RESUMEN
Decreased tissue perfusion increases the risk of developing insulin resistance and cardiovascular disease in obesity, and decreased levels of globular adiponectin (gAdn) have been proposed to contribute to this risk. We hypothesized that gAdn controls insulin's vasoactive effects through AMP-activated protein kinase (AMPK), specifically its α2 subunit, and studied the mechanisms involved. In healthy volunteers, we found that decreased plasma gAdn levels in obese subjects associate with insulin resistance and reduced capillary perfusion during hyperinsulinemia. In cultured human microvascular endothelial cells (HMEC), gAdn increased AMPK activity. In isolated muscle resistance arteries gAdn uncovered insulin-induced vasodilation by selectively inhibiting insulin-induced activation of ERK1/2, and the AMPK inhibitor compound C as well as genetic deletion of AMPKα2 blunted insulin-induced vasodilation. In HMEC deletion of AMPKα2 abolished insulin-induced Ser(1177) phosphorylation of eNOS. In mice we confirmed that AMPKα2 deficiency decreases insulin sensitivity, and this was accompanied by decreased muscle microvascular blood volume during hyperinsulinemia in vivo. This impairment was accompanied by a decrease in arterial Ser(1177) phosphorylation of eNOS, which closely related to AMPK activity. In conclusion, globular adiponectin controls muscle perfusion during hyperinsulinemia through AMPKα2, which determines the balance between NO and ET-1 activity in muscle resistance arteries. Our findings provide a novel mechanism linking reduced gAdn-AMPK signaling to insulin resistance and impaired organ perfusion.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Adiponectina/metabolismo , Insulina/metabolismo , Obesidad/complicaciones , Adulto , Animales , Células Endoteliales/metabolismo , Endotelina-1/metabolismo , Femenino , Humanos , Insulina/administración & dosificación , Insulina/sangre , Resistencia a la Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Óxido Nítrico/metabolismo , Obesidad/metabolismo , Ratas , Ratas Wistar , Transducción de Señal , Vasodilatación/fisiologíaRESUMEN
AIMS/HYPOTHESIS: Obesity increases the risk of cardiovascular disease and type 2 diabetes, partly through reduced insulin-induced microvascular vasodilation, which causes impairment of glucose delivery and uptake. We studied whether perivascular adipose tissue (PVAT) controls insulin-induced vasodilation in human muscle, and whether altered properties of PVAT relate to reduced insulin-induced vasodilation in obesity. METHODS: Insulin-induced microvascular recruitment was measured using contrast enhanced ultrasound (CEU), before and during a hyperinsulinaemic-euglycaemic clamp in 15 lean and 18 obese healthy women (18-55 years). Surgical skeletal muscle biopsies were taken on a separate day to study perivascular adipocyte size in histological slices, as well as to study ex vivo insulin-induced vasoreactivity in microvessels in the absence and presence of PVAT in the pressure myograph. Statistical mediation of the relation between BMI and microvascular recruitment by PVAT was studied in a mediation model. RESULTS: Obese women showed impaired insulin-induced microvascular recruitment and lower metabolic insulin sensitivity compared with lean women. Microvascular recruitment was a mediator in the association between obesity and insulin sensitivity. Perivascular adipocyte size, determined in skeletal muscle biopsies, was larger in obese than in lean women, and statistically explained the difference in microvascular recruitment between obese and lean women. PVAT from lean women enhanced insulin-induced vasodilation in isolated skeletal muscle resistance arteries, while PVAT from obese women revealed insulin-induced vasoconstriction. CONCLUSIONS/INTERPRETATION: PVAT from lean women enhances insulin-induced vasodilation and microvascular recruitment whereas PVAT from obese women does not. PVAT adipocyte size partly explains the difference in insulin-induced microvascular recruitment between lean and obese women.
Asunto(s)
Tejido Adiposo/efectos de los fármacos , Diabetes Mellitus Tipo 2/fisiopatología , Insulina/farmacología , Microvasos/efectos de los fármacos , Músculo Esquelético/irrigación sanguínea , Obesidad/fisiopatología , Tejido Adiposo/fisiología , Adolescente , Adulto , Femenino , Humanos , Resistencia a la Insulina/fisiología , Microvasos/fisiología , Persona de Mediana Edad , Músculo Esquelético/fisiología , Adulto JovenRESUMEN
OBJECTIVE: obesity-related microvascular dysfunction, including alterations in rhythmic changes in vascular diameter, so-called 'vasomotion', may be important in the clustering of obesity with other cardiovascular risk factors. Adipokines have been suggested to play a role in obesity-related vascular dysfunction. Alterations in vasomotion have been found using extreme body mass index (BMI) phenotypes. Whether these alterations can be translated to the general population is unknown. The aim was to retrospectively investigate relationships between BMI, vasomotion and adipokines in a population-based cohort. METHODS: Adiposity, vasomotion, adiponectin and leptin were determined in 94 apparently healthy participants (age 42 years, 46 men, mean BMI 25·5 ± 3·8 kg/m(2) ) of the Amsterdam Growth and Health Longitudinal Study (AGHLS). Vasomotion was assessed via wavelet analysis of skin laser Doppler flowmetry (LDF). RESULTS: BMI was associated with the neurogenic domain of the vasomotion spectrum (ß -0·011, P = 0·046), adiponectin (ß -0·18, P = 0·028) and leptin (ß 2·22, P < 0·0001). Adiponectin was positively associated with the neurogenic domain of vasomotion (ß 0·016, P = 0·019). Leptin did not show any significant relationship with vasomotion. The association between BMI and the neurogenic domain of the vasomotion spectrum was partly explained by adiponectin. CONCLUSIONS: The association between adiposity and microvascular vasomotion also applies to the normal population and is partly explained by adiponectin.
Asunto(s)
Adiponectina/fisiología , Adiposidad/fisiología , Índice de Masa Corporal , Microvasos/fisiología , Adiponectina/metabolismo , Adulto , Distribución de la Grasa Corporal , Femenino , Humanos , Flujometría por Láser-Doppler , Leptina/metabolismo , Masculino , Microcirculación/fisiología , Obesidad/fisiopatología , Estudios RetrospectivosRESUMEN
OBJECTIVE: Insulin-induced capillary recruitment is considered a significant regulator of overall insulin-stimulated glucose uptake. Insulin's action to recruit capillaries has been hypothesized to involve insulin-induced changes in vasomotion. Data directly linking vasomotion to capillary perfusion, however, are presently lacking. We, therefore, investigated whether insulin's actions on capillary recruitment and vasomotion were interrelated in a group of healthy individuals. We further assessed the role of capillary recruitment in the association between vasomotion and insulin-mediated glucose uptake. METHODS: Changes in vasomotion and capillary density were determined by LDF and capillary videomicroscopy in skin, respectively, before and during a hyperinsulinemic euglycemic clamp in 19 healthy volunteers. RESULTS: Insulin-induced increase in the neurogenic vasomotion domain was positively related to insulin-augmented capillary recruitment (r = 0.51, p = 0.04), and both parameters were related to insulin-mediated glucose uptake (r = 0.47, p = 0.06 and r = 0.73, p = 0.001, respectively). The change in insulin-augmented capillary recruitment could, at least statistically, largely explain the association between the neurogenic domain and insulin-mediated glucose uptake. CONCLUSIONS: Insulin-induced changes in vasomotion and capillary recruitment are associated in healthy volunteers. These data suggest that insulin's action to recruit capillaries may in part involve action on the neurogenic vasomotion domain, thereby enhancing capillary perfusion and glucose uptake.
Asunto(s)
Capilares/fisiología , Glucosa/metabolismo , Hemodinámica/efectos de los fármacos , Hipoglucemiantes/farmacología , Insulina/farmacología , Adulto , Hemodinámica/fisiología , Humanos , MasculinoRESUMEN
OBJECTIVE We investigated whether proliferative diabetic retinopathy in type 1 diabetic patients can be generalized to cerebral small vessel disease and whether it is associated with impaired peripheral microvascular function. RESEARCH DESIGN AND METHODS Thirty-three patients with proliferative diabetic retinopathy (PDR+), 34 patients without proliferative diabetic retinopathy, and 33 controls underwent magnetic resonance imaging to assess cerebral microangiopathy (cerebral microbleeds) and ischemic damage (white matter hyperintensities and lacunes). Peripheral microvascular function, i.e., skin capillary density and capillary recruitment, was assessed by capillary microscopy. RESULTS Cerebral microbleeds, but not ischemic damage, were more prevalent in PDR+ patients versus the other groups (P < 0.05). A trend was found across groups for the lowest baseline capillary density in PDR+ patients (P for trend = 0.05). In individuals with microbleeds, capillary recruitment was impaired compared with those without microbleeds (P = 0.04). CONCLUSIONS In PDR+ patients, cerebral microbleed prevalence was higher and seems part of generalized microangiopathy that may affect the skin and the brain.
Asunto(s)
Hemorragia Cerebral/etiología , Diabetes Mellitus Tipo 1/complicaciones , Retinopatía Diabética/etiología , Adulto , Retinopatía Diabética/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: Insulin-induced capillary recruitment is considered a determinant of insulin-mediated glucose uptake. Insulin action on the microvasculature has been assessed in skin; however, there is concern as to whether the vascular responses observed in skin reflect those in the muscle. We hypothesized that insulin-induced capillary recruitment in skin would correlate with microvascular recruitment in muscle in a group of subjects displaying a wide variation in insulin sensitivity. METHODS: Capillary recruitment in skin was assessed using capillary videomicroscopy, and skeletal muscle microvascular recruitment (i.e., increase in MBV) was studied using CEU in healthy volunteers (n = 18, mean age: 30.6 ± 11.1 years). Both microvascular measurements were performed during saline infusion, and during a hyperinsulinemic euglycemic clamp. RESULTS: During hyperinsulinemia, capillary recruitment in skin was augmented from 58.1 ± 18.2% to 81.0 ± 23.9% (p < 0.0001). Hyperinsulinemia increased MBV in muscle from 7.00 (2.66-17.67) to 10.06 (2.70-41.81) units (p = 0.003). Insulin's vascular effect in skin and muscle was correlated (r = 0.57). Insulin's microvascular effects in skin and muscle showed comparable strong correlations with insulin-mediated glucose uptake (r = 0.73 and 0.68, respectively). CONCLUSIONS: Insulin-augmented capillary recruitment in skin parallels insulin-mediated microvascular recruitment in muscle and both are related to insulin-mediated glucose uptake.
Asunto(s)
Capilares/fisiopatología , Glucosa/metabolismo , Hiperinsulinismo , Hipoglucemiantes/efectos adversos , Insulina/efectos adversos , Músculo Esquelético , Piel , Adulto , Capilares/metabolismo , Humanos , Hiperinsulinismo/inducido químicamente , Hiperinsulinismo/metabolismo , Hiperinsulinismo/fisiopatología , Hipoglucemiantes/farmacología , Insulina/farmacología , Masculino , Microcirculación/efectos de los fármacos , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Piel/irrigación sanguínea , Piel/metabolismo , Piel/fisiopatologíaRESUMEN
Current strategies combining anti-angiogenic drugs with chemotherapy provide clinical benefit in cancer patients. It is assumed that anti-angiogenic drugs, such as bevacizumab, transiently normalize abnormal tumor vasculature and contribute to improved delivery of subsequent chemotherapy. To investigate this concept, a study was performed in non-small cell lung cancer (NSCLC) patients using positron emission tomography (PET) and radiolabeled docetaxel ([(11)C]docetaxel). In NSCLC, bevacizumab reduced both perfusion and net influx rate of [(11)C]docetaxel within 5 hr. These effects persisted after 4 days. The clinical relevance of these findings is notable, as there was no evidence for a substantial improvement in drug delivery to tumors. These findings highlight the importance of drug scheduling and advocate further studies to optimize scheduling of anti-angiogenic drugs.
Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Taxoides/farmacocinética , Anciano , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Bevacizumab , Médula Ósea/metabolismo , Docetaxel , Esquema de Medicación , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neovascularización Patológica/tratamiento farmacológico , Tomografía de Emisión de Positrones , Taxoides/administración & dosificación , Taxoides/uso terapéutico , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/metabolismo , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
The intertwined epidemics of obesity and related disorders such as hypertension, insulin resistance, type 2 diabetes, and subsequent cardiovascular disease pose a major public health challenge. To meet this challenge, we must understand the interplay between adipose tissue and the vasculature. Microvascular dysfunction is important not only in the development of obesity-related target-organ damage but also in the development of cardiovascular risk factors such as hypertension and insulin resistance. The present review examines the role of microvascular dysfunction as an explanation for the associations among obesity, hypertension, and impaired insulin-mediated glucose disposal. We also discuss communicative pathways from adipose tissue to the microcirculation.
Asunto(s)
Tejido Adiposo/fisiopatología , Hipertensión/fisiopatología , Resistencia a la Insulina , Microcirculación , Obesidad/fisiopatología , Tejido Adiposo/irrigación sanguínea , Animales , Humanos , Hipertensión/etiología , Obesidad/complicacionesRESUMEN
Hypertension is a common side effect in cancer patients treated with inhibitors of vascular endothelial growth factor/vascular endothelial growth factor receptor-2 signaling and may represent a marker of clinical benefit. Functional rarefaction (a decrease in perfused microvessels) or structural rarefaction (a reduction in anatomic capillary density) may play an important role in the development of hypertension. We investigated whether sunitinib caused impairment of microvascular function and/or reduction of capillary density in patients with metastatic renal cell cancer (mRCC). Sixteen mRCC patients were treated with sunitinib (50 mg/day). Assessments of 24-h ambulatory blood pressure, microvascular endothelial function by laser Doppler fluxmetry, and capillary density by capillary microscopy were performed at baseline and days 14 and 28. Median blood pressure had increased on day 14 (systolic 10 mmHg, P<0.01 and diastolic blood pressure 8 mmHg, P<0.01). Capillary density had decreased from 69 to 61 capillaries/mm (P<0.01). This decrease was related to the increase in systolic and diastolic blood pressure (r=-0.57, P<0.05 and r=-0.68, P<0.01, respectively). A more pronounced decrease in capillary density was associated with increased visibility of the subpapillary plexus (P=0.041). Preliminary findings indicated that median progression-free survival was significantly prolonged in patients with a greater than 6 capillaries/mm decrease in density as compared with patients with a less pronounced decrease (P=0.044). In conclusion, reduction in skin capillary density is associated with a rise in blood pressure during sunitinib therapy and, by itself, might be useful as a predictive marker of clinical outcome.
Asunto(s)
Inhibidores de la Angiogénesis/efectos adversos , Capilares/efectos de los fármacos , Indoles/efectos adversos , Pirroles/efectos adversos , Piel/irrigación sanguínea , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/uso terapéutico , Capilares/anatomía & histología , Capilares/fisiopatología , Femenino , Humanos , Hipertensión/inducido químicamente , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pirroles/uso terapéutico , Piel/efectos de los fármacos , Piel/fisiopatología , SunitinibRESUMEN
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 ( approximately 235 mmol NaCl/d) versus low-salt diet ( approximately 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.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Hipertensión Renal/inducido químicamente , Hipertensión Renal/fisiopatología , Recién Nacido de Bajo Peso , Cloruro de Sodio Dietético/efectos adversos , Adulto , Creatinina/sangre , Femenino , Humanos , Hipertensión Renal/epidemiología , Recién Nacido , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores de Riesgo , Ácido Úrico/sangreRESUMEN
The metabolic syndrome defines a clustering of metabolic risk factors that confers an increased risk for type 2 diabetes and cardiovascular disease. The metabolic syndrome seems to have multiple etiological factors and microvascular dysfunction may be one potential factor explaining the clustering of multiple metabolic risk factors including hypertension, obesity, insulin resistance and glucose intolerance. Microvascular dysfunction may increase not only peripheral vascular resistance and blood pressure, but may also decrease insulin-mediated glucose uptake in muscle. The present article summarizes some of the data concerning the role of microvascular dysfunction in the metabolic syndrome.