Richard G. IJzerman

Impaired Microvascular Function in Obesity Implications for Obesity-Associated Microangiopathy, Hypertension, and Insulin Resistance

Background—Obesity is associated with an increased risk of developing microangiopathy, hypertension, and insulin resistance. We hypothesized that obesity is a primary cause of microvascular dysfunction, which may contribute to the development of these obesity-related disorders. Methods and Results—We examined microvascular function in 16 lean (body mass index <24 kg/m2) and 12 obese (body mass index >30 kg/m2) healthy women (mean age, 38.9±6.7 years) in the basal state and during physiological systemic hyperinsulinemia. We determined skin capillary recruitment after arterial occlusion with capillaroscopy and skin endothelium–(in)dependent vasodilation by iontophoresis of acetylcholine and sodium nitroprusside. Obese women, compared with lean women, had higher systolic blood pressure (P <0.05), impaired insulin sensitivity (P <0.01), impaired capillary recruitment in the basal state (P <0.05) and during hyperinsulinemia (P <0.05), and impaired acetylcholine-mediated vasodilation in the basal state (P <0.05) and during hyperinsulinemia (P <0.01). Sodium nitroprusside–mediated vasodilation was similar in lean and obese women. Capillary recruitment and acetylcholine-mediated vasodilation were positively correlated with insulin sensitivity (r =0.58, P <0.01 and r =0.55, P <0.01, respectively) and negatively with blood pressure (r =−0.64, P <0.001 and r =−0.42, P <0.05, respectively) in both lean and obese women. Conclusions—Obesity is characterized by impaired microvascular function in the basal state and during hyperinsulinemia and, in both lean and obese women, microvascular dysfunction is associated with increased blood pressure and decreased insulin sensitivity. These findings are consistent with a contribution of impaired microvascular function to the development of obesity-related microangiopathy, hypertension, and insulin resistance.

Individuals at increased coronary heart disease risk are characterized by an impaired microvascular function in skin.

Background To investigate whether microvascular function in skin is a valid model to study the relationships between cardiovascular risk factors and microvascular function, we investigated skin microvascular function in individuals with increased coronary heart disease (CHD) risk.

Cytosolic triglycerides and oxidative stress in central obesity: the missing link between excessive atherosclerosis, endothelial dysfunction, and β-cell failure?

Central obesity is increasingly recognized as a risk factor for atherosclerosis and type 2 diabetes mellitus. Here we present a hypothesis that may explain the excess atherosclerosis, endothelial dysfunction and progressive beta-cell failure. Central obesity is associated with increased cytosolic triglyceride stores in non-adipose tissues such as muscles, liver and pancreatic beta-cells. A high cytosolic triglyceride content is accompanied by elevated concentrations of cytosolic long-chain acyl-CoA esters, the metabolically active form of fatty acids. These esters inhibit mitochondrial adenine nucleotide translocators, resulting in an intramitochondrial ADP deficiency. In vitro, such ADP deficiency is a potent stimulator of mitochondrial oxygen free radical production, and we assume that this mechanism is also active in vivo. The decline of organ function with normal ageing is thought to be due, at least partly, to a continuous low-grade mitochondrial oxygen free radical production. In tissues containing increased cytosolic triglyceride stores this process will be accelerated. Tissues with a high-energy demand or poor free radical scavenging capacity, such as pancreatic beta-cells, are likely to be more susceptible to this process. This is how we explain their gradual dysfunctioning in central obesity. Likewise we propose that the enhanced production of oxygen free radicals in endothelial cells, or vascular smooth muscle cells, leads to the increased subendothelial oxidation of LDL and atherosclerosis, as well as to the endothelial dysfunction and microalbuminuria.

Microvascular Dysfunction: A Potential Pathophysiological Role in the Metabolic Syndrome

Obesity and a central body fat distribution, hypertension, insulin resistance, glucose intolerance, dyslipidemia, and proinflammatory and prothrombotic factors are all part of the metabolic syndrome. The metabolic syndrome defines a clustering of metabolic risk factors which confers an increased risk for type 2 diabetes and cardiovascular disease.1 In the past years a large amount of research has been aimed at elucidating the pathophysiology underlying this clustering of risk factors, because a better understanding may lead to new therapeutic approaches that specifically target underlying causes of the metabolic syndrome. Recently, it has become clear that microvascular dysfunction, by affecting both pressure and flow patterns, may have consequences not only for peripheral vascular resistance, but also for insulin-mediated changes in muscle perfusion and glucose metabolism, providing a novel pathophysiological framework for understanding the association between hypertension, obesity, and impaired insulin-mediated glucose disposal.2–4 The present article examines recent data concerning the role of microvascular dysfunction as an explanation for the associations among hypertension, obesity, and impaired insulin-mediated glucose disposal. Description of the Microcirculation An exact definition of the microcirculation is elusive. Morphologically, the microcirculation is widely taken to encompass vessels 150 m in diameter. It therefore includes arterioles, capillaries, and venules. Alternatively, a definition based on arterial vessel physiology rather than diameter or structure has been proposed. 3 By this definition, all arterial vessels that respond to increasing pressure by a myogenic reduction in lumen diameter are included in the microcirculation. Such a definition would include the smallest arteries and arterioles in the microcirculation in addition to capillaries and venules. Small arterial and arteriolar components should, therefore, be considered a continuum rather than distinct sites of resistance control. A primary function of the microcirculation is to optimize nutrient and oxygen supply within the tissue in response to variations in demand. A second important function is to avoid large fluctuations in hydrostatic pressure at the level of the capillaries causing disturbances in capillary exchange. Finally, it is at the level of the microcirculation that a substantial proportion of the drop in hydrostatic pressure occurs. The microcirculation is therefore extremely important in determining overall peripheral vascular resistance.

GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans

Gut-derived hormones, such as GLP-1, have been proposed to relay information to the brain to regulate appetite. GLP-1 receptor agonists, currently used for the treatment of type 2 diabetes (T2DM), improve glycemic control and stimulate satiety, leading to decreases in food intake and body weight. We hypothesized that food intake reduction after GLP-1 receptor activation is mediated through appetite- and reward-related brain areas. Obese T2DM patients and normoglycemic obese and lean individuals (n = 48) were studied in a randomized, crossover, placebo-controlled trial. Using functional MRI, we determined the acute effects of intravenous administration of the GLP-1 receptor agonist exenatide, with or without prior GLP-1 receptor blockade using exendin 9-39, on brain responses to food pictures during a somatostatin pancreatic-pituitary clamp. Obese T2DM patients and normoglycemic obese versus lean subjects showed increased brain responses to food pictures in appetite- and reward-related brain regions (insula and amygdala). Exenatide versus placebo decreased food intake and food-related brain responses in T2DM patients and obese subjects (in insula, amygdala, putamen, and orbitofrontal cortex). These effects were largely blocked by prior GLP-1 receptor blockade using exendin 9-39. Our findings provide novel insights into the mechanisms by which GLP-1 regulates food intake and how GLP-1 receptor agonists cause weight loss.

Low Birth Weight Is Associated With Increased Sympathetic Activity Dependence on Genetic Factors

Background—Low birth weight may be associated with high blood pressure in later life through genetic factors, an association that may be explained by alterations in sympathetic and parasympathetic activity. We examined the association of birth weight with cardiac pre-ejection period and respiratory sinus arrhythmia (indicators of cardiac sympathetic and parasympathetic activity, respectively) and with blood pressure in 53 dizygotic and 61 monozygotic adolescent twin pairs. Methods and Results—Birth weight of the twins was obtained from the mothers. Pre-ejection period and respiratory sinus arrhythmia were measured with electrocardiography and impedance cardiography at rest, during a reaction time task, and during a mental arithmetic task. In the overall sample, lower birth weight was significantly associated with shorter pre-ejection period at rest, during the reaction time task, and during the mental arithmetic task (P =0.0001, P <0.0001, and P =0.0001, respectively) and with larger pre-ejection period reactivity to the stress tasks (P =0.02 and P =0.06, respectively). In within-pair analyses, differences in birth weight were associated with differences in pre-ejection period at rest and during both stress tasks in dizygotic twin pairs (P =0.01, P =0.06, and P =0.2, respectively) but not in monozygotic twin pairs (P =0.9, P =1.0, and P =0.5, respectively). Shorter pre-ejection period explained approximately 63% to 84% of the birth weight and blood pressure relation. Conclusions—Low birth weight is associated with increased sympathetic activity, and this explains a large part of the association between birth weight and blood pressure. In addition, our findings suggest that the association between birth weight and sympathetic activity depends on genetic factors.

Evidence for Genetic Factors Explaining the Birth Weight–Blood Pressure Relation: Analysis in Twins

Epidemiological studies have consistently shown an inverse association between birth weight and systolic blood pressure in later life after adjustment for current size. To examine whether this association is explained by intrauterine or genetic factors, we investigated birth weight and blood pressure data in 53 dizygotic and 61 monozygotic adolescent twin pairs. Birth weight was obtained from the mothers. Blood pressure measurements were performed 6 times at rest and during mental stress. The dizygotic but not the monozygotic twins with the lowest birth weight from each pair had a systolic blood pressure measured at rest and during the reaction time experiment that was higher compared with their cotwins with the highest birth weight (dizygotic twins: blood pressure at rest, 119.4±9.7 mm Hg versus 117.3±8.5 mm Hg, P =0.07, and during a reaction time task, 126.2±10.8 versus 123.6±9.5, P =0.09; monozygotic twins: blood pressure at rest, 117.4±6.4 versus 118.4±9.0, P =0.4, and during a reaction time task, 122.9±8.4 versus 124.2±10.8, P =0.2). The differences in blood pressure between the cotwins with the lowest and the cotwins with the highest birth weight were different in dizygotic compared with monozygotic twin pairs (for blood pressure at rest, P =0.05; for blood pressure during reaction time, P =0.03). After adjustment for differences in current weight, intrapair differences in birth weight were negatively and significantly associated with differences in systolic blood pressure at rest and during the reaction time task in dizygotic twins (regression coefficient, −5.7 mm Hg/kg [95% confidence interval, −10.4 to −1.0] and −6.3 [−12.7 to 0], respectively) but not in monozygotic twins (−0.1 [−5.4 to 5.2] and +3.5 [−1.8 to 8.8], respectively). Interaction analysis indicated that the associations were different between dizygotic twins and monozygotic twins (P =0.1 and P <0.05, respectively). These data suggest that genetic factors may play an important role in the association between birth weight and blood pressure.

Cigarette smoking is associated with an acute impairment of microvascular function in humans.

An effect on microvascular function has been proposed as a possible mechanism explaining the association of acute smoking with increased blood pressure and decreased insulin sensitivity. However, the effects of smoking on microvascular function have not been studied. We have investigated the acute effects of smoking on microvascular function in 12 healthy smokers. Before and after smoking a cigarette, we measured heart rate, blood pressure and capillary recruitment during peak reactive hyperaemia. We also measured endothelium-dependent and endothelium-independent vasodilatation of the skin microcirculation with iontophoresis of acetylcholine and sodium nitroprusside respectively combined with laser Doppler fluxmetry. To exclude non-specific changes, a control study with sham smoking was performed. The smoking and sham smoking studies were conducted in a randomized order. Compared with sham smoking, acute smoking caused increases in heart rate (smoking, 9.3+/-4.1 beats/min; sham, -1.3+/-3.0 beats/min; P < 0.001) and systolic blood pressure (smoking, 6.3+/-8.8 mmHg; sham, 0.8+/-4.4 mmHg; P < 0.05); decreases in absolute (smoking, -4.9+/-6.9 per mm(2); sham, 0.8+/-2.1 per mm(2); P = 0.01) and relative (smoking, -13.8+/-21.4%; sham, 1.9+/-6.9%; P = 0.02) capillary recruitment during peak reactive hyperaemia; and decreases in absolute [smoking, -62.4+/-47.7 perfusion units (PU); sham, -30.8+/-32.6 PU; P = 0.04] and relative (smoking, -147+/-163%; sham, 32+/-225%; P = 0.07) vasodilatation caused by acetylcholine. Absolute (smoking, -31.6+/-58.5 PU; sham, -8.4+/-44.0 PU; P = 0.3) and relative (smoking, -50.2+/-219.0%; sham, -17.1+/-139%; P = 0.7) vasodilatation caused by sodium nitroprusside were not affected. Thus acute smoking is associated with impaired capillary recruitment during peak reactive hyperaemia and impaired microvascular endothelium-dependent vasodilatation. These findings may explain the increased blood pressure and decreased insulin sensitivity that have been observed after acute smoking.

Resting-State Brain Networks in Type 1 Diabetic Patients With and Without Microangiopathy and Their Relation to Cognitive Functions and Disease Variables

Cognitive functioning depends on intact brain networks that can be assessed with functional magnetic resonance imaging (fMRI) techniques. We hypothesized that cognitive decrements in type 1 diabetes mellitus (T1DM) are associated with alterations in resting-state neural connectivity and that these changes vary according to the degree of microangiopathy. T1DM patients with (MA+: n = 49) and without (MA−: n = 52) microangiopathy were compared with 48 healthy control subjects. All completed a neuropsychological assessment and resting-state fMRI. Networks were identified using multisubject independent component analysis; specific group differences within each network were analyzed using the dual-regression method, corrected for confounding factors and multiple comparisons. Relative to control subjects, MA− patients showed increased connectivity in networks involved in motor and visual processes, whereas MA+ patients showed decreased connectivity in networks involving attention, working memory, auditory and language processing, and motor and visual processes. Better information-processing speed and general cognitive ability were related to increased degree of connectivity. T1DM is associated with a functional reorganization of neural networks that varies, dependent on the presence or absence of microangiopathy.

Birth Weight Relates to Salt Sensitivity of Blood Pressure in Healthy Adults

The association between birth weight and blood pressure is well established but at present unexplained. According to the Borst-Guyton concept, chronic hypertension can occur only with a shift in the renal pressure–natriuresis relationship resulting in increased salt sensitivity of blood pressure. We assessed salt sensitivity of blood pressure in a group of 27 healthy adults whose birth weight was available. Birth weight was ascertained from birth certificates or announcements. Salt sensitivity of blood pressure was determined as difference in mean arterial pressure (MAP) between a 1-week high-salt (≈235 mmol NaCl/d) versus low-salt diet (≈55 mmol NaCl/d). Creatinine clearance was estimated according to the formula of Cockcroft and Gault. Birth weight was negatively associated with salt sensitivity of blood pressure (r=−0.60, P=0.002). The creatinine clearance was positively associated with birth weight (r=0.53; P=0.008) but did not influence the association between birth weight and salt sensitivity of blood pressure. Birth weight is associated with salt sensitivity of blood pressure, and this may play a role in the maintenance of elevated blood pressure in individuals with a low birth weight.