Alfons J. H. M. Houben

Endothelial dysfunction in (pre)diabetes: Characteristics, causative mechanisms and pathogenic role in type 2 diabetes

Endothelial dysfunction associated with diabetes and cardiovascular disease is characterized by changes in vasoregulation, enhanced generation of reactive oxygen intermediates, inflammatory activation, and altered barrier function. These endothelial alterations contribute to excess cardiovascular disease in diabetes, but may also play a role in the pathogenesis of diabetes, especially type 2. The mechanisms underlying endothelial dysfunction in diabetes differ between type 1 (T1D) and type 2 diabetes (T2D): hyperglycemia contributes to endothelial dysfunction in all individuals with diabetes, whereas the causative mechanisms in T2D also include impaired insulin signaling in endothelial cells, dyslipidemia and altered secretion of bioactive substances (adipokines) by adipose tissue. The close association of so-called perivascular adipose tissue with arteries and arterioles facilitates the exposure of vascular endothelium to adipokines, particularly if inflammation activates the adipose tissue. Glucose and adipokines activate specific intracellular signaling pathways in endothelium, which in concert result in endothelial dysfunction in diabetes. Here, we review the characteristics of endothelial dysfunction in diabetes, the causative mechanisms involved and the role of endothelial dysfunction(s) in the pathogenesis of T2D. Finally, we will discuss the therapeutic potential of endothelial dysfunction in T2D.

Microvascular Dysfunction Is Associated With a Higher Incidence of Type 2 Diabetes Mellitus A Systematic Review and Meta-Analysis

Objective—Recent data support the hypothesis that microvascular dysfunction may be a potential mechanism in the development of insulin resistance. We examined the association of microvascular dysfunction with incident type 2 diabetes mellitus (T2DM) and impaired glucose metabolism by reviewing the literature and conducting a meta-analysis of longitudinal studies on this topic. Methods and Results—We searched Medline and Embase for articles published up to October 2011. Prospective cohort studies that focused on microvascular measurements in participants free of T2DM at baseline were included. Pooled relative risks were calculated using random effects models. Thirteen studies met the inclusion criteria for this meta-analysis. These studies focused on T2DM or impaired fasting glucose, not on impaired glucose tolerance. The pooled relative risks for incident T2DM (3846 cases) was 1.25 (95% confidence interval, 1.15; 1.36) per 1 SD greater microvascular dysfunction when all estimates of microvascular dysfunction were combined. In analyses of single estimates of microvascular dysfunction, the pooled relative risks for incident T2DM was 1.49 (1.36; 1.64) per 1 SD higher plasma soluble E-selectin levels; 1.21(1.11; 1.31) per 1 SD higher plasma soluble intercellular adhesion molecule-1 levels; 1.48 (1.03; 2.12) per 1 SD lower response to acetylcholine-mediated peripheral vascular reactivity; 1.18 (1.08; 1.29) per 1 SD lower retinal arteriole-to-venule ratio; and 1.43 (1.33; 1.54) per 1 logarithmically transformed unit higher albumin-to-creatinine ratio. In addition, the pooled relative risks for incident impaired fasting glucose (409 cases) was 1.15 (1.01–1.31) per 1 SD greater retinal venular diameters. Conclusion—These data indicate that various estimates of microvascular dysfunction were associated with incident T2DM and, possibly, impaired fasting glucose, suggesting a role for the microcirculation in the pathogenesis of T2DM.

Neural activity of the cardiac baroreflex decreases with age in normotensive and hypertensive subjects.

Objectives Baroreflex control of the heart rate is impaired in hypertensive subjects and decreases with age. The decrease in cardiac baroreflex sensitivity (BRS) is often ascribed to decreased distension of the pressure-sensing arterial wall segments. However, alterations in the sensing and processing of neural signals may be involved as well. Design Conventionally, both vessel wall stiffness and the sensing and neural processing of the baroreflex are incorporated in the measure of pressure-derived BRS. We introduce stretch-derived BRS, which only considers the sensing and neural components of the baroreflex. Methods To determine stretch-derived BRS in a non-invasive manner, we measured the spontaneously occurring low-frequency variations (range, 0.06–0.12 Hz) in the carotid artery diameter and the corresponding R–R interval fluctuations, and determined the associated transfer function. The stretch-derived BRS in a group of age-matched (age range, 25–72 years) normotensive (n = 20) and hypertensive (n = 21) subjects was compared. Results In both subject groups the stretch-derived BRS decreased significantly with age. Moreover, the stretch-derived BRS of both groups was only different below 50 years of age. Conclusions The analysis of low-frequency fluctuations in the carotid artery diameter demonstrates that aging as well as hypertension are associated with impaired neural control of the baroreflex. Beyond 50 years of age the effect of hypertension cannot be distinguished from the effect of aging.

Microvascular dysfunction: An emerging pathway in the pathogenesis of obesity-related insulin resistance

The prevalence of type 2 diabetes mellitus (T2DM) and its major risk factor, obesity, has reached epidemic proportions in Western society. How obesity leads to insulin resistance and subsequent T2DM is incompletely understood. It has been established that insulin can redirect blood flow in skeletal muscle from non-nutritive to nutritive capillary networks, without increasing total blood flow. This results in a net increase of the overall number of perfused nutritive capillary networks and thereby increases insulin-mediated glucose uptake by skeletal muscle. This process, referred to as functional (nutritive) capillary recruitment, has been shown to be endothelium-dependent and to require activation of the phosphatidylinositol-kinase (PI3K) pathway in the endothelial cell. Several studies have demonstrated that these processes are impaired in states of microvascular dysfunction. In obesity, changes in several adipokines are likely candidates to influence insulin signaling pathways in endothelial cells, thereby causing microvascular dysfunction. Microvascular dysfunction, in turn, impairs the timely access of glucose and insulin to their target tissues, and may therefore be an additional cause of insulin resistance. Thus, microvascular dysfunction may be a key feature in the development of obesity-related insulin resistance. In the present review, we will discuss the evidence for this emerging role for the microcirculation as a possible link between obesity and insulin resistance.

Microvascular dysfunction as a link between obesity, insulin resistance and hypertension

Impaired microvascular dilatation from any cause and impaired insulin-mediated capillary recruitment in particular result in suboptimal delivery of glucose and insulin to skeletal muscle, and subsequently impairment of glucose disposal (insulin resistance). In addition, microvascular dysfunction, through functional and/or structural arteriolar and capillary drop-out, and arteriolar constriction, increases peripheral resistance and thus blood pressure. Microvascular dysfunction may thus constitute a pathway that links insulin resistance and hypertension. Overweight and obesity may be an important cause of microvascular dysfunction. Mechanisms linking overweight and obesity to microvascular dysfunction include changes in the secretion of adipokines leading to increased levels of free fatty acids and inflammatory mediators, and decreased levels of adiponectin all of which may impair endothelial insulin signaling. Microvascular dysfunction may thus constitute a new treatment target in the prevention of type 2 diabetes mellitus and hypertension.

Effect of antioxidant vitamin supplementation on endothelial function in type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials

Controversy exists among trials assessing whether prolonged antioxidant vitamin supplementation improves endothelial function in type 2 diabetes mellitus (T2DM) subjects. The aim of this study was to systematically review and quantify the effect of antioxidant vitamin supplementation on endothelial function in T2DM subjects. MEDLINE, Cochrane, Scopus and Web of Science were searched up to February 2013 for randomized controlled trials assessing the effect of antioxidant vitamin E and/or C supplementation on endothelial function in T2DM subjects. Ten randomized controlled trials comparing antioxidant vitamin‐supplemented and control groups (overall n = 296) met the inclusion criteria. Post‐intervention standardized mean difference (SMD) in endothelial function did not reach statistical significance between groups (0.35; 95% confidence interval = −0.17, 0.88; P = 0.18). In subgroup analysis, post‐intervention endothelial function was significantly improved by antioxidant vitamin supplementation in T2DM subgroups with body mass index (BMI) ≤ 29.45 kg m−2 (SMD = 1.02; P < 0.05), but not in T2DM subgroups with BMI > 29.45 kg m−2 (SMD = −0.07; P = 0.70). In meta‐regression, an inverse association was found between BMI and post‐intervention SMD in endothelial function (B = −0.024, P = 0.02). Prolonged antioxidant vitamin E and/or C supplementation could be effective to improve endothelial function in non‐obese T2DM subjects.

Perivascular Fat and the Microcirculation: Relevance to Insulin Resistance, Diabetes, and Cardiovascular Disease.

Type 2 diabetes and its major risk factor, obesity, are a growing burden for public health. The mechanisms that connect obesity and its related disorders, such as insulin resistance, type 2 diabetes, and hypertension, are still undefined. Microvascular dysfunction may be a pathophysiologic link between insulin resistance and hypertension in obesity. Many studies have shown that adipose tissue-derived substances (adipokines) interact with (micro)vascular function and influence insulin sensitivity. In the past, research focused on adipokines from perivascular adipose tissue (PVAT). In this review, we focus on the interactions between adipokines, predominantly from PVAT, and microvascular function in relation to the development of insulin resistance, diabetes, and cardiovascular disease.

Prediabetes and type 2 diabetes are associated with generalized microvascular dysfunction: the Maastricht Study

Background: Type 2 diabetes (T2DM) is associated with an increased risk of cardiovascular disease. This can be partly explained by large-artery dysfunction, which already occurs in prediabetes (“ticking clock hypothesis”). Whether a similar phenomenon also applies to microvascular dysfunction is not known. We therefore tested the hypothesis that microvascular dysfunction is already present in prediabetes and is more severe in T2DM. To do so, we investigated the associations of prediabetes, T2DM, and measures of hyperglycemia with microvascular function measured as flicker light-induced retinal arteriolar dilation and heat-induced skin hyperemia. Methods: In the Maastricht Study, a T2DM-enriched population-based cohort study (n=2213, 51% men, aged [mean±standard deviation] 59.7±8.2 years), we determined flicker light-induced retinal arteriolar %-dilation (Dynamic Vessel Analyzer), heat-induced skin %-hyperemia (laser-Doppler flowmetry), and glucose metabolism status (oral glucose tolerance test; normal glucose metabolism [n=1269], prediabetes [n=335], or T2DM [n=609]). Differences were assessed with multivariable regression analyses adjusted for age, sex, body mass index, smoking, physical activity, systolic blood pressure, lipid profile, retinopathy, estimated glomerular filtration rate, (micro)albuminuria, the use of lipid-modifying and blood pressure-lowering medication, and prior cardiovascular disease. Results: Retinal arteriolar %-dilation was (mean±standard deviation) 3.4±2.8 in normal glucose metabolism, 3.0±2.7 in prediabetes, and 2.3±2.6 in T2DM. Adjusted analyses showed a lower arteriolar %-dilation in prediabetes (B=–0.20, 95% confidence interval –0.56 to 0.15) with further deterioration in T2DM (B=–0.61 [–0.97 to –0.25]) versus normal glucose metabolism (P for trend=0.001). Skin %-hyperemia was (mean±standard deviation) 1235±810 in normal glucose metabolism, 1109±748 in prediabetes, and 937±683 in T2DM. Adjusted analyses showed a lower %-hyperemia in prediabetes (B=–46 [–163 to 72]) with further deterioration in T2DM (B=–184 [–297 to –71]) versus normal glucose metabolism (P for trend=0.001). In addition, higher glycohemoglobin A1c and fasting plasma glucose were associated with lower retinal arteriolar %-dilation and skin %-hyperemia in fully adjusted models (for glycohemoglobin A1c, standardized B=–0.10 [–0.15 to –0.05], P<0.001 and standardized B=–0.13 [–0.19 to –0.07], P<0.001, respectively; for fasting plasma glucose, standardized B=–0.09 [–0.15 to –0.04], P<0.001 and standardized B=–0.10 [–0.15 to –0.04], P=0.002, respectively). Conclusion: Prediabetes, T2DM, and measures of hyperglycemia are independently associated with impaired microvascular function in the retina and skin. These findings support the concept that microvascular dysfunction precedes and thus may contribute to T2DM-associated cardiovascular disease and other complications, which may in part have a microvascular origin such as impaired cognition and heart failure.

Angiotensin II Enhances Insulin-Stimulated Whole-Body Glucose Disposal but Impairs Insulin-Induced Capillary Recruitment in Healthy Volunteers

CONTEXT Angiotensin II (AngII) increases insulin-mediated glucose uptake in healthy individuals. The underlying mechanisms are undefined. AngII may increase glucose uptake through a direct effect on muscle cell insulin signaling or through increasing insulin delivery to muscle cells through effects on the microvasculature. OBJECTIVE Our objective was to determine whether AngII increases insulin-mediated glucose uptake through effects on insulin-induced capillary recruitment. DESIGN We examined the effects of AngII on hyperinsulinemia-induced capillary density by measuring skin capillary density, capillary recruitment, and capillary density during venous congestion in 18 healthy subjects in the basal state, during systemic hyperinsulinemia, and during hyperinsulinemia with coinfusion of AngII or phenylephrine (pressor control). In addition, whole-body glucose uptake and blood pressure were measured. RESULTS Capillaroscopy data of 13 subjects were available for analysis. Compared with the basal state, hyperinsulinemia increased baseline capillary density (51.5+/-9.0 vs. 55.2+/-10.8 n/mm2, P<0.01), capillary recruitment (67.8+/-6.8 vs. 70.6+/-7.5 n/mm2, P<0.05), and capillary density during venous congestion (78.5+/-12.0 vs. 80.3+/-12.0 n/mm2, P<0.01). Infusion of AngII, but not phenylephrine, reduced insulin-induced capillary recruitment (69.3+/-8.6 vs. 65.2+/-8.0 n/mm2, P<0.05) and capillary density during venous congestion (79.7+/-15.3 vs. 73.9+/-12.1, P<0.05) while enhancing glucose uptake [2.40+/-0.7 vs. 2.68+/-0.6 (mg/kg.min per pmol/l)x100, P<0.01)] (n=18). CONCLUSION AngII increases insulin-mediated glucose uptake in healthy individuals. This increase was probably not related to increases in microvascular perfusion because infusion of AngII during hyperinsulinemia reduced insulin-mediated skin capillary recruitment. Additional studies are needed to investigate whether AngII directly affects insulin delivery through increasing insulin transport across the microvasculature.

Predictors of clinical outcome after stent placement in atherosclerotic renal artery stenosis: a systematic review and meta-analysis of prospective studies

Objective To determine clinical predictors for blood pressure and/or renal function improvement after renal artery stent placement in atherosclerotic renal artery stenosis (ARAS). Methods We searched PubMed, EMBASE and Cochrane databases for prospective studies investigating clinical predictive variables for renal function and/or blood pressure improvement after stent placement in ARAS. Eleven studies (1552 participants) were selected for our systematic review and meta-analysis. Meta-regression analysis was performed to investigate heterogeneity and to determine independent predictors for the outcome variables. Bias was evaluated by use of the Cochrane risk of bias tool. Results Multivariate meta-regression analysis showed no predictors for renal function improvement. High baseline diastolic blood pressure (DBP) and pulse pressure were significantly associated with the decrease in blood pressure after intervention. These results were consistent with the predictors reported by the individual studies. Meta-analysis showed a nonsignificant decline in serum creatinine of 4.7 μmol/l [95% confidence interval (Cl) −13.8 to 4.5]. Overall, systolic blood pressure (SBP) fell by 19.2 mmHg (95% Cl −22.7 to −15.7) and DBP decreased 8.9 mmHg (95% Cl −10.8 to −7.0). Risk of bias was present in the majority of the studies. Conclusions The present review did not find a clinical characteristic that reliably predicts renal function outcome. High baseline pulse pressure predicted a smaller decrease in SBP after intervention and the best clinical predictor for a larger DBP reduction was a high pretreatment DBP.