Renate T. de Jongh

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.

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.

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.

Role of Vitamin D in the Development of Insulin Resistance and Type 2 Diabetes

Vitamin D deficiency is mainly a consequence of insufficient sunlight induced vitamin D production in the skin and has been associated with various chronic diseases including type 2 diabetes. Experimental data have shown that vitamin D is important for glucose induced insulin secretion, improves insulin resistance, and exerts anti-inflammatory actions. Epidemiological studies have largely documented that a poor vitamin D status is associated with higher risk of insulin resistance and type 2 diabetes. The majority of randomized controlled trials (RCTs) in healthy or prediabetic individuals have, however, failed to demonstrate relevant vitamin D effects on insulin resistance or diabetes incidence. In patients with type 2 diabetes, a few RCTs reported some moderate effects of vitamin D on glycemic control and insulin resistance. While these findings warrant further in-depth studies, the current evidence is insufficient to recommend vitamin D supplementation for the prevention or treatment of type 2 diabetes.

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.

Older individuals with diabetes have an increased risk of recurrent falls: analysis of potential mediating factors: the Longitudinal Ageing Study Amsterdam

OBJECTIVES to compare the incidence of recurrent falls in older people with and without diabetes, and to examine diabetes- and fall-related risk factors explaining the increased risk of recurrent falls associated with diabetes. METHODS population-based cohort study of 1,145 (85 with diabetes) community-dwelling participants, aged ≥65 years, from The Longitudinal Aging Study Amsterdam (LASA). Falls were assessed prospectively (every 3 months) during a 3-year follow-up period. Incidence of recurrent falls was estimated with Poisson regression analyses. The associations between diabetes and time to recurrent falls, defined as at least two falls occurring within a 6-month period, and the potential explanatory role of several risk factors herein, were analysed with the use of Cox-regression models. RESULTS during a mean follow-up of 139 weeks, 30.6% of the individuals with and 19.4% of the individuals without diabetes fell recurrently [incidence rate of 129.7 versus 77.4 per 1,000 persons-years, respectively, HR = 1.67 (95% CI: 1.11-2.51)]. Adjustments for potential confounders did not change the increased risk associated with diabetes [HR = 1.63 (1.06-2.52)]. Factors that partly explained this increased risk were: greater number of medication, higher levels of pain, poorer self-perceived health, lower physical activity and grip strength, more limitations in ADLs, lower-extremity physical performance and cognitive impairment. Altogether, these variables accounted for 47% of the increased risk of recurrent falls associated with diabetes [adjusted HR = 1.30 (0.79-2.11)]. CONCLUSION fall prevention efforts targeting the factors identified above may need to be incorporated into the care and treatment of older individuals with diabetes.

Obese But Not Normal-Weight Women with Polycystic Ovary Syndrome Are Characterized by Metabolic and Microvascular Insulin Resistance

CONTEXT Polycystic ovary syndrome (PCOS) and obesity are associated with diabetes and cardiovascular disease, but it is unclear to what extent PCOS contributes independently of obesity. OBJECTIVE The objective of the study was to investigate whether insulin sensitivity and insulins effects on the microcirculation are impaired in normal-weight and obese women with PCOS. DESIGN AND POPULATION Thirty-five women with PCOS (19 normal weight and 16 obese) and 27 age- and body mass index-matched controls (14 normal weight and 13 obese) were included. Metabolic Insulin sensitivity (isoglycemic-hyperinsulinemic clamp) and microvascular insulin sensitivity [endothelium dependent (acetylcholine [ACh])] and endothelium-independent [sodium nitroprusside (SNP)] vasodilation with laser Doppler flowmetry was assessed at baseline and during hyperinsulinemia. MAIN OUTCOME MEASURES Metabolic insulin sensitivity (M/I value) and the area under the response curves to ACh and SNP curves were measured to assess microcirculatory function at baseline and during insulin infusion (microvascular insulin sensitivity). RESULTS Obese women were more insulin resistant than normal-weight women (P < 0.001), and obese PCOS women were more resistant than obese controls (P = 0.02). In contrast, normal-weight women with PCOS had similar insulin sensitivity, compared with normal-weight women without PCOS. Baseline responses to ACh showed no difference in the four groups. ACh responses during insulin infusion were significantly greater in normal-weight PCOS and controls than in obese PCOS and controls. PCOS per se had no significant influence on ACh responses during insulin infusion. During hyperinsulinemia, SNP-dependent vasodilatation did not significantly increase, compared with baseline in the four groups. CONCLUSION PCOS per se was not associated with impaired metabolic insulin sensitivity in normal-weight women but aggravates impairment of metabolic insulin sensitivity in obese women. In obese but not normal-weight women, microvascular and metabolic insulin sensitivity are decreased, independent of PCOS. Therefore, obese PCOS women in particular may be at increased risk of metabolic and cardiovascular diseases.

Diet, sun, and lifestyle as determinants of vitamin D status

Vitamin D status can be assessed by measuring concentrations of 25‐hydroxyvitamin D (25(OH)D). Sunlight is the most important source of vitamin D and stimulates the production of vitamin D3 in the skin during the summer, depending on age, skin pigmentation, clothing style, and sunscreen use. Seasonal variation in serum 25(OH)D is between 10 and 20 nmol/L in adults and almost absent in nursing home residents. Sunscreen use decreases, but does not abolish, vitamin D production in the skin. Clothing style has a large influence on vitamin D production. Furthermore, vitamin D status can be improved by ingestion of fatty fish and the fortification of milk or orange juice. A high dietary calcium intake has a vitamin D–sparing effect, because it increases the half‐life of 25(OH)D. A combination of sunlight exposure, nutrition, food fortification, and supplements is desirable to obtain sufficient vitamin D status in the population of most countries throughout the year.

Microvascular function: a potential link between salt sensitivity, insulin resistance and hypertension.

Objective Generalized microvascular dysfunction may contribute to the development of salt sensitivity, insulin resistance and hypertension, and may thus link these cardiovascular risk factors. To test this hypothesis, we examined skin microvascular function, salt sensitivity, insulin sensitivity and blood pressure in 27 normotensive and 26 hypertensive individuals. Methods Capillary density was examined by videomicroscopy during venous congestion and postocclusive reactive hyperaemia. Endothelium-(in)dependent vasodilation was assessed by iontophoresis of acetylcholine and sodium nitroprusside and by laser Doppler flowmetry. Salt sensitivity was determined as the difference in mean arterial pressure (MAP) between a 1-week high-salt diet (∼235 mmol NaCl/day) versus low-salt diet (∼55 mmol NaCl/day). Insulin sensitivity was measured with the hyperinsulinaemic, euglycaemic clamp, and blood pressure was assessed by 24-h ambulatory blood pressure monitoring. Results Salt sensitivity of blood pressure was inversely associated with postocclusive capillary recruitment and endothelium-dependent vasodilation (r = −0.67, P < 0.001 and r = −0.60, P < 0.01, respectively), but not with capillary density during venous congestion or endothelium-independent vasodilation. Salt sensitivity was negatively associated with insulin sensitivity (r = −0.55, P < 0.001) and positively with MAP (r = 0.58, P < 0.001). Multiple regression analyses suggested that associations between salt sensitivity and both insulin sensitivity and MAP were dependent on microvascular function. Conclusion Our results suggest a close inverse association between skin microvascular function and salt sensitivity and a role for generalized microvascular defects as a link between salt sensitivity, insulin resistance and hypertension.

Biological and behavioural determinants of the frequency of mild, biochemical hypoglycaemia in patients with Type 1 diabetes on multiple insulin injection therapy

Severe hypoglycaemic episodes are an important source of morbidity in people with Type 1 diabetes. The occurrence of severe hypoglycaemia is strongly related to the frequency of low blood glucose readings. The aim of this exploratory study was to identify determinants of the frequency of mild, biochemical hypoglycaemia in patients with Type 1 diabetes treated with multiple insulin injection therapy.