Insulin‐Induced Microvascular Recruitment in Skin and Muscle are Related and Both are Associated with Whole‐Body Glucose Uptake

Meijer, Rick I.; Boer, Michiel P. de; Groen, Martine R.; Eringa, Etto C.; Rattigan, Stephen; Barrett, Eugene J.; Smulders, Yvo M.; Serné, Erik H.

doi:10.1111/j.1549-8719.2012.00174.x

Cited by 73 publications

(79 citation statements)

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“…Regardless of the method used, insulin-stimulated microvascular changes were related to insulin-mediated glucose uptake [6]. Indeed, our results are in agreement with previous studies using contrast-enhanced ultrasound technique that showed enhanced postprandial microvascular function in healthy individuals [7] and blunted function in obese individuals [8].…”

Section: Discussionsupporting

confidence: 92%

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Postprandial microvascular function deteriorates in parallel with gradual worsening of insulin sensitivity and glucose tolerance in men with the metabolic syndrome or type 2 diabetes

et al. 2012

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Aims/hypothesis Hyperinsulinaemia-induced whole-body glucose uptake during a euglycaemic-hyperinsulinaemic clamp is partly mediated by increased capillary density. We hypothesised that physiological insulinaemia in response to a mixed meal may also enhance microvascular function, and that this may be impaired in insulin-resistant individuals and patients with type 2 diabetes. Methods Twelve men with uncomplicated type 2 diabetes, 13 with metabolic syndrome and 12 age-matched healthy normoglycaemic controls, mean age 57±6 years, underwent skin capillary video microscopy before and 60 and 120 min following a standardised mixed meal to measure baseline capillary density (BCD) and capillary density during post-occlusive peak reactive hyperaemia (PRH), also termed capillary recruitment. Oral glucose insulin sensitivity (Matsuda index) and postprandial hyperglycaemia (2 h AUC glucose ) were calculated. Results Fasting BCD was similar among groups, but fasting PRH was lowest in diabetes (p<0.05). Postprandially, both BCD and PRH increased in all groups (p<0.001); however, the meal-related increase in BCD was significantly lower in diabetes and metabolic syndrome vs controls (both p<0.05). At all time points, postprandial PRH was lower in both diabetes and metabolic syndrome vs controls (both p<0.05). In pooled analysis, postprandial mean PRH correlated with Matsuda index (r00.386, p00.018) and inversely with 2 h AUC glucose (r0−0.336, p00.042). Conclusions/interpretation Gradual deterioration in mealrelated capillary recruitment was paralleled by decreasing insulin sensitivity and postprandial hyperglycaemia, as assessed in healthy normoglycaemic men, men with the metabolic syndrome and those with type 2 diabetes. These findings suggest that in both impaired glucose tolerance and in overt diabetes microvascular dysfunction might contribute to postprandial dysglycaemia.Trial registration: ClinicalTrials.gov NCT00721552

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Section: Discussionsupporting

confidence: 92%

“…We used capillary video microscopy, which enables direct visualisation of microvascular capillaries in the skin in a noninvasive manner. We have recently shown that insulinmediated capillary recruitment in skin parallels insulinmediated microvascular recruitment in skeletal muscle, as measured by contrast-enhanced ultrasound [6].…”

Section: Discussionmentioning

confidence: 99%

Postprandial microvascular function deteriorates in parallel with gradual worsening of insulin sensitivity and glucose tolerance in men with the metabolic syndrome or type 2 diabetes

et al. 2012

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“…However, in previous studies, we demonstrated that the cutaneous microcirculation is a representative vascular bed to examine insulin's actions on the microcirculation. 31 Moreover, assessment of the effects of exenatide on skin microvasculature has 2 benefits. First, in contrast to measurements of muscle microcirculation, direct capillary videomicroscopy allowed us to assess the effects of exenatide not only on microvascular perfusion but also on functional capillary capacity.…”

Section: Smits Et Al Exenatide Increases Capillary Perfusion 1541mentioning

confidence: 99%

GLP-1 Receptor Agonist Exenatide Increases Capillary Perfusion Independent of Nitric Oxide in Healthy Overweight Men

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et al. 2015

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Objective-The insulinotropic gut-derived hormone glucagon-like peptide-1 (GLP-1) increases capillary perfusion via a nitric oxide-dependent mechanism in rodents. This improves skeletal muscle glucose use and cardiac function. In humans, the effect of clinically used GLP-1 receptor agonists (GLP-1RAs) on capillary density is unknown. We aimed to assess the effects of the GLP-1RA exenatide on capillary density as well as the involvement of nitric oxide in humans. Approach and Results-We included 10 healthy overweight men (age, 20-27 years; body mass index, 26-31 kg/m 2 ). Measurements were performed during intravenous infusion of placebo (saline 0.9%), exenatide, and a combination of exenatide and the nonselective nitric oxide-synthase inhibitor l-N G -monomethyl arginine. Capillary videomicroscopy was performed, and baseline and postocclusive (peak) capillary densities were counted. Compared with placebo, exenatide increased baseline and peak capillary density by 20.1% and 8.3%, respectively (both P=0.016). Concomitant l-N G -monomethyl arginine infusion did not alter the effects of exenatide. Vasomotion was assessed using laser Doppler fluxmetry. Exenatide nonsignificantly reduced the neurogenic domain of vasomotion measurements (R=−5.6%; P=0.092), which was strongly and inversely associated with capillary perfusion (R=−0.928; P=0.036). Glucose levels were reduced during exenatide infusion, whereas levels of insulin were unchanged. Conclusions-Acute exenatide infusion increases capillary perfusion via nitric oxide-independent pathways in Materials and MethodsIn this mechanistic cross-over study, healthy overweight participants were subjected to continuous intravenous infusion of placebo (isotonic saline), GLP-1RA exenatide, l-NMMA or a combination of l-NMMA and exenatide. During these conditions, microvascular perfusion was assessed using intravital videomicroscopy and laser Doppler fluxmetry. A complete description of Materials and Methods are available in the Online-only Data Supplement. Results Patient CharacteristicsTen healthy overweight men were included in this analysis. Full characteristics of the subjects can be found in the Table. Capillary VideomicroscopyCompared with placebo, exenatide increased baseline capillary density with 8.0 (5.3-10.5) cap/mm 2 (P=0.016) and peak postarterial occlusion capillary density with 6.5 (4.8-7.8) cap/ mm 2 (P=0.016). This corresponds with an increase of 20.1% and 8.3%, respectively. When exenatide was coinfused with l-NMMA, no significant differences compared with exenatide infused alone were observed (Figure 1).Tests were performed during 2 study days. Day-to-day variation for baseline capillary density and postocclusive peak density were 4.7% and 1.7%, respectively. We conducted sensitivity analyses to assess potential interference of day-to-day variation by including unstimulated measurements (before any intervention) in the statistical model. These sensitivity analyses showed no different results compared with the original analyses. Laser Doppler FluxmetryDuring p...

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“…[2][3][4][5] It uses gas-filled microbubbles, typically with a lipid shell, that are inert, remain entirely within the vascular space, and possess an intravascular rheology similar to that of erythrocytes.…”

Section: To the Editormentioning

confidence: 99%

“…In a post hoc analysis of a recent study measuring microvascular perfusion in skeletal muscle with CEU, 5 we assessed the association of muscle microvascular perfusion with blood pressure. In this healthy, normotensive group, blood pressure was inversely related with skeletal muscle perfusion in the forearm (systolic blood pressure β=−0.50, P=0.05; diastolic blood pressure β=−0.49, P=0.03; and mean arterial pressure β=−0.53, P=0.02) after adjustment for sex and age.…”

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confidence: 99%

Phenotyping the Microcirculation With Contrast-Enhanced Ultrasound

et al. 2012

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In their interesting review, Struijker-Boudier et al 1 provide a critical appraisal of current methods to study the microcirculation. In the extensive review, contrast-enhanced ultrasonography (CEU) remains undiscussed, whereas this method holds great promise as a tool in hypertension research.CEU is an imaging tool that enables quantification of microvascular perfusion in organs and tissues.2-5 It uses gas-filled microbubbles, typically with a lipid shell, that are inert, remain entirely within the vascular space, and possess an intravascular rheology similar to that of erythrocytes.2 Therefore, they specifically enhance imaging of the (micro-)vessels. During intravenous infusion of these microbubbles and attainment of a steady state, microbubbles can be destroyed with high-energy ultrasound. Subsequently, new microbubbles will flow into the region of interest. The rate of microbubble replenishment represents microvascular flow velocity. When the microbubbles are fully replenished, a plateau of video intensity is reached corresponding with the relative microvascular blood volume. The product of microvascular flow velocity and microvascular blood volume is a measure of microvascular perfusion.3 Because microbubbles are distributed throughout the entire vasculature, simultaneous study of microvascular beds of different organs (eg, skeletal muscle, the heart, and kidney) is possible.4 Surprisingly, although CEU has been used to study the pathophysiological role of microvascular perfusion in obesity-related insulin resistance and other metabolic syndrome characteristics, no data are available on the relation with blood pressure/hypertension. In a post hoc analysis of a recent study measuring microvascular perfusion in skeletal muscle with CEU, 5 we assessed the association of muscle microvascular perfusion with blood pressure. In this healthy, normotensive group, blood pressure was inversely related with skeletal muscle perfusion in the forearm (systolic blood pressure β=−0.50, P=0.05; diastolic blood pressure β=−0.49, P=0.03; and mean arterial pressure β=−0.53, P=0.02) after adjustment for sex and age. These relationships did not change after additional adjustment for body mass index. This post hoc analysis shows the potential of CEU to be applied in blood pressure and hypertension research.Apart from the mentioned imaging capabilities, microbubbles can be targeted using antibodies and loaded with interventional drugs. Therefore, CEU combines the assets of intravital microscopy, capillary videomicroscopy, and other imaging strategies. Minimally invasive, low cost and patient friendly, CEU has proven itself as a validated and valuable technique to phenotype the microcirculation in metabolic, as well as blood pressure, research. DisclosuresNone.

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Insulin‐Induced Microvascular Recruitment in Skin and Muscle are Related and Both are Associated with Whole‐Body Glucose Uptake

Abstract: Insulin-augmented capillary recruitment in skin parallels insulin-mediated microvascular recruitment in muscle and both are related to insulin-mediated glucose uptake.

Cited by 73 publications

References 27 publications

Postprandial microvascular function deteriorates in parallel with gradual worsening of insulin sensitivity and glucose tolerance in men with the metabolic syndrome or type 2 diabetes

Postprandial microvascular function deteriorates in parallel with gradual worsening of insulin sensitivity and glucose tolerance in men with the metabolic syndrome or type 2 diabetes

GLP-1 Receptor Agonist Exenatide Increases Capillary Perfusion Independent of Nitric Oxide in Healthy Overweight Men

Phenotyping the Microcirculation With Contrast-Enhanced Ultrasound

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