo in humans, with some describing a neutral or a very mild and short-lasting effect [16][17][18][19][20][21] and others a negative impact [22][23][24][25][26]. Part of this heterogeneity can be ascribed to differences in the vascular district investigated (large, small or micro-vessels), the experimental technique adopted and the stimulus applied.…”

Diabetic dyslipidaemia: from basic research to clinical practice*

“…A number of studies have shown that postprandial lipemia is linked with the endothelial dysfunction and generation of oxidative stress in Type 2 diabetic patients [92,93,94,95]. Remnant particles particularly cholesterol ester rich remnants are considered to be highly atherogenic [8,9,78,85,86].…”