Amy M. Jonk

Microvascular Dysfunction: A Potential Mechanism in the Pathogenesis of Obesity‐associated Insulin Resistance and Hypertension

Please cite this paper as: de Boer, Meijer, Wijnstok, Jonk, Houben, Stehouwer, Smulders, Eringa and Serné (2012). Microvascular Dysfunction: A Potential Mechanism in the Pathogenesis of Obesity‐associated Insulin Resistance and Hypertension. Microcirculation 19(1), 5–18.

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.

Meal-Related Increases in Microvascular Vasomotion Are Impaired in Obese Individuals A potential mechanism in the pathogenesis of obesity-related insulin resistance

Obesity is associated with insulin resistance, hypertension, cardiovascular disease, and type 2 diabetes (1), but the mechanisms underlying these associations are incompletely understood. This article reviews and adds original data (i.e., in the postprandial state) to the evidence for microvascular dysfunction, including impairment of insulin-stimulated microvascular perfusion as a key element in the pathogenesis of obesity-related hypertension and insulin resistance (2,3). The microcirculation is widely taken to encompass vessels <150 μm (i.e., arterioles, capillaries, and venules) (4) and has two important functions. First, arterioles regulate hydrostatic pressure and peripheral vascular resistance (4). Importantly, dysfunction of the microcirculation, with concomitant increases in vasoconstrictor tone, will increase total peripheral resistance and, other things being equal, blood pressure, as reviewed elsewhere (2,3). Second, it regulates tissue perfusion to optimize the delivery of nutrients and removal of waste products within tissues in response to variations in demand. In this respect, insulin has been shown to play an important role (5). Insulin redirects blood flow within the muscle microvascular bed to increase available capillary surface area, an effect referred to as “capillary recruitment” (6,7). In addition, insulin induces vasodilation of resistance vessels, resulting in an increase in total muscle blood flow (8). Whether this increase in total muscle blood flow, which occurs later in time compared with the redirection of flow to nutritive capillary beds, serves to enhance insulin-mediated glucose uptake remains controversial (9). However, it has been generally accepted that capillary recruitment is crucial for the delivery of insulin and glucose to tissue. Indeed, several studies have shown that insulin-mediated increases in capillary recruitment account for approximately half of insulin-mediated muscle glucose uptake in vivo (10–14). Insulin’s effect on microvascular blood flow is, therefore, an important regulator of insulin-mediated muscle glucose uptake, the main …

Obesity is associated with impaired endothelial function in the postprandial state.

Adequate microvascular perfusion is essential for the regulation of tissue metabolism. Therefore, defects in microvascular function may play a role in obesity-associated insulin resistance. Steady-state hyperinsulinemia during a euglycemic hyperinsulinemic clamp stimulates endothelium-dependent vasodilation and capillary recruitment, which contribute to increased glucose uptake. These phenomena have been shown to be blunted in obesity. If insulins effects on microcirculatory function indeed play a physiological role in regulating insulin-mediated glucose uptake, such effects should be demonstrable not only during steady-state hyperinsulinemia, but also after meal ingestion. We investigated whether similar responses occur after ingestion of a glucose load or a mixed meal. We examined the effects of a glucose drink, a mixed meal drink, or a control drink (water) on skin capillary density (i.e. baseline capillary density, hyperemic capillary recruitment, and density during venous congestion, using capillaroscopy) and skin endothelium-(in)dependent vasodilation (using laser-Doppler flowmetry with iontophoresis of acetylcholine and sodium nitroprusside) in 20 lean and 19 obese individuals. In lean individuals, neither the glucose nor the mixed meal drink induced a significant effect on capillary density or endothelium-(in)dependent vasodilation. Possibly this is related to the modest plasma insulin levels as compared to the insulin clamp. In obese individuals, the mixed meal drink, compared to the control drink, decreased baseline skin perfusion (P<0.05) and acetylcholine-mediated vasodilation (P<0.05), while no effect of the drinks on capillary density was found. Compared to lean individuals, obese individuals had impaired acetylcholine-mediated vasodilation after meal ingestion (P=0.02). The latter findings are consistent with impaired postprandial microvascular function in obesity.

Acute angiotensin II receptor blockade improves insulin-induced microvascular function in hypertensive individuals

OBJECTIVE An effect of insulin that is crucial for stimulating glucose uptake is its ability to increase the number of perfused capillaries, and thereby enhance its own delivery, and that of glucose, to muscle cells. To unravel possible mechanisms involved in the insulin-sensitizing effects of angiotensin II receptor blockers (ARBs) in hypertensive individuals we investigated the effect of single-dose ARB administration on insulin-mediated microvascular perfusion in hypertensive individuals. METHODS We examined the effects of ARB administration on hyperinsulinemia-associated capillary density by measuring baseline skin capillary density, capillary density during reactive hyperemia (hyperemic capillary recruitment), and capillary density during venous congestion in 17 hypertensive individuals in the basal state, during a hyperinsulinemic euglycemic clamp, and during a hyperinsulinemic clamp with acute ARB administration (600 mg irbesartan), acute calcium channel blockade (CCB; 10mg felodipine ER), as a control for the reduction in blood pressure, or placebo. In addition, insulin sensitivity and blood pressure were measured. RESULTS Compared to the basal state, hyperinsulinemia increased baseline capillary density (57.3 ± 6.8 vs. 60.3 ± 7.9 n/mm(2), P<0.01), but not hyperemic capillary recruitment. ARB and CCB treatment induced similar blood pressure reductions. Compared to placebo, ARB, but not CCB, increased hyperinsulinemia-associated baseline capillary density (+2.3 ± 3.4 (P=0.02) and -0.4 ± 4.4n/mm(2), respectively). Hyperinsulinemia-associated hyperemic capillary recruitment was not altered by either treatment. Compared to placebo, neither ARB nor CCB treatment enhanced insulin sensitivity. CONCLUSIONS Acute ARB administration increases insulin-induced microvascular perfusion in mildly hypertensive individuals; this beneficial effect on microvascular perfusion was however not associated with increased insulin-mediated glucose uptake.

EFFECTS OF PHYSIOLOGICAL HYPERINSULINAEMIA ON THE MICROCIRCULATION: PP.11.424

Objective: Steady state hyperinsulinaemia during a hyperinsulinaemic euglycaemic clamp stimulates endothelium-dependent vasomotion and vasodilation as well as capillary recruitment, which contribute to increased glucose uptake; these phenomena have been shown to be blunted in obesity. The aim of the present study was to investigate whether similar results can be obtained during dynamic hyperinsulinaemia as induced by a glucose load or a mixed meal. Design and Methods: A randomised, placebo-controlled trial was performed in 18 healthy (BMI 22.5 ± 1.7 kg/m2) and 13 obese (BMI 34.0 ± 3.5 kg/m2) subjects, to examine the effects of a glucose drink (75 g glucose), a 495-kcal liquid mixed meal (60% carbohydrates, 25% proteins, 15% fat) or placebo (a similar amount of tap water) on microvascular function. Skin endothelium-(in)dependent vasodilatation was evaluated by laser Doppler flowmetry (LDF) with iontophoresis of acetylcholine (Ach) and sodium nitroprusside (SNP). Vasomotion was examined by Fourier analysis of the LDF signal. Results: Both the glucose drink and the liquid mixed meal, but not placebo, induced hyperinsulinaemia. The levels of hyperinsulinaemia were higher in obese compared to healthy subjects (peak levels glucose drink: 95.9 vs. 54.2 mU/l, P < 0.05; mixed meal: 107.6 vs. 59.7 mU/l P < 0.05). Compared to placebo, vasomotion analysis showed increased endothelial activity in healthy subjects following the glucose drink (delta energy density (median (interquartile range) +0.11 (−0.04 – +0.25); P < 0.05) and meal drink (+0.16 (0.05 – 0.29); P = 0.001). Compared to healthy subjects, a significant decrease of endothelial activity was found in obese subjects following the meal drink (−0.09 (−0.23–0.13) vs 0.16 (0.05 – 0.29); P < 0.05). No changes in endothelium-(in)dependent vasodilatation following iontophoresis of Ach or SNP were found in either group. Conclusion: A glucose load and a mixed meal, which are accompanied by non-steady state hyperinsulinaemia, increase endothelial vasomotion in healthy individuals. These responses are blunted in obese subjects. These data suggest impairment of microvascular function in the postprandial state in obese individuals.

AT1-RECEPTOR BLOCKADE AND INSULIN SENSITIVITY IN HYPERTENSIVE SUBJECTS: THE ROLE OF CAPILLARY RECRUITMENT: PP.11.435

Objective: Blocking the renin-angiotensin system (RAS) improves insulin sensitivity in hypertensive subjects. However, the underlying mechanisms are undefined. An effect of insulin that is crucial for stimulating glucose uptake is the ability of insulin to regulate its own delivery, and that of glucose, to muscle cells via recruitment of the microvasculature. This study was designed to investigate the effect of acute angiotensin II AT1 receptor blockade (ARB) on insulin-mediated microvascular function and insulin-mediated glucose uptake in hypertensive subjects. Design and Methods: A randomised, double-blind placebo-controlled trial was performed in 15 untreated mildly hypertensive subjects (age 53 ± 5 yrs; BMI 26.9 ± 2 kg/m2); BP 150/92 mmHg), to examine the effects of acute ARB treatment (irbesartan, 600 mg, oral single dose) or Ca2+-blockade (felodipine, 10 mg idem) as a pressor control on insulin-induced microvascular function and on insulin-mediated whole body glucose uptake (WBGU, mg/kg/min) during a hyperinsulinaemic euglycaemic clamp (50mU/kg/h). Effects of irbesartan and felodipine were compared to placebo. Skin capillary density (n/mm2) and capillary recruitment (peak n/mm2 during postocclusive reactive hyperaemia, PRH) were measured with capillaroscopy. All subjects were tested on a low sodium diet (100 mmol/day). Results: Compared to the basal state, hyperinsulinaemia increased baseline capillary density (56.8 ± 7.1 vs. 60.2 ± 8.3 n/mm2, P < 0.02). Relative to placebo, irbesartan, but not felodipine, increased insulin-induced capillary density (Ä cap density (median (interquartile range) +3.5 (−1.3 - +5.0) n/mm2, P < 0.02). Insulin-induced capillary recruitment was not altered by either treatment. Neither irbesartan nor felodipine enhanced WBGU. Conclusion: Our data demonstrate that acute AT1-blockade augments insulin-induced capillary density in mildly hypertensive subjects. Although glucose uptake did not increase significantly, the increased insulin-induced microvascular function found with ARB might point to improved insulin and glucose delivery as the underlying mechanism for the improved insulin sensitivity with longterm ARB treatment.