RESUMEN
AIMS/HYPOTHESIS: The aim of the study was to assess the effect of hyperglycaemia on regional concentrations of glucose and other substrates within the brain in non-diabetic individuals and in patients with type 1 diabetes. METHODS: The brain metabolites of 17 men with type 1 diabetes and 12 age-matched non-diabetic men (22-43 years old) were studied after an overnight fast (plasma glucose 9.2 +/- 3.0 vs 4.8 +/- 0.5 mmol/l, respectively). N-Acetylaspartate (NAA), creatine, choline, myo-inositol (mI) and glucose in the frontal cortex, frontal white matter and thalamus were quantified with proton magnetic resonance spectroscopy. RESULTS: In the non-diabetic participants, the glucose level was 47% higher (p < 0.01) in the frontal cortex than in the frontal white matter. In contrast, this regional variation was not observed in the diabetic participants, in whom the glucose level in the frontal white matter was 64% higher (p < 0.001) and in the frontal cortex 25% higher (p = 0.033) than that of the non-diabetic participants. In the diabetic participants, the glucose level in each of the three regions studied correlated with fasting plasma glucose (r = 0.88-0.67, p < 0.01). In addition, in the diabetic participants, mI was 20% higher (p < 0.001) and NAA 6% lower (p = 0.037) in the frontal white matter, and mI was 8% higher (p = 0.042) in the frontal cortex, than in the non-diabetic participants. CONCLUSIONS/INTERPRETATION: In type 1 diabetes, hyperglycaemia is associated with accumulation of glucose and mI in the cortex and in the white matter.
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Encéfalo/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Glucosa/metabolismo , Hiperglucemia/metabolismo , Inositol/metabolismo , Adulto , Glucemia/metabolismo , Presión Sanguínea , Índice de Masa Corporal , Proteína C-Reactiva/metabolismo , HDL-Colesterol/sangre , Diabetes Mellitus Tipo 1/fisiopatología , Hemoglobina Glucada/metabolismo , Frecuencia Cardíaca , Humanos , Lípidos/sangre , Imagen por Resonancia Magnética , Masculino , Selección de Paciente , Valores de Referencia , Adulto JovenRESUMEN
Defects in insulin stimulation of blood flow have been used suggested to contribute to insulin resistance. To directly test whether glucose uptake can be altered by changing blood flow, we infused bradykinin (27 microgram over 100 min), an endothelium-dependent vasodilator, into the femoral artery of 12 normal subjects (age 25+/-1 yr, body mass index 22+/-1 kg/m2) after an overnight fast (n = 5) and during normoglycemic hyperinsulinemic (n = 7) conditions (serum insulin 465+/-11 pmol/liter, 0-100 min). Blood flow was measured simultaneously in both femoral regions using [15O]-labeled water ([15O]H2O) and positron emission tomography (PET), before and during (50 min) the bradykinin infusion. Glucose uptake was measured immediately after the blood flow measurement simultaneously in both femoral regions using [18F]-fluoro-deoxy-glucose ([18F]FDG) and PET. During hyperinsulinemia, muscle blood flow was 58% higher in the bradykinin-infused (38+/-9 ml/kg muscle x min) than in the control leg (24+/-5, P<0.01). Femoral muscle glucose uptake was identical in both legs (60.6+/-9.5 vs. 58.7+/-9.0 micromol/kg x min, bradykinin-infused vs control leg, NS). Glucose extraction by skeletal muscle was 44% higher in the control (2.6+/-0.2 mmol/liter) than the bradykinin-infused leg (1.8+/-0.2 mmol/liter, P<0.01). When bradykinin was infused in the basal state, flow was 98% higher in the bradykinin-infused (58+/-12 ml/kg muscle x min) than the control leg (28+/-6 ml/kg muscle x min, P<0.01) but rates of muscle glucose uptake were identical in both legs (10.1+/-0.9 vs. 10.6+/-0.8 micromol/kg x min). We conclude that bradykinin increases skeletal muscle blood flow but not muscle glucose uptake in vivo. These data provide direct evidence against the hypothesis that blood flow is an independent regulator of insulin-stimulated glucose uptake in humans.
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Glucosa/metabolismo , Hemodinámica/fisiología , Insulina/fisiología , Adulto , Transporte Biológico Activo/efectos de los fármacos , Bradiquinina/administración & dosificación , Desoxiglucosa/análogos & derivados , Desoxiglucosa/metabolismo , Radioisótopos de Flúor , Fluorodesoxiglucosa F18 , Hemodinámica/efectos de los fármacos , Humanos , Insulina/administración & dosificación , Insulina/sangre , Resistencia a la Insulina/fisiología , Masculino , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Radioisótopos de Oxígeno , Tomografía Computarizada de Emisión , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
BACKGROUND: It is unknown whether LDL particle size is, independent of other lipids and lipoproteins, associated with endothelial dysfunction in vivo. METHODS AND RESULTS: We determined in vivo endothelial function in 34 healthy men by measuring forearm blood flow responses to intrabrachial artery infusions of acetylcholine (ACh, an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator). LDL peak particle size was measured with gradient gel electrophoresis. Men with small LDL particles (LDL diameter =25.5 nm, n=10) had a 39% lower blood flow response to ACh than men with large LDL particles (LDL diameter >25. 5 nm, n=24, blood flow 6.9+/-3.6 versus 11.4+/-5.1 mL/dL. min, P=0. 006). The groups had comparable LDL cholesterol concentrations (3. 9+/-0.6 versus 3.7+/-1.0 mmol/L, men with small versus large LDL particles), blood pressure, glucose concentrations, and body mass indexes. LDL size (r=0.45, P=0.01) but not HDL cholesterol (r=0.31, P=0.09) or triglycerides (r=-0.19, P=0.30) was significantly correlated with endothelium-dependent vasodilation. Serum triglyceride concentrations and LDL size were inversely correlated (r=-0.44, P=0.01). In multivariate regression analysis, LDL size was the only significant determinant of the ACh-induced increase in blood flow. Sodium nitroprusside-stimulated endothelium-independent vasodilation was similar in both groups. CONCLUSIONS: Small LDL particles are associated with impaired in vivo endothelial function independent of HDL and LDL cholesterol and triglyceride concentrations. LDL size may therefore mediate adverse effects of hypertriglyceridemia on vascular function.
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Endotelio Vascular/fisiopatología , Lipoproteínas LDL/química , Lipoproteínas LDL/fisiología , Acetilcolina/administración & dosificación , Acetilcolina/farmacología , Adulto , Vasos Sanguíneos/fisiopatología , Relación Dosis-Respuesta a Droga , Antebrazo/irrigación sanguínea , Humanos , Masculino , Persona de Mediana Edad , Nitroprusiato/farmacología , Tamaño de la Partícula , Flujo Sanguíneo Regional/efectos de los fármacos , Resistencia Vascular , Vasodilatadores/administración & dosificación , Vasodilatadores/farmacologíaRESUMEN
In rodents, food intake and insulin increase ob gene expression and circulating leptin concentrations, but it is unknown whether insulin regulates plasma leptin concentrations in humans. We measured plasma leptin concentrations in 27 normal subjects (16 men, 11 women; age, 24 +/- 1 years; BMI, 22.6 +/- 0.5 kg/m2; body fat, 18 +/- 1%) during a 6-h euglycemic hyperinsulinemic clamp (sequential insulin infusions of 1, 2, and 5 mU.kg-1.min-1 for 2 h each). During these insulin infusions, plasma leptin increased from a basal concentration of 7.4 +/- 1.6 ng/ml by -2 +/- 2, 17 +/- 4, and 50 +/- 6% to 7.2 +/- 1.5 (NS vs. basal), 8.5 +/- 1.7 (P < 0.001), and 10.4 +/- 2.0 ng/ml (P < 0.001), respectively. Of the subjects, eight also participated in a control study where saline was infused for 6 h. In these subjects, plasma leptin increased by 5 +/- 4, 26 +/- 10, and 62 +/- 10% during the insulin infusions, and decreased by 9 +/- 4 (P = 0.07 for change during saline vs. insulin), 13 +/- 4 (P < 0.01), and 17 +/- 4% (P < 0.001) after 2, 4, and 6 h of the saline infusion, respectively. Women had higher plasma leptin concentrations basally and during hyperinsulinemia (P < 0.001) than men, but this difference was entirely accounted for by greater adiposity in women (22 +/- 2 vs. 14 +/- 1%, P < 0.001). These data provide evidence for the insulin regulation of plasma leptin concentrations in humans. This effect requires hours of high insulin concentrations, implying that postprandial satiety is not regulated via changes in plasma leptin concentrations. Insulin may, however, be of importance in the long-term or diurnal regulation of plasma leptin concentrations.
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Tejido Adiposo/fisiología , Glucemia/metabolismo , Hiperinsulinismo , Insulina/farmacología , Proteínas/metabolismo , Tejido Adiposo/anatomía & histología , Adulto , Femenino , Humanos , Infusiones Intravenosas , Insulina/administración & dosificación , Cinética , Leptina , Masculino , Obesidad , Proteínas/análisis , Valores de Referencia , Caracteres Sexuales , Factores de TiempoRESUMEN
Overactivity of the hexosamine pathway mediates glucose-induced insulin resistance in rat adipocytes. Glutamine:fructose-6-phosphate amidotransferase (GFA) is the rate-limiting enzyme of this pathway. We determined GFA activity in human skeletal muscle biopsies and rates of insulin-stimulated whole-body, oxidative, and nonoxidative glucose disposal using the euglycemic insulin clamp technique combined with indirect calorimetry (insulin infusion rate (1.5 mU x kg-1 x min-1)) in 12 male patients with NIDDM (age 54 +/- 2 years, BMI 27.5 +/- 0.9 kg/m2, fasting plasma glucose 8.5 +/- 0.6 mmol/l) and 9 matched normal men. GFA activity was detectable in human skeletal muscles and completely inhibited by uridine-5'-diphospho-N-acetylglucosamine (UDP-GlcNAc) in all subjects. GFA activity was 46% increased in the NIDDM patients compared with the normal subjects (9.5 +/- 1.3 vs. 6.5 +/- 1.2 pmol, P < 0.05). Whole-body glucose uptake was 58% decreased in patients with NIDDM (20 +/- 3 micromol x kg body wt-1 x min-1) compared with normal subjects (47 +/- 4 micromol x kg body wt-1 x min-1, P < 0.001). This decrease was attributable to decreases in both glucose oxidation (9 +/- 1 vs. 15 +/- 1 micromol x kg-1 x min-1, NIDDM patients vs. control subjects, P < 0.002) and nonoxidative glucose disposal (11 +/- 2 vs. 31 +/- 4 micromol x kg-1 x min-1, P < 0.001). In patients with NIDDM, both HbA1c (r= 0.51, P < 0.05) and BMI (r= -0.57, P < 0.05) correlated with whole-body glucose uptake. HbA1c but not BMI or insulin sensitivity was correlated with basal GFA activity (r = -0.57,P < 0.01) in NIDDM patients and control subjects. We conclude that GFA is found in human skeletal muscle and that all this activity is sensitive to feedback inhibition by UDP-GlcNAc. Chronic hyperglycemia is associated with an increase in skeletal muscle GFA activity, suggesting that increased activity of the hexosamine pathway may contribute to glucose toxicity and insulin resistance in humans.
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Diabetes Mellitus Tipo 2/enzimología , Glutamina-Fructosa-6-Fosfato Transaminasa (Isomerizadora)/metabolismo , Músculo Esquelético/enzimología , Glucemia/metabolismo , Índice de Masa Corporal , Calorimetría Indirecta , Diabetes Mellitus/enzimología , Ayuno , Técnica de Clampeo de la Glucosa , Hemoglobina Glucada/metabolismo , Humanos , Insulina/sangre , Insulina/farmacología , Masculino , Análisis por Apareamiento , Persona de Mediana Edad , Obesidad , Oxidación-ReducciónRESUMEN
We determined the effect of insulin on muscle blood flow and glucose uptake in humans using [15O]H2O, [18F]fluoro-2-deoxy-D-glucose ([18F]FDG), and positron emission tomography (PET). Femoral muscle blood flow was measured in 14 healthy volunteers (age 34 +/- 8 years, BMI 24.6 +/- 3.4 kg/m2 [means +/- SD]) before and at 75 min during a 140-min high-dose insulin infusion (serum insulin 2,820 +/- 540 pmol/l) under normoglycemic conditions. A dynamic scan of the femoral region was performed using PET for 6 min after injection of [15O]H2O to determine the 15O concentration in tissue. Regional femoral muscle blood flow was calculated using an autoradiographic method from the dynamic data obtained with PET and [15O]H2O. Femoral muscle glucose uptake was measured during hyperinsulinemia immediately after the flow measurement using PET-derived [18F]FDG kinetics and a three-compartment model. Whole-body glucose uptake was quantitated using the euglycemic insulin clamp technique. In the basal state, 84 +/- 8% of blood flow was confined to skeletal muscle. Insulin increased leg blood flow from 29 +/- 14 to 54 +/- 29 ml x kg-1 leg x min-1 (P < 0.001) and muscle flow from 31 +/- 18 to 58 +/- 35 ml x kg-1 muscle x min-1 (P < 0.005). Under insulin-stimulated conditions, 81 +/- 8% of blood flow was in muscle tissue (NS versus basal). Skeletal muscle explained 70 +/- 25% of the increase in leg blood flow. No correlation was observed between blood flow and glucose uptake when analyzed individually in identical regions of interest within femoral muscles. These data demonstrate that skeletal muscle accounts for most of the insulin-induced increase in blood flow. Insulin-stimulated rates of blood flow and glucose uptake do not colocalize in the same regions of muscle tissue, suggesting that insulin's hemodynamic and metabolic effects are differentially regulated.
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Desoxiglucosa/análogos & derivados , Radioisótopos de Flúor , Glucosa/metabolismo , Insulina/farmacología , Músculo Esquelético/fisiología , Radioisótopos de Oxígeno , Adulto , Glucemia/metabolismo , Desoxiglucosa/farmacocinética , Radioisótopos de Flúor/farmacocinética , Fluorodesoxiglucosa F18 , Humanos , Hiperinsulinismo , Cinética , Masculino , Modelos Biológicos , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/efectos de los fármacos , Radioisótopos de Oxígeno/farmacocinética , Pletismografía , Valores de Referencia , Flujo Sanguíneo Regional/efectos de los fármacos , Reproducibilidad de los Resultados , Tomografía Computarizada de Emisión , AguaRESUMEN
OBJECTIVE: Frequency domain analysis of heart rate variability (HRV) is used to assess cardiovascular autonomic function. There are no prospective data on the sensitivity of its various components to glycemia or other diabetes-related risk factors compared with conventional tests and with other complications of diabetes. RESEARCH DESIGN AND METHODS: In 1985, possible risk factors of future complications were determined in 115 children with type 1 diabetes. In 1996, the presence of complications (HRV analysis, conventional tests of autonomic function, urinary albumin excretion rate [UAER], and retinopathy) were assessed in 83 of these patients (age 32 +/- 1 years, duration of diabetes 22 +/- 1 years). RESULTS: Poor glycemic control (measured as lifetime glycemic exposure or HbA1c in 1985) was the most important independent predictor of decreases in all measures of absolute power of HRV (total power [TP] and very low frequency, low frequency [LF], and high frequency [HF] power) and square root of the mean square of R-R interval differences but not of changes of normalized measures or ratios (normalized HF and LF LF/HF). Other significant independent predictors of autonomic dysfunction were late age of onset of diabetes, female sex, and high BMI. To examine the sensitivity of the various tests to glycemia, the patients were divided into tertiles based on lifetime glycemic exposure (A1c months). Glycemic exposure in the tertiles averaged 194 +/- 25 A1c months (20 years of HbA1c 0.8% above normal), 556 +/- 19 A1c months(20 years of HbA1c 2.3% above normal), and 963 +/- 30 A1c months (20 years of HbA1c 4% above normal). Tests of complications that were significantly abnormal in patients already in the lowest tertile and were correlated with glycemia were TP and severity of retinopathy. Of conventional tests, only the ratio of length of R-R intervals during expiration to inspiration (E/I ratio) was significantly related to glycemic exposure, but it required high glycemic exposure (20 years of HbA1c 4% above normal) to be abnormal. UAER was significantly increased only in the highest tertile of glycemic exposure. CONCLUSIONS: TP and retinopathy score were much more sensitive to antecedent glycemia than conventional tests of autonomic function or UAER and were significantly abnormal in patients exposed to approximately 20 years' duration of an HbA1c 0.8% above normal.
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Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 1/fisiopatología , Angiopatías Diabéticas/epidemiología , Neuropatías Diabéticas/epidemiología , Frecuencia Cardíaca/fisiología , Adulto , Edad de Inicio , Albuminuria , Glucemia/metabolismo , Niño , Nefropatías Diabéticas/epidemiología , Retinopatía Diabética/epidemiología , Femenino , Hemoglobina Glucada/análisis , Humanos , Estudios Longitudinales , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Factores de RiesgoRESUMEN
OBJECTIVE: To search for determinants of endothelial dysfunction in type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a comprehensive analysis of cardiovascular risk markers and measured blood flow responses to endothelium-dependent (acetylcholine [ACh] and NG-monomethyl-L-arginine) and -independent (sodium nitroprusside [SNP]) vasoactive agents in 30 nonsmoking men with type 2 diabetes (age 51 +/- 1 years, BMI 27.8 +/- 0.4 kg/m2, HbA1c 7.4 +/- 0.3%) and 12 matched normal control men. RESULTS: ACh-induced vasodilation was 37% lower in type 2 diabetic (6.1 +/- 0.5) than in normal subjects (9.7 +/- 1.5 ml.dl-1.min-1, P < 0.01), while flows during SNP were similar (9.1 +/- 0.6 vs. 9.9 +/- 1.3 ml.dl-1.min-1, NS). The ratio of endothelium-dependent vs. -independent flow (ACh:SNP ratio) was 31% lower in type 2 diabetic (0.70 +/- 0.05) than in normal subjects (1.10 +/- 0.18, P < 0.01). Total (2.2 +/- 0.4 vs. 1.3 +/- 0.2 mmol/l, P < 0.05), VLDL, and intermediate-density lipoprotein triglycerides were significantly higher, and the mean LDL particle diameter was significantly smaller in type 2 diabetic than in normal subjects. The lag times for LDL oxidation by Cu2+ in vitro were similar in patients with type 2 diabetes (183 +/- 7) and in normal subjects (183 +/- 9 min, NS). Measured and calculated (sum of concentration of individual antioxidants in serum) total peroxyl radical-trapping capacities (TRAPs) were comparable between the groups. In the patients with type 2 diabetes, LDL size was significantly correlated with endothelium-dependent vasodilation (r = 0.43, P < 0.05), serum triglycerides (r = -0.75, P < 0.001), and the lag time for LDL oxidation in vitro (r = 0.38, P < 0.05). HbA1c was inversely correlated with the lag time for LDL oxidation in vitro (r = -0.41, P < 0.05) and TRAP. CONCLUSIONS: In summary, patients with type 2 diabetes exhibited impaired endothelium-dependent vasodilation in vivo, elevated serum triglycerides, decreased LDL size, and normal antioxidant capacity. Of these parameters, LDL size was significantly correlated with endothelial function.
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Antioxidantes/análisis , Velocidad del Flujo Sanguíneo/fisiología , Diabetes Mellitus Tipo 2/fisiopatología , Endotelio Vascular/fisiopatología , Lipoproteínas LDL/sangre , Vasodilatación , Acetilcolina/farmacología , Apolipoproteínas/sangre , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Enfermedades Cardiovasculares/epidemiología , Colesterol/sangre , Cromatografía Líquida de Alta Presión , Diabetes Mellitus Tipo 2/sangre , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Humanos , Lipoproteínas/sangre , Lipoproteínas LDL/química , Masculino , Persona de Mediana Edad , Nitroprusiato/farmacología , Valores de Referencia , Factores de Riesgo , Vasodilatación/efectos de los fármacos , Vitamina A/sangre , Vitamina E/sangre , beta Caroteno/sangre , omega-N-Metilarginina/farmacologíaRESUMEN
This study was undertaken to characterize first and second phase secretory profiles of total and nonglycosylated amylin and insulin and to determine whether excessive glycosylation of amylin or hyperamylinemia is a feature of abnormal glucose tolerance in humans. Plasma concentrations of total and nonglycosylated amylin and serum immunoreactive insulin were measured under identical hyperglycemic conditions using the hyperglycemic clamp technique in subjects with type 2 diabetes, impaired and normal glucose tolerance. Both amylin and insulin concentrations followed a biphasic pattern in subjects with normal and impaired glucose tolerance. In the subjects with normal and impaired glucose tolerance, the second phase amylin concentrations markedly exceeded those of the first phase, whereas the reverse was true for insulin. The first phase concentrations of both peptides were significantly lower in impaired than the normal glucose tolerance subjects. In patients with type 2 diabetes no first phase peak for either amylin or insulin could be identified, and the second phases of both amylin and insulin were significantly lower compared to subjects with normal or impaired glucose tolerance. Nonglycosylated amylin concentrations accounted for 25-45% of total amylin, regardless of glucose tolerance, and mimicked the pattern of total amylin concentrations. In summary: 1) glucose-induced increases in the magnitude of the first and second phase amylin plasma concentrations differed from those of insulin; 2) subjects with impaired glucose tolerance and more strikingly those with type 2 diabetes have impaired amylin responses; and 3) the ratio of nonglycosylated to total amylin is normal irrespective of glucose tolerance. These data imply, in view of many reports describing accumulation of amyloid in the pancreas, that circulating levels of amylin decrease as amyloid deposits accumulate and beta-cell function deteriorates and that the amount of glycosylated amylin in plasma is not increased in patients with type 2 diabetes.
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Amiloide/sangre , Amiloide/química , Diabetes Mellitus Tipo 2/sangre , Intolerancia a la Glucosa/sangre , Insulina/metabolismo , Biomarcadores/sangre , Glucemia/metabolismo , Péptido C/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Técnica de Clampeo de la Glucosa , Intolerancia a la Glucosa/diagnóstico , Prueba de Tolerancia a la Glucosa , Glicosilación , Humanos , Insulina/sangre , Secreción de Insulina , Polipéptido Amiloide de los Islotes Pancreáticos , Masculino , Persona de Mediana Edad , Valores de ReferenciaRESUMEN
Patients with autonomic neuropathy are more susceptible to insulin-induced hypotension than normal subjects, but the mechanisms are unclear. We quantitated the hemodynamic and metabolic effects of two doses of i.v. insulin (1 and 5 mU/kg.min, 120 min each) and several aspects of autonomic function in 28 patients with insulin-dependent diabetes mellitus (IDDM) and in 7 matched normal subjects under standardized normoglycemic conditions. The autonomic function tests included those predominantly assessing the integrity of vagal heart rate control (the expiration inspiration ratio during deep breathing and high frequency power of heart rate variability) and tests measuring sympathetic nervous function (reflex vasoconstriction to cold and blood pressure responses to standing and handgrip). During hyperinsulinemia, heart rate increased less (2 +/- 1 vs. 6 +/- 2 beats/min; P < 0.04) and diastolic blood pressure fell more (-3.1 +/- 1.2 vs. 0.9 +/- 2.1; P = NS) in the patients with IDDM than in the normal subjects. Forearm vascular resistance decreased significantly in the patients with IDDM [by -7.1 +/- 1.4 mm Hg/(mL/dL.min); P < 0.001 for high vs. low dose insulin], but not in the normal subjects (-0.1 +/- 2.5 mm Hg/(mL/dL.min; P = NS). Reflex vasoconstriction to cold was inversely correlated with the decreases in diastolic (r = -0.51; P < 0.005) and systolic (r = -0.59; P < 0.001) blood pressure and forearm vascular resistance (r = -0.53; P < 0.005), but not with the change in heart rate. The expiration inspiration ratio was, however, directly correlated with the insulin-induced change in heart rate (r = 0.63; P < 0.001), but not with diastolic or systolic blood pressure or forearm vascular resistance. Whole body (48 +/- 2 vs. 67 +/- 5 mumol/kg.min; P < 0.005) and forearm (44 +/- 4 vs. 67 +/- 8 mumol/kg.min; P < 0.05) glucose uptake were significantly lower in the IDDM patients than in the normal subjects. The latter could be attributed to a defect in the forearm glucose arterio-venous difference (1.5 +/- 0.1 vs. 2.2 +/- 0.2 mmol/L, respectively; P < 0.01), but not in blood flow. We conclude that both impaired vagal heart rate control and sympathetic nervous dysfunction exaggerate the hemodynamic effects of insulin in patients with IDDM and could contribute to insulin-induced hypotension.
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Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/fisiopatología , Neuropatías Diabéticas/fisiopatología , Hemodinámica/efectos de los fármacos , Insulina/efectos adversos , Adolescente , Adulto , Brazo/irrigación sanguínea , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Insulina/uso terapéutico , Masculino , Persona de Mediana Edad , Resistencia Vascular/efectos de los fármacosRESUMEN
Serum sex hormone-binding globulin (SHBG) and insulin-like growth factor-binding protein 1 (IGFBP-1) concentrations have been suggested to be useful markers of insulin sensitivity. As the production of both proteins is inhibited by insulin in the liver, we postulated that their concentrations reflect whole body insulin sensitivity only when the latter parallels changes in endogenous insulin secretion. To test this hypothesis, we determined SHBG and IGFBP-1 concentrations, whole body insulin sensitivity (euglycemic insulin clamp; serum free insulin, approximately 400 pmol/L), and serum insulin and C peptide concentrations in 13 type 1 diabetic patients lacking endogenous insulin secretion and 34 matched normal subjects. Whole body insulin sensitivity was 50% lower in the type 1 diabetic patients (20 +/- 3 mumol/kg.min) than that in the normal subjects (40 +/- 3 mumol/kg.min; P < 0.001). Despite this, serum SHBG (45 +/- 4 vs. 29 +/- 2nmol/L; P < 0.002) and IGFBP-1 (14 +/- 3 vs. 2 +/- 1 micrograms/L; P < 0.002) concentrations were increased in the type 1 diabetic patients. In the normal subjects, SHBG (r = -0.49; P < 0.01) and IGFBP-1 (r = -0.49; P < 0.01) were inversely correlated with serum C peptide and positively correlated with whole body insulin sensitivity (r = 0.54; P < 0.005 and r = 0.54; P < 0.005, respectively). In the type 1 diabetic patients, SHBG and IGFBP-1 concentrations were disproportionately increased when related to insulin sensitivity, but appropriate when related to estimated portal insulin concentrations. Serum T4, free testosterone, and estradiol concentrations were similar in both groups. We conclude that SHBG and IGFBP-1 reflect hepatic insulinization and can only be used as markers of insulin sensitivity in individuals with intact insulin secretion.
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Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Insulina/sangre , Vena Porta , Globulina de Unión a Hormona Sexual/metabolismo , Adulto , Péptido C/sangre , Diabetes Mellitus Tipo 1/sangre , Estradiol/sangre , Humanos , Insulina/fisiología , Masculino , Concentración Osmolar , Valores de Referencia , Testosterona/sangre , Tiroxina/sangreRESUMEN
We determined whether insulin resistance in Type I diabetes is caused by a defect in glucose extraction or blood flow and whether it is the rate of glucose metabolism rather than insulin that increases blood flow in these patients. To make this determination, 9 Type I diabetic patients (age 33 +/- 3 yr, body mass index 24 +/- 1 kg/m2, HbA1c 8.3 +/- 0.1%) and 10 matched normal subjects were first studied under normoglycemic hyperinsulinemic conditions. The diabetic patients were then restudied under similar conditions, but now whole body glucose uptake was normalized by glucose mass-action (glucose 8.7 +/- 0.6 mmol/L). During normoglycemia, rates of whole body (46 +/- 2 vs. 66 +/- 3 mumol/kg.min, P < 0.001) and forearm (47 +/- 9 vs. 78 +/- 7 mumol/kg forearm.min, P < 0.05) glucose uptake were decreased in the diabetic patients, because of a 32% decrease in the glucose AV-difference (1.5 +/- 0.2 vs. 2.2 +/- 0.2 mmol/L, P < 0.05). Forearm blood flow was similar in the diabetic patients (3.6 +/- 0.7 mL/dl.min) and normal subjects (3.7 +/- 0.3 mL/dL.min). During matched rates of whole body glucose uptake (68 +/- 1 vs. 66 +/- 3 mumol/kg.min, normoglycemic study in controls vs. hyperglycemic study in the diabetic patients), the glucose AV-difference across the forearm was 64% higher than during normoglycemia (2.4 +/- 0.3 vs. 1.5 +/- 0.2 mmol/L, P < 0.05). Forearm blood flow (3.6 +/- 0.4 mL/dL.min) under conditions of matched glucose flux was similar to that during the normoglycemic study. We conclude that a defect in glucose extraction rather than blood flow characterizes insulin resistance in uncomplicated Type I diabetes. The signal for the flow increase is insulin and not the rate of glucose metabolism.
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Diabetes Mellitus Tipo 1/fisiopatología , Glucosa/metabolismo , Resistencia a la Insulina , Adulto , Velocidad del Flujo Sanguíneo , Glucemia/metabolismo , Antebrazo/irrigación sanguínea , Técnica de Clampeo de la Glucosa , Humanos , Insulina/sangre , Cinética , MasculinoRESUMEN
Insulin induces vasodilation via stimulation of nitric oxide (NO) synthesis. This action of insulin exhibits considerable interindividual variation. We determined whether the response of blood flow to endothelium-dependent vasoactive agents correlates with that to insulin or whether other factors, such as physical fitness, limb muscularity, or vasodilatory capacity, better explain variations in insulin-stimulated blood flow. Direct measurements of the forearm blood flow response to three 2-h sequential doses of insulin (1, 2, and 5 mU/ kg.min), endothelium-dependent (acetylcholine and NG-monomethyl-L-arginine) and endothelium-independent (sodium nitroprusside) vasoactive agents, and ischemia (reactive hyperemic forearm blood flow) were performed in 22 normal subjects (age, 24 +/- 1 yr; body mass index, 22.2 +/- 0.6 kg/m2; maximal aerobic power, 40 +/- 2 mL/kg.min). The highest insulin dose increased blood flow by 111 +/- 17%. The fraction of basal blood flow inhibited by NG-monomethyl-L-arginine (NO synthesis-dependent flow) varied from 6-47%. Maximal aerobic power (r = 0.52; P < 0.02), the percentage of forearm muscle (r = 0.50; P < 0.02), and the NO synthesis-dependent flow (r = 0.42; P < 0.05), but not reactive hyperemic, acetylcholine-stimulated, or sodium nitroprusside-stimulated flow, were significantly correlated with insulin-stimulated (5 mU/kg.min) blood flow. In multiple linear regression analysis, 52% of the variation (multiple R = 0.72; P < 0.001) in insulin-stimulated blood flow was explained by NO synthesis-dependent flow (P < 0.005) and the percentage of forearm muscle (P < 0.005). We conclude that endothelial function (NO synthesis-dependent basal blood flow) and forearm muscularity are independent determinants of insulin-stimulated blood flow.
Asunto(s)
Endotelio Vascular/fisiología , Extremidades/irrigación sanguínea , Insulina/farmacología , Óxido Nítrico/biosíntesis , Aptitud Física , Adulto , Femenino , Humanos , Masculino , Consumo de Oxígeno , Flujo Sanguíneo Regional/efectos de los fármacos , omega-N-Metilarginina/farmacologíaRESUMEN
Effects of two experimental diets with a relatively high fat content--one enriched with saturated fatty acids (SAFA-diet) and the other with a low content of erucic acid rapeseed oil and rich in monounsaturated fatty acids (MUFA-diet)--on glucose and lipid metabolism were examined in healthy young women. The study was carried out with a randomized, crossover study design with each diet lasting 3 wk and a 2-wk washout period between the experimental diets. Glucose area under the curve during the intravenous glucose tolerance test (glucose dose 300 mg/kg, plasma samples before glucose dose and at 10-min intervals for 90 min) was significantly lower and the glucose disappearance rate after a glucose injection tended to be steeper after the MUFA-diet than after the SAFA-diet. After the MUFA-diet serum total cholesterol was 21.6% lower and serum low-density-lipoprotein cholesterol 29.5% lower than after the SAFA-diet, but high-density-lipoprotein cholesterol did not differ between the diets. The results give suggestive evidence that the dietary fatty acid composition affects glucose tolerance of healthy subjects.
Asunto(s)
Grasas de la Dieta/metabolismo , Ácidos Grasos Monoinsaturados/metabolismo , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Metabolismo de los Lípidos , Adulto , Grasas de la Dieta/administración & dosificación , Ácidos Grasos/administración & dosificación , Ácidos Grasos Monoinsaturados/administración & dosificación , Femenino , Prueba de Tolerancia a la Glucosa , HumanosRESUMEN
Physical training increases free radical production and consumes antioxidants. It has previously been shown that acute exercise markedly increases the susceptibility of LDL to oxidation but whether such changes are observed during physical training is unknown. We measured circulating antioxidants, lipids and lipoproteins, and blood flow responses to intrabrachial infusions of endothelium-dependent (acetylcholine, ACh, L-N-monomethyl-arginine, L-NMMA) and -independent (sodium nitroprusside, SNP) vasoactive agents, before and after 3 months of running in 9 fit male subjects. Maximal aerobic power increased from 53 +/- 1 to 58 +/- 2 ml/kg min (P < 0.02). All circulating antioxidants (uric acid, SH-groups, alpha-tocopherol, beta-carotene, retinol) except ascorbate decreased significantly during training. Endothelium-dependent vasodilatation in forearm vessels decreased by 32-35% (P < 0.05), as determined from blood flow responses to both a low (10.8 +/- 2.1 vs. 7.3 +/- 1.5 ml/dl min, 0 vs. 3 months) and a high (14.8 +/- 2.6 vs. 9.6 +/- 1.8) ACh dose. The % endothelium-dependent blood flow (% decrease in basal flow by L-NMMA), decreased through training from 37 +/- 3 to 22 +/- 7% (P < 0.05). Blood flow responses to SNP remained unchanged. The decrease in uric acid was significantly correlated with the change in the % decrease in blood flow by L-NMMA (r = 0.74, P < 0.05). The lag time for the susceptibility of plasma LDL to oxidation in vitro, LDL size and the concentration of LDL cholestetol remained unchanged. We conclude that relatively intense aerobic training decreases circulating antioxidant concentrations and impairs endothelial function in forearm vessels.
Asunto(s)
Antioxidantes/metabolismo , Endotelio Vascular/metabolismo , Ejercicio Físico , Vasodilatación/fisiología , Acetilcolina/farmacología , Adulto , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Arteria Braquial/efectos de los fármacos , Arteria Braquial/fisiología , Endotelio Vascular/efectos de los fármacos , Radicales Libres/sangre , Humanos , Inyecciones Intraarteriales , Lipoproteínas LDL/sangre , Masculino , Nitroprusiato/farmacología , Estrés Oxidativo , Vasodilatadores/farmacología , omega-N-Metilarginina/farmacologíaRESUMEN
We determined whether autoantibodies against oxidized LDL are increased in patients with IDDM, and if so, whether they are associated with endothelial dysfunction in vivo. Autoantibodies against oxidized LDL (ratio of antibodies against oxidized vs. native LDL, oxLDLab) were determined in 38 patients with IDDM (HbA(1c) 8.4+/-0.2%), who were clinically free of macrovascular disease, and 33 healthy normolipidemic subjects (HbA(1c) 5.1+/-0.1%, P<0.001 vs. IDDM). The groups had comparable serum total-, LDL- (2. 9+/-0.1 vs. 2.8+/-0.1 mmol/l, IDDM vs. controls), and HDL-cholesterol concentrations. OxLDLab were 1.5-fold higher in the IDDM patients (1.8+/-0.1) than in the normal subjects (1.2+/-0.1, P<0.001). OxLDLab were correlated with age in normal subjects, but not with age, duration of disease, LDL-cholesterol, HbA(1c) or degree of microvascular complications in patients with IDDM. To determine whether oxLDLab are associated with endothelial dysfunction in vivo, blood flow responses to intrabrachial infusions of acetylcholine, sodium nitroprusside and L-NMMA were determined in 23 of the patients with IDDM (age 33+/-1 years, body mass index 24. 3+/-0.6 kg/m(2), HbA(1c) 8.5+/-0.3%) and in the 33 matched normal males. OxLDLab were 41% increased in IDDM (1.7+/-0.2 vs. 1.2+/-0.1, P<0.01). Within the group of IDDM patients, HbA(1c) but not oxLDLab or LDL-cholesterol, was inversely correlated with the forearm blood flow response to acetylcholine (r=-0.51, P<0.02), an endothelium-dependent vasodilator, but not to sodium nitroprusside (r=0.06, NS). These data demonstrate that oxLDLab concentrations are increased in patients with IDDM, but show that chronic hyperglycemia rather than oxLDLab, is associated with impaired endothelium-dependent vasodilation in these patients.
Asunto(s)
Autoanticuerpos/análisis , Diabetes Mellitus Tipo 1/fisiopatología , Endotelio Vascular/fisiopatología , Lipoproteínas LDL/inmunología , Vasodilatación , Adolescente , Adulto , Diabetes Mellitus Tipo 1/inmunología , Antebrazo/irrigación sanguínea , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana Edad , Oxidación-Reducción , Flujo Sanguíneo RegionalRESUMEN
The incidence of diabetes is increased in patients with pancreatic cancer, but the mechanisms underlying this association are not clear. Alterations in beta-cell function, such as formation of amyloid from excessive production of amylin and reduced expression of GLUT2, have been suggested to be possible mechanisms. We compared in vivo secretory responses of amylin and insulin (n = 37) and expression of GLUT2 in pancreata (n = 10) obtained at surgery between diabetic and nondiabetic patients with and without pancreatic tumors. Fourteen had pancreatic adenocarcinoma, 7 had diabetes (duration 6 +/- 3 years) and a pancreatic tumor, 8 had type 2 diabetes (duration 6 +/- 2 years), and 8 were normal subjects. First (0 to 10 minutes) and second (10 to 120 minutes) phase insulin and amylin secretion were characterized using the hyperglycemic clamp technique. Both amylin and insulin concentrations followed a biphasic pattern in nondiabetic subjects. In nondiabetic patients with pancreatic cancer, total, as well as nonglycosylated amylin concentrations, were increased compared with nondiabetic subjects without pancreatic cancer. Both first- and second-phase plasma amylin and serum immunoreactive insulin concentrations were low in all patients with diabetes, ie, both in type 2 diabetes and in those patients with diabetes and pancreatic tumors. At surgery, specimens were obtained for characterization of GLUT2 expression in beta cells, which was unaltered in nondiabetic (n = 7) and diabetic (n = 3) patients. Amyloid staining was similarly negative in diabetic and nondiabetic pancreata independent of pancreatic carcinoma. In conclusion, plasma amylin, but not insulin concentrations, are increased in nondiabetic patients with pancreatic cancer, but low in all patients with diabetes. These data support the potential of using an increase in the ratio of circulating amylin to insulin as a marker for pancreatic cancer in nondiabetic patients.
Asunto(s)
Adenocarcinoma/metabolismo , Amiloide/metabolismo , Diabetes Mellitus/metabolismo , Glucosa , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma/complicaciones , Amiloide/sangre , Glucemia , Complicaciones de la Diabetes , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Glucagón/metabolismo , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Transportador de Glucosa de Tipo 2 , Humanos , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Polipéptido Amiloide de los Islotes Pancreáticos , Masculino , Persona de Mediana Edad , Proteínas de Transporte de Monosacáridos/metabolismo , Páncreas/metabolismo , Páncreas/patología , Neoplasias Pancreáticas/complicaciones , Valor Predictivo de las Pruebas , Valores de ReferenciaRESUMEN
BACKGROUND/AIMS: Recent studies have demonstrated marked renin and prorenin concentration gradients between ocular tissues and blood, and local expression of the renin-angiotensin system (RAS) in the eye. The authors determined whether serum total renin, which mostly consists of prorenin, is a marker of the activity and severity of diabetic retinopathy independent of other microvascular complications. METHODS: Total renin concentrations (TRC) were measured with a time resolved immunofluorometric assay in 38 patients with IDDM (age 34 (SD 7) years, duration of disease 22 (7) years, serum creatinine 95 (15) mumol/l, urinary albumin excretion rate (UAER) 207 (829) micrograms/min, HbA1c 8.5% (1.2%)), and in 13 matched normal subjects. All subjects were carefully characterised with respect to the presence and severity of retinopathy (RP score), nephropathy, and neuropathy using seven different tests of autonomic neuropathy. RESULTS: Serum TRC was on average twofold higher in IDDM (396 (SE 211) ng/l) than in normal subjects (201 (88) ng/l, p < 0.001). It was nearly twofold higher in patients with preproliferative or active proliferative retinopathy requiring careful follow up or therapy (TRC 596 (268) ng/l, n = 11) compared with those with quiescent proliferative retinopathy after laser treatment (TRC 338 (183) ng/l, p < 0.01, n = 5); moderately severe non-proliferative retinopathy (337 (106) ng/l, p < 0.01, n = 13), no retinopathy, or only minimal non-proliferative retinopathy (270 (43) ng/l, p < 0.001, n = 9). In multiple linear regression analysis, RP score (p < 0.01), but not the UAER or any index of autonomic neuropathy, was an independent determinant of serum TRC, and explained 32% of its variation (R = 0.57, p < 0.005). CONCLUSIONS: Serum TRC in patients with diabetic retinopathy is increased independent of renal function and autonomic neuropathy especially in those with severe active changes requiring careful follow up or treatment. These findings support the idea that diabetic retinopathy is the most important determinant of serum TRC in patients with IDDM, and that TRC is produced when retinopathy is active.