RESUMEN
BACKGROUND: Ramucirumab, the human immunoglobulin G1 monoclonal antibody receptor antagonist of vascular endothelial growth factor receptor 2, has been approved for treating gastric/gastroesophageal junction, non-small-cell lung, and metastatic colorectal cancers. With the completion of six global, randomized, double-blind, placebo-controlled, phase III trials across multiple tumor types, an opportunity now exists to further establish the safety parameters of ramucirumab across a large patient population. MATERIALS AND METHODS: An individual patient meta-analysis across the six completed phase III trials was conducted and the relative risk (RR) and associated 95% confidence intervals (CIs) were derived using fixed-effects or mixed-effects models for all-grade and high-grade adverse events (AEs) possibly related to vascular endothelial growth factor pathway inhibition. The number needed to harm was also calculable due to the placebo-controlled nature of all six registration standard trials. RESULTS: A total of 4996 treated patients (N = 2748 in the ramucirumab arm and N = 2248 in the control, placebo arm) were included in this meta-analysis. Arterial thromboembolic events [ATE; all-grade, RR: 0.8, 95% CI 0.5-1.3; high-grade (grade ≥3), RR: 0.9, 95% CI 0.5-1.7], venous thromboembolic events (VTE; all-grade, RR: 0.7, 95% CI 0.5-1.1; high-grade, RR: 0.7, 95% CI 0.4-1.2), high-grade bleeding (RR: 1.1, 95% CI 0.8-1.5), and high-grade gastrointestinal (GI) bleeding (RR: 1.1, 95% CI 0.7-1.7) did not demonstrate a definite increased risk with ramucirumab. A higher percentage of hypertension, proteinuria, low-grade (grade 1-2) bleeding, GI perforation, infusion-related reaction, and wound-healing complications were observed in the ramucirumab arm compared with the control arm. CONCLUSIONS: Ramucirumab may be distinct among antiangiogenic agents in terms of ATE, VTE, high-grade bleeding, or high-grade GI bleeding by showing no clear evidence for an increased risk of these AEs in this meta-analysis of a large and diverse patient population. Ramucirumab is consistent with other angiogenic inhibitors in the risk of developing certain AEs. Clinical Trial Numbers: NCT00917384 (REGARD), NCT01170663 (RAINBOW), NCT01168973 (REVEL), NCT01183780 (RAISE), NCT01140347 (REACH), and NCT00703326 (ROSE).
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/inmunología , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/inmunología , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/inmunología , RamucirumabRESUMEN
BACKGROUND: Drug resistance mechanisms can reduce response rate and duration in men with castration-resistant prostate cancer (CRPC) receiving docetaxel-based therapy. Patupilone (epothilone B), a microtubule-targeting agent, may be unaffected by some resistance mechanisms. Therefore, a phase II study assessed the patupilone safety and activity in CRPC patients with and without previous chemotherapy. METHODS: CRPC patients received patupilone 2.5 mg/m(2) weekly for 3 weeks of a 4-week cycle. Patients were required to have measurable disease or prostate-specific antigen (PSA) progression (levels>20 ng/ml). RESULTS: All 45 enrolled patients (median age, 69 years) were safety and response assessable. Sixty-four percent had previous chemotherapy (55% had previous taxane therapy). Patients received a median of three patupilone cycles. Patupilone was generally well tolerated. Ten (22%) patients experienced grade 3 diarrhea, six (13%) grade 3 fatigue, and one (2%) grade 3 neuropathy with no neutropenia or thrombocytopenia incidence. Six (13%) patients had >or= 50% decline in PSA (three had previous taxane therapy). No patient with measurable disease had a response. Median overall survival was 13.4 months. CONCLUSIONS: The safety profile of weekly patupilone in CRPC patients compares favorably with that of other microtubule inhibitors. At the dose and schedule tested, patupilone demonstrated minimal activity in CRPC.
Asunto(s)
Antineoplásicos/uso terapéutico , Epotilonas/uso terapéutico , Orquiectomía , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Epotilonas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/cirugíaRESUMEN
Obesity is characterized by decreased rates of skeletal muscle insulin-mediated glucose uptake (IMGU). Since IMGU equals the product of the arteriovenous glucose difference (AVGd) across muscle and blood flow into muscle, reduced blood flow and/or tissue activity (AVGd) can lead to decreased IMGU. To examine this issue, we studied six lean (weight 68 +/- 3 kg, mean +/- SEM) and six obese (94 +/- 3 kg) men. The insulin dose-response curves for whole body and leg IMGU were constructed using the euglycemic clamp and leg balance techniques over a large range of serum insulin concentrations. In lean and obese subjects, whole body IMGU, AVGd, blood flow, and leg IMGU increased in a dose dependent fashion and maximal rates of all parameters were reduced in obese subjects compared to lean subjects. The dose-response curves for whole body IMGU, leg IMGU, and AVGd were right-shifted in obese subjects with an ED50 two- to threefold higher than that of lean subjects for each parameter. Leg blood flow increased approximately twofold from basal 2.7 +/- 0.2 to 4.4 +/- 0.2 dl/min in lean, P less than 0.01, and from 2.5 +/- 0.3 to 4.4 +/- 0.4 dl/min in obese subjects, P less than 0.01. The ED50 for insulin's effect to increase leg blood flow was about fourfold higher for obese (957 pmol/liter) than lean subjects (266 pmol/liter), P less than 0.01. Therefore, decreased insulin sensitivity in human obesity is not only due to lower glucose extraction in insulin-sensitive tissues but also to lower blood flow to these tissues. Thus, in vivo insulin resistance can be due to a defect in insulin action at the tissue level and/or a defect in insulin's hemodynamic action to increase blood flow to insulin sensitive tissues.
Asunto(s)
Resistencia a la Insulina , Insulina/farmacología , Músculos/irrigación sanguínea , Obesidad/fisiopatología , Adulto , Transporte Biológico , Ácidos Grasos no Esterificados/metabolismo , Glucosa/metabolismo , Humanos , Lactatos/sangre , Pierna/irrigación sanguínea , Flujo Sanguíneo Regional , Análisis de RegresiónRESUMEN
We have estimated the capacity and affinity of insulin-mediated glucose uptake (IMGU) in whole body and in leg muscle of obese non-insulin-dependent diabetics (NIDDM, n = 6) with severe hyperglycemia, glycohemoglobin (GHb 14.4 +/- 1.2%), lean controls (ln, n = 7) and obese nondiabetic controls (ob, n = 7). Mean +/- SEM weight (kg) was 67 +/- 2 (ln), 100 +/- 7 (ob), and 114 +/- 11 (NIDDM), P = NS between obese groups. NIDDM were also studied after 3 wk of intensive insulin therapy, GHb post therapy was 10.1 +/- 0.9, P less than 0.01 vs. pretherapy. Insulin (120 mu/m2 per min) was infused and the arterial blood glucose (G) sequentially maintained at approximately 4, 7, 12, and 21 mmol/liter utilizing the G clamp technique. Leg glucose uptake (LGU) was calculated as the product of the femoral arteriovenous glucose difference (FAVGd) and leg blood flow measured by thermodilution. Compared to ln, ob and NIDDM had significantly lower rates of whole body IMGU and LGU at all G levels. Compared to ob, the NIDDM exhibited approximately 50% and approximately 40% lower rates of whole body IMGU over the first two G levels (P less than 0.02) but did not differ at the highest G, P = NS. LGU was 83% lower in NIDDM vs. ob, P less than 0.05 at the first G level only. After insulin therapy NIDDM were indistinguishable from ob with respect to whole body IMGU or LGU at all G levels. A significant correlation was noted between the percent GHb and the EG50 (G at which 1/2 maximal FAVGd occurs) r = 0.73, P less than 0.05. Thus, (a) insulin resistance in NIDDM and obese subjects are characterized by similar decreases in capacity for skeletal muscle IMGU, but differs in that poorly controlled NIDDM display a decrease in affinity for skeletal muscle IMGU, and (b) this affinity defect is related to the degree of antecedent glycemic control and is reversible with insulin therapy, suggesting that it is an acquired defect.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Insulina/farmacología , Músculos/metabolismo , Transporte Biológico/efectos de los fármacos , Velocidad del Flujo Sanguíneo , Glucemia/metabolismo , Glucosa/farmacocinética , Hemoglobina Glucada/metabolismo , Humanos , Pierna/irrigación sanguínea , Masculino , Obesidad/metabolismoRESUMEN
The purpose of this study was to examine whether insulin's effect to vasodilate skeletal muscle vasculature is mediated by endothelium-derived nitric oxide (EDNO). N-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO synthase, was administered directly into the femoral artery of normal subjects at a dose of 16 mg/min and leg blood flow (LBF) was measured during an infusion of saline (NS) or during a euglycemic hyperinsulinemic clamp (HIC) designed to approximately double LBF. In response to the intrafemoral artery infusion of L-NMMA, LBF decreased from 0.296 +/- 0.032 to 0.235 +/- 0.022 liters/min during NS and from 0.479 +/- 0.118 to 0.266 +/- 0.052 liters/min during HIC, P < 0.03. The proportion of NO-dependent LBF during NS and HIC was approximately 20% and approximately 40%, respectively, P < 0.003 (NS vs. HIC). To elucidate whether insulin increases EDNO synthesis/release or EDNO action, vasodilative responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (MCh) or the endothelium-independent vasodilator sodium nitroprusside (SNP) were studied in normal subjects during either NS or HIC. LBF increments in response to intrafemoral artery infusions of MCh but not SNP were augmented during HIC versus NS, P < 0.03. In summary, insulin-mediated vasodilation is EDNO dependent. Insulin vasodilation of skeletal muscle vasculature most likely occurs via increasing EDNO synthesis/release. Thus, insulin appears to be a novel modulator of the EDNO system.
Asunto(s)
Arginina/análogos & derivados , Insulina/farmacología , Músculos/irrigación sanguínea , Óxido Nítrico/fisiología , Vasodilatación/fisiología , Adulto , Análisis de Varianza , Arginina/administración & dosificación , Arginina/farmacología , Presión Sanguínea/efectos de los fármacos , Índice de Masa Corporal , Relación Dosis-Respuesta a Droga , Femenino , Arteria Femoral , Humanos , Infusiones Intraarteriales , Masculino , Cloruro de Metacolina/administración & dosificación , Cloruro de Metacolina/farmacología , Nitroprusiato/administración & dosificación , Nitroprusiato/farmacología , Flujo Sanguíneo Regional/efectos de los fármacos , Factores de Tiempo , Resistencia Vascular/efectos de los fármacos , Vasodilatación/efectos de los fármacos , omega-N-MetilargininaRESUMEN
We have recently shown that insulin-resistant obese subjects exhibit impaired endothelial function. Here, we test the hypothesis that elevation of circulating FFA to levels seen in insulin-resistant subjects can impair endothelial function. We studied leg blood flow responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (Mch) or the endothelium-independent vasodilator sodium nitroprusside during the infusion of saline and after raising systemic circulating FFA levels exogenously via a low- or high-dose infusion of Intralipid plus heparin or endogenously by an infusion of somatostatin (SRIF) to produce insulinopenia in groups of lean healthy humans. After 2 h of infusion of Intralipid plus heparin, FFA levels increased from 562+/-95 to 1,303+/-188 micromol, and from 350+/-35 to 3,850+/-371 micromol (P < 0.001) vs. saline for both low- and high-dose groups, respectively. Mch-induced vasodilation relative to baseline was reduced by approximately 20% in response to the raised FFA levels in both groups (P < 0.05, saline vs. FFA, ANOVA). In contrast, similar FFA elevation did not change leg blood flow responses to sodium nitroprusside. During the 2-h SRIF infusion, insulin levels fell, and FFA levels rose from 474+/-22 to 1,042+/-116 micromol (P < 0.01); Mch-induced vasodilation was reduced by approximately 20% (P < 0.02, saline vs. SRIF, ANOVA). Replacement of basal insulin levels during SRIF resulted in a fall of FFA levels from 545+/-47 to 228+/-61 micromol, and prevented the impairment of Mch-induced vasodilation seen with SRIF alone. In conclusion, (a) elevated circulating FFA levels cause endothelial dysfunction, and (b) impaired endothelial function in insulin-resistant humans may be secondary to the elevated FFA concentrations observed in these patients.
Asunto(s)
Endotelio Vascular/fisiología , Ácidos Grasos no Esterificados/sangre , Vasodilatación , Adulto , Presión Sanguínea , Emulsiones Grasas Intravenosas/farmacología , Femenino , Humanos , Insulina/farmacología , Pierna/irrigación sanguínea , Masculino , Cloruro de Metacolina/farmacología , Nitroprusiato/farmacología , Somatostatina/farmacologíaRESUMEN
To explore the interactions between insulin action and norepinephrine (NE) on blood pressure and muscle vascular resistance, we studied seven lean (66 +/- 1 kg) sensitive and seven age-matched obese (96 +/- 3 kg) insulin-resistant men after an overnight fast. Both groups were normotensive; however, the obese exhibited higher basal blood pressure, 90.8 +/- 2.2 vs. 83.4 +/- 1.6 mmHg, P < 0.04. Each subject was studied on two separate days during either saline (S) infusion or a euglycemic hyperinsulinemic clamp (I) achieving insulin concentrations of approximately 70 microU/ml. After 180 min of either S or I, NE was infused systemically at rates of approximately 50, 75, and 100 pg/kg per min. Glucose uptake was measured in whole body ([3-3H]glucose) and in leg by the balance technique. The results indicate: (a) the NE/pressor dose-response curve was decreased (shifted to the right) during I in lean but not in obese subjects, (b) I enhanced NE metabolic clearance by 20% in lean but not in obese, (c) NE decreases leg vascular resistance more in lean than in obese, and (d) NE causes a approximately 20% increase in insulin-mediated glucose uptake in both groups. In conclusion, insulin resistance of obesity is associated with an apparent augmented NE pressor sensitivity and decreased NE metabolic clearance. Both of these mechanisms can potentially contribute to the higher incidence of hypertension in obese man. Insulin resistance is likely to be a predisposing but not sufficient factor in the pathogenesis of hypertension. Because the obese group exhibited higher basal blood pressure, it is possible that our results reflect this difference. Further studies will be required to clarify this issue.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Insulina/farmacología , Norepinefrina/farmacología , Obesidad/fisiopatología , Glucemia/análisis , Gasto Cardíaco/efectos de los fármacos , Glucosa/metabolismo , Humanos , Pierna/irrigación sanguínea , Masculino , Resistencia Vascular/efectos de los fármacosRESUMEN
Glucosamine (Glmn), a product of glucose metabolism via the hexosamine pathway, causes insulin resistance in isolated adipocytes by impairing insulin-induced GLUT 4 glucose transporter translocation to the plasma membrane. We hypothesized that Glmn causes insulin resistance in vivo by a similar mechanism in skeletal muscle. We performed euglycemic hyperinsulinemic clamps (12 mU/kg/min + 3H-3-glucose) in awake male Sprague-Dawley rats with and without Glmn infusion at rates ranging from 0.1 to 6.5 mg/kg/min. After 4h of euglycemic clamping, hindquarter muscles were quick-frozen and homogenized, and membranes were subfractionated by differential centrifugation and separated on a discontinuous sucrose gradient (25, 30, and 35% sucrose). Membrane proteins were solubilized and immunoblotted for GLUT 4. With Glmn, glucose uptake (GU) was maximally reduced by 33 +/- 1%, P < 0.001. The apparent Glmn dose to reduce maximal GU by 50% was 0.1 mg/kg/min or 1/70th the rate of GU on a molar basis. Control galactosamine and mannosamine infusions had no effect on GU. Relative to baseline, insulin caused a 2.6-fold increase in GLUT 4 in the 25% membrane fraction (f), P < 0.01, and a 40% reduction in the 35%f, P < 0.05, but had no effect on GLUT 4 in the 30% f, P= NS. Addition of Glmn to insulin caused a 41% reduction of GLUT 4 in the 25%f, P < 0.05, a 29% fall in the 30%f, and prevented the reduction of GLUT 4 in the 35% f. The 30%f membranes were subjected to a second separation with a 27 and 30% sucrose gradient. Insulin mobilized GLUT 4 away from the 30%f, P < 0.05, but not the 27% f. In contrast, Glmn reduced GLUT 4 in the 27%f, P < 0.05, but not the 30%f. Thus Glmn appears to alter translocation of an insulin-insensitive GLUT 4 pool. Coinfusion of Glmn did not alter enrichment of the sarcolemmal markers 5'-nucleotidase, Na+/K+ATPase, and phospholemman in either 25, 30, or 35% f. Thus Glmn completely blocked movement of Glut 4 induced by insulin. Glmn is a potent inducer of insulin resistance in vivo by causing (at least in part) a defect intrinsic to GLUT 4 translocation and/or trafficking. These data support a potential role for Glmn to cause glucose-induced insulin resistance (glucose toxicity).
Asunto(s)
Glucosamina/farmacología , Glucosa/toxicidad , Resistencia a la Insulina , Proteínas de Transporte de Monosacáridos/metabolismo , Proteínas Musculares , Músculo Esquelético/metabolismo , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Membrana Celular/metabolismo , Relación Dosis-Respuesta a Droga , Glucosamina/administración & dosificación , Técnica de Clampeo de la Glucosa , Transportador de Glucosa de Tipo 4 , Hiperinsulinismo , Infusiones Intravenosas , Insulina/administración & dosificación , Insulina/farmacología , Cinética , Masculino , Proteínas de Transporte de Monosacáridos/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Whether insulin-mediated vasodilation is important in determining insulin's overall action to stimulate glucose uptake is unknown. To this end, we measured leg glucose uptake during euglycemic hyperinsulinemic clamps performed at two insulin doses (40 mU/m2 per min, n = 6 and 120 mU/m2 per min, n = 15) alone and during a superimposed intrafemoral artery infusion of GN-monomethyl-L-arginine (L-NMMA) designed to blunt insulin-mediated vasodilation. During the higher dose study, hyperinsulinemia resulted in about a twofold rise in basal leg blood flow from 0.24 +/- 0.02 to 0.45 +/- 0.05 liter/min, P < 0.0001. L-NMMA infusion resulted in a net 21% reduction in leg glucose uptake from 114 +/- 18 mg/min to 85 +/- 13 mg/min, P < 0.001. We also found a significant relationship between the rate of insulin-stimulated whole body glucose uptake and the magnitude of flow dependent glucose uptake (r = 0.57, P = 0.02). Data obtained during the lower dose insulin infusion resulted in similar findings. In conclusion, in healthy lean subjects, insulin-stimulated muscle blood flow contributes to both insulin responsiveness and insulin sensitivity. The most insulin-sensitive subjects appear to be the most reliant on muscle perfusion for insulin action. Insulin-mediated vasodilation is an important physiological determinant of insulin action.
Asunto(s)
Composición Corporal/fisiología , Glucosa/farmacocinética , Insulina/fisiología , Músculo Esquelético/irrigación sanguínea , Vasodilatación/fisiología , Adulto , Arginina/análogos & derivados , Arginina/farmacología , Índice de Masa Corporal , Ayuno , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Humanos , Insulina/farmacología , Resistencia a la Insulina/fisiología , Pierna/irrigación sanguínea , Músculo Esquelético/metabolismo , Flujo Sanguíneo Regional/efectos de los fármacos , Vasodilatación/efectos de los fármacos , omega-N-MetilargininaRESUMEN
Systemic inhibition of nitric oxide synthase (NOS) with NG-monomethyl-L-arginine (L-NMMA) causes acute insulin resistance (IR), but the mechanism is unknown. We tested whether L-NMMA-induced IR occurs via NOS blockade in the central nervous system (CNS). Six groups of Sprague-Dawley rats were studied after chronic implantation of an intracerebroventricular (ICV) catheter into the lateral ventricle and catheters into the carotid artery and jugular vein. Animals were studied after overnight food deprivation, awake, unrestrained, and unstressed; all ICV infusion of L-NMMA or D-NMMA (control) were performed with artificial cerebrospinal fluid. ICV administration of L-NMMA resulted in a 30% rise in the basal glucose level after 2 h, while ICV D-NMMA had no effect on glucose levels. Insulin, epinephrine, and norepinephrine levels were unchanged from baseline in both groups. Tracer (3H-3-glucose)-determined glucose disposal rates during 2 h euglycemic hyperinsulinemic (300 microU/ml) clamps performed after ICV administration of L-NMMA were reduced by 22% compared with D-NMMA. Insulin secretory responses to a hyperglycemic clamp and to a superimposed arginine bolus were reduced by 28% in L-NMMA-infused rats compared with D-NMMA. In conclusion, ICV administration of L-NMMA causes hyperglycemia via the induction of defects in insulin secretion and insulin action, thus recapitulating abnormalities observed in type 2 diabetes. The data suggest the novel concept that central NOS-dependent pathways may control peripheral insulin action and secretion. This control is not likely to be mediated via adrenergic mechanisms and could occur via nonadrenergic, noncholinergic nitrergic neural and/or endocrine pathways. These data support previously published data suggesting that CNS mechanisms may be involved in the pathogenesis of some forms of insulin resistance and type 2 diabetes independent of adiposity.
Asunto(s)
Glucemia/metabolismo , Ventrículos Cerebrales/fisiología , Inhibidores Enzimáticos/farmacología , Insulina/metabolismo , Óxido Nítrico Sintasa/metabolismo , omega-N-Metilarginina/farmacología , Animales , Glucemia/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Ventrículos Cerebrales/efectos de los fármacos , Inhibidores Enzimáticos/administración & dosificación , Epinefrina/sangre , Técnica de Clampeo de la Glucosa , Infusiones Intravenosas , Infusiones Parenterales , Inyecciones Intraventriculares , Insulina/sangre , Insulina/farmacología , Secreción de Insulina , Masculino , Óxido Nítrico Sintasa/antagonistas & inhibidores , Norepinefrina/sangre , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Vigilia , omega-N-Metilarginina/administración & dosificaciónRESUMEN
To test the hypothesis that obesity/insulin resistance impairs both endothelium-dependent vasodilation and insulin-mediated augmentation of endothelium-dependent vasodilation, we studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of methacholine chloride (MCh) or sodium nitroprusside (SNP) during saline infusion and euglycemic hyperinsulinemia in lean insulin-sensitive controls (C), in obese insulin-resistant subjects (OB), and in subjects with non-insulin-dependent diabetes mellitus (NIDDM). MCh induced increments in LBF were approximately 40% and 55% lower in OB and NIDDM, respectively, as compared with C (P < 0.05). Euglycemic hyperinsulinemia augmented the LBF response to MCh by - 50% in C (P < 0.05 vs saline) but not in OB and NIDDM. SNP caused comparable increments in LBF in all groups. Regression analysis revealed a significant inverse correlation between the maximal LBF change in response to MCh and body fat content. Thus, obesity/insulin resistance is associated with (a) blunted endothelium-dependent, but normal endothelium-independent vasodilation and (b) failure of euglycemic hyperinsulinemia to augment endothelium-dependent vasodilation. Therefore, obese/insulin-resistant subjects are characterized by endothelial dysfunction and endothelial resistance to insulin's effect on enhancement of endothelium-dependent vasodilation. This endothelial dysfunction could contribute to the increased risk of atherosclerosis in obese insulin-resistant subjects.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Tipo 2/fisiopatología , Endotelio Vascular/fisiopatología , Resistencia a la Insulina , Insulina/farmacología , Cloruro de Metacolina/farmacología , Nitroprusiato/farmacología , Obesidad/fisiopatología , Flujo Sanguíneo Regional/efectos de los fármacos , Adulto , Glucemia/efectos de los fármacos , Índice de Masa Corporal , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Ácidos Grasos no Esterificados/sangre , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Humanos , Hiperinsulinismo/fisiopatología , Infusiones Intraarteriales , Infusiones Intravenosas , Insulina/administración & dosificación , Pierna/irrigación sanguínea , Cloruro de Metacolina/administración & dosificación , Nitroprusiato/administración & dosificación , Obesidad/sangre , Valores de Referencia , Síndrome , Factores de Tiempo , Triglicéridos/sangre , VasodilataciónRESUMEN
Although insulin is extremely potent in regulating glucose transport in insulin-sensitive tissues, all tissues are capable of taking up glucose by facilitated diffusion by means of a noninsulin-mediated glucose uptake (NIMGU) system. Several reports have estimated that in the postabsorptive state the majority of glucose disposal occurs via a NIMGU mechanism. However, these estimates have been either derived or extrapolated in normal humans. In the present study we have directly measured NIMGU rates in 11 normal (C) and 7 Type II noninsulin-dependent diabetic subjects (NIDDM; mean +/- SE fasting serum glucose, 249 +/- 24 mg/dl). To accomplish this, the serum glucose was clamped at a desired level during a period of insulin deficiency induced by a somatostatin infusion (SRIF, 550 micrograms/h). With a concomitant [3-3H]glucose infusion, we could isotopically quantitate glucose disposal rates (Rd) during basal (basal insulin present) and insulin-deficient (SRIF) conditions. With this approach we found that (a) basal Rd was greater in NIDDM than in C, 274 +/- 31 vs. 150 +/- 7 mg/min, due to elevated hepatic glucose output, (b) NIMGU composes 75 +/- 5% of basal Rd in C and 71 +/- 4% in NIDDM, (c) NIDDMS have absolute basal NIMGU rates that are twice that of C (195 +/- 23 vs. 113 +/- 8 mg/min, P less than 0.05), (d) when C were studied under conditions of insulin deficiency (SRIF infusion) and at a serum glucose level comparable to that of the NIDDM group (250 mg/dl), their rates of NIMGU were the same as that of the NIDDM group (186 +/- 19 vs. 195 +/- 23 mg/min; NS). We conclude that (a) in the postabsorptive state, NIMGU is the major pathway for glucose disposal for both C and NIDDM; (b) for a given glucose level the efficiency of NIMGU (NIMGU divided by serum glucose level) is equal in C and NIDDM, but since basal Rd is elevated in NIDDMs their absolute basal rates of NIMGU are higher; and (c) elevated basal rates of NIMGU in NIDDM may play a role in the pathogenesis of the late complications of diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Adulto , Transporte Biológico , Glucemia/metabolismo , Humanos , Insulina/sangre , SomatostatinaRESUMEN
Insulin resistance is instrumental in the pathogenesis of type 2 diabetes mellitus and the Insulin Resistance Syndrome. While insulin resistance involves decreased glucose transport activity in skeletal muscle, its molecular basis is unknown. Since muscle GLUT4 glucose transporter levels are normal in type 2 diabetes, we have tested the hypothesis that insulin resistance is due to impaired translocation of intracellular GLUT4 to sarcolemma. Both insulin-sensitive and insulin-resistant nondiabetic subgroups were studied, in addition to type 2 diabetic patients. Biopsies were obtained from basal and insulin-stimulated muscle, and membranes were subfractionated on discontinuous sucrose density gradients to equilibrium or under nonequilibrium conditions after a shortened centrifugation time. In equilibrium fractions from basal muscle, GLUT4 was decreased by 25-29% in both 25 and 28% sucrose density fractions and increased twofold in both the 32% sucrose fraction and bottom pellet in diabetics compared with insulin-sensitive controls, without any differences in membrane markers (phospholemman, phosphalamban, dihydropyridine-binding complex alpha-1 subunit). Thus, insulin resistance was associated with redistribution of GLUT4 to denser membrane vesicles. No effects of insulin stimulation on GLUT4 localization were observed. In non-equilibrium fractions, insulin led to small GLUT4 decrements in the 25 and 28% sucrose fractions and increased GLUT4 in the 32% sucrose fraction by 2.8-fold over basal in insulin-sensitive but only by 1.5-fold in both insulin-resistant and diabetic subgroups. The GLUT4 increments in the 32% sucrose fraction were correlated with maximal in vivo glucose disposal rates (r = +0.51, P = 0.026), and, therefore, represented GLUT4 recruitment to sarcolemma or a quantitative marker for this process. Similar to GLUT4, the insulin-regulated aminopeptidase (vp165) was redistributed to a dense membrane compartment and did not translocate in response to insulin in insulin-resistant subgroups. In conclusion, insulin alters the subcellular localization of GLUT4 vesicles in human muscle, and this effect is impaired equally in insulin-resistant subjects with and without diabetes. This translocation defect is associated with abnormal accumulation of GLUT4 in a dense membrane compartment demonstrable in basal muscle. We have previously observed a similar pattern of defects causing insulin resistance in human adipocytes. Based on these data, we propose that human insulin resistance involves a defect in GLUT4 traffic and targeting leading to accumulation in a dense membrane compartment from which insulin is unable to recruit GLUT4 to the cell surface.
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Resistencia a la Insulina , Proteínas de Transporte de Monosacáridos/metabolismo , Proteínas Musculares , Músculo Esquelético/metabolismo , Adulto , Aminopeptidasas/metabolismo , Transporte Biológico , Centrifugación por Gradiente de Densidad , Cistinil Aminopeptidasa , Femenino , Transportador de Glucosa de Tipo 4 , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The hexosamine biosynthetic pathway has been hypothesized to be involved in mediating some of the toxic effects of hyperglycemia. Glutamine:fructose-6-phosphate amidotransferase (GFA), the first and rate limiting enzyme of the hexosamine biosynthetic pathway, was overexpressed in skeletal muscle and adipose tissue of transgenic mice. A 2.4-fold increase of GFA activity in muscle of the transgenic mice led to weight-dependent hyperinsulinemia in random-fed mice. The hyperinsulinemic-euglycemic clamp technique confirmed that transgenic mice develop insulin resistance, with a glucose disposal rate of 68.5 +/- 3.5 compared with 129.4 +/- 9.4 mg/kg per min (P < 0.001) for littermate controls. The decrease in the glucose disposal rate of the transgenic mice is accompanied by decreased protein but not mRNA levels of the insulin-stimulated glucose transporter (GLUT4). These data support the hypothesis that excessive flux through the hexosamine biosynthesis pathway mediates adverse regulatory and metabolic effects of hyperglycemia, specifically insulin resistance of glucose disposal. These mice can serve as a model system to study the mechanism for the regulation of glucose homeostasis by hexosamines.
Asunto(s)
Glutamina-Fructosa-6-Fosfato Transaminasa (Isomerizadora)/fisiología , Hexosaminas/metabolismo , Resistencia a la Insulina , Ratones Transgénicos , Proteínas Musculares , Tejido Adiposo/metabolismo , Animales , Femenino , Expresión Génica , Glucosa/metabolismo , Transportador de Glucosa de Tipo 4 , Hemoglobina Glucada/metabolismo , Hemoglobinas/metabolismo , Masculino , Ratones , Proteínas de Transporte de Monosacáridos/genética , Músculos/metabolismo , ARN Mensajero/genética , Transgenes/genéticaRESUMEN
BACKGROUND: We recently reported endothelial dysfunction as a novel cardiovascular risk factor associated with insulin resistance/obesity. Here, we tested whether hyperandrogenic insulin-resistant women with polycystic ovary syndrome (PCOS) who are at increased risk of macrovascular disease display impaired endothelium-dependent vasodilation and whether endothelial function in PCOS is associated with particular metabolic and/or hormonal characteristics. METHODS AND RESULTS: We studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (MCh) and to euglycemic hyperinsulinemia in 12 obese women with PCOS and in 13 healthy age- and weight-matched control subjects (OBW). LBF increments in response to MCh were 50% lower in the PCOS group than in the OBW group (P:<0.01). Euglycemic hyperinsulinemia increased LBF above baseline by 30% in the PCOS and 60% in OBW group (P:<0.05 between groups). Across all subjects, the maximal LBF response to MCh exhibited a strong inverse correlation with free testosterone levels (r=-0.52, P:<0.007). This relationship was stronger than with any other parameter, including insulin sensitivity. CONCLUSIONS: PCOS is characterized by (1) endothelial dysfunction and (2) resistance to the vasodilating action of insulin. This endothelial dysfunction appears to be associated with both elevated androgen levels and insulin resistance. Given the central vasoprotective role of endothelium, these findings could explain, at least in part, the increased risk for macrovascular disease in women with PCOS.
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Endotelio Vascular/fisiopatología , Síndrome del Ovario Poliquístico/patología , Adulto , Análisis de Varianza , Andrógenos/metabolismo , Presión Sanguínea , Endotelio Vascular/metabolismo , Femenino , Glucosa/metabolismo , Humanos , Resistencia a la Insulina , Pierna/irrigación sanguínea , Metabolismo de los Lípidos , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/fisiopatología , Flujo Sanguíneo Regional , Factores de Riesgo , Estadística como Asunto , Testosterona/metabolismo , VasodilataciónRESUMEN
BACKGROUND: Obesity is a more potent cardiovascular risk factor (CVRF) in men than in women. Because traditional CVRFs cannot fully account for this sex difference, we tested the hypothesis that compared with men, women exhibit more robust endothelial function independent of obesity and that this sex difference is abrogated by diabetes. METHODS AND RESULTS: We studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (Mch) and the endothelium-independent vasodilator sodium nitroprusside (SNP) in groups of lean, obese (OB), and type II diabetic (DM) premenopausal women and age- and body mass index-matched men. LBF response to intrafemoral administration of L-NMMA, an inhibitor of nitric oxide synthase, was also assessed in normal men and women. Maximum LBF increments in response to Mch were 347+/-57% versus 231+/-22% in lean women versus men (P<0.05) and 203+/-25% versus 111+/-17% in OB women versus men (P<0.01), respectively. In DM, maximum LBF increments in response to Mch were 104+/-24% and 138+/-33% in women and men, respectively, (P=NS). LBF decrements in response to L-NMMA were 34.9+/-4.1% and 17.1+/-4.2% in women and men, respectively (P<0.01). The response to SNP was not different between sexes and groups. CONCLUSIONS: Premenopausal nondiabetic women exhibit more robust endothelium-dependent vasodilation owing to higher rates of nitric oxide release than men. Given the protective vascular action of nitric oxide, this difference may partially explain the lower incidence of macrovascular disease in women. In premenopausal women, DM causes impairment of endothelial function beyond that observed with obesity alone and leads to endothelial dysfunction similar to that observed in DM men. These findings may help explain the similar rates of coronary artery disease and mortality in diabetic men and women.
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Diabetes Mellitus Tipo 2/fisiopatología , Endotelio Vascular/efectos de los fármacos , Premenopausia/fisiología , Vasodilatadores/farmacología , Adulto , Diabetes Mellitus/fisiopatología , Endotelio Vascular/fisiología , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Pierna/irrigación sanguínea , Masculino , Cloruro de Metacolina/farmacología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Nitroprusiato/farmacología , Obesidad/fisiopatología , Factores de Riesgo , Caracteres Sexuales , omega-N-Metilarginina/farmacologíaRESUMEN
Insulin-mediated glucose metabolism in skeletal muscle is associated with a commensurate increase in muscle perfusion. The link between insulin action and vasodilation may be mediated by endothelium-derived nitric oxide (EDNO). The evidence suggests that insulin causes an increase in the production of EDNO in insulin-sensitive but not insulin-resistant subjects. This defect in insulin-mediated vasodilation may contribute to 1) enhanced pressor sensitivity and 2) reduced rates of insulin-mediated glucose uptake. We propose that the endothelium is an insulin target tissue that exhibits an increase in the release of EDNO in response to insulin. We postulate that the insulin-resistant state of obesity is associated with insulin resistance at the level of the endothelium, reduced EDNO release, and impaired vasodilation. Thus EDNO may act as the mediator coupling glucose metabolism to vasodilation. The interaction between insulin and the endothelium to enhance EDNO release describes a novel insulin action that deserves further exploration.
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Glucosa/metabolismo , Insulina/fisiología , Músculos/irrigación sanguínea , Músculos/metabolismo , Óxido Nítrico/fisiología , Endotelio Vascular/fisiología , Humanos , Resistencia a la Insulina , Flujo Sanguíneo Regional , VasodilataciónRESUMEN
In vivo glucose uptake (Rd) occurs via two mechanisms: insulin-mediated glucose uptake (IMGU), which occurs in insulin-sensitive tissues, and non-insulin-mediated glucose uptake (NIMGU), which occurs in both insulin-sensitive and non-insulin-sensitive tissues. To determine whether these two pathways for in vivo glucose disposal are regulated independently, we studied the effect of stress levels of cortisol on IMGU and NIMGU in seven normal subjects after an overnight fast. To study NIMGU, somatostatin (SRIF, 600 micrograms/h) was infused to suppress endogenous insulin secretion and create severe insulinopenia, and glucose turnover was measured isotopically while serum glucose was clamped at approximately 200 mg/dl for 240 min. Separate studies were performed during the overnight infusion of saline or hydrocortisone (HCT; 2.0 micrograms.kg-1.min-1). The final 120 min of each study were used for data analysis. Under these conditions, insulin action is absent, and Rd = NIMGU. NIMGU was 204 +/- 11 mg/min and 208 +/- 8 mg/dl during saline and HCT, respectively (P NS). Therefore, HCT did not modulate NIMGU. To measure the effect of cortisol on Rd, hyperglycemic (200 mg/dl)-hyperinsulinemic clamp studies (30 mU.m-2. min-1) were performed during the infusion of saline or HCT. The results demonstrate that during saline infusion, steady-state rates of Rd (10.4 +/- 0.8 mg.kg-1.min-1) were achieved by 160 min; in contrast, during HCT infusion, Rd never reached steady state but increased from 4.5 +/- 0.2 in the 2nd h to 7.6 +/- 0.4 mg.kg-1.min-1 in the 4th h, P less than .01.(ABSTRACT TRUNCATED AT 250 WORDS)
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Glucemia/metabolismo , Glucosa/farmacocinética , Hidrocortisona/sangre , Insulina/farmacología , Somatostatina/farmacología , Péptido C/sangre , Humanos , Hidrocortisona/metabolismo , Insulina/sangre , Cinética , Hígado/metabolismo , MasculinoRESUMEN
Somatostatin (SRIF) has been widely used in the study of in vivo carbohydrate metabolism to suppress pancreatic hormone secretion and thereby interrupt the glucoregulatory feedback loops between insulin, glucagon, and glucose. A critical assumption in the use of SRIF is that it has no effect on hepatic or peripheral glucose metabolism other than those mediated through the inhibition of hormone secretion. To assess whether doses of SRIF commonly used in human investigation have any effect on insulin-stimulated glucose disposal rates, we measured the rate in 6 normal subjects (mean fasting serum glucose level, 93 +/- 2 mg/dl) during euglycemic (approximately equal to 85 mg/dl) hyperinsulinemic (40 mU X m-2 X min-1) clamp studies both with and without the concomitant infusion of SRIF (600 micrograms/hr). The steady-state insulin levels achieved were 85 +/- 6 microU/ml and 74 +/- 8 microU/ml with and without SRIF, respectively (difference not significant). Glucose disposal rates between 120 and 180 min of the clamp were 7.11 +/- 0.10 and 7.35 +/- 0.10 mg X kg-1 X min-1 with and without SRIF, respectively (difference not significant). We concluded that in doses commonly used in human investigation, SRIF does not increase glucose disposal.
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Glucosa/metabolismo , Insulina/farmacología , Somatostatina/farmacología , Adulto , Glucemia/análisis , Humanos , Insulina/sangre , Persona de Mediana Edad , Somatostatina/sangreRESUMEN
Patients with non-insulin-dependent diabetes mellitus (NIDDM) exhibit decreased rates of skeletal muscle insulin-mediated glucose uptake (IMGU). Because IMGU is equal to the product of the arteriovenous glucose difference (AVG delta) across and blood flow (F) into muscle (IMGU = AVG delta x F), reduced tissue permeability (AVG delta) and/or glucose and insulin delivery (F) can potentially lead to decreased IMGU. The components of skeletal muscle IMGU were studied in six obese NIDDM subjects (103 +/- 9 kg) and compared with those previously determined in six lean (weight 68 +/- 3 kg), and six obese (94 +/- 3 kg) with normal glucose tolerance. The insulin dose-response curves for whole body and leg muscle IMGU were constructed using the combined euglycemic clamp and leg balance techniques during sequential insulin infusions (range of serum insulin 130-80,000 pmol/L). In lean, obese, and NIDDM subjects, whole body IMGU, femoral AVG delta, and leg IMGU increased in a dose-dependent fashion over the range of insulin with an ED50 of 400-500 pmol/L in lean, 1000-1200 pmol/L in obese, and 4000-7000 pmol/L in NIDDM subjects (P less than 0.01 lean vs. obese and NIDDM). In lean and obese subjects, maximally effective insulin concentrations increased leg blood flow approximately 2-fold from basal with an ED50 of 266 pmol/L and 957 pmol/L, respectively (P less than 0.01 lean vs. obese). In contrast, leg F did not increase from the basal value in NIDDM subjects (2.7 +/- 0.1 vs. 3.5 +/- 0.5 dl/min, NS).(ABSTRACT TRUNCATED AT 250 WORDS)