RESUMEN
BACKGROUND: Elderly people are exposed to an increased load of stressful events and neuro-hormonal stimulation is a key finding in metabolic syndrome and its related disorders. AIMS: To determine the role of cortisol in elderly subjects, with or without metabolic syndrome (MetS), by means of a national multicentre observational study, AGICO (AGIng and Cortisol). METHODS: From 2012 to 2017, the AGICO study enrolled n.339 subjects (aged > 65), after obtaining their informed consent. The investigators assessed a cardio-metabolic panel (including electrocardiogram, carotid ultrasonography and echocardiography), the presence of MetS (on Adult Treatment Panel III criteria), a neurological examination (including brain imaging), and cortisol activity (using a consecutive collection of diurnal and nocturnal urine). RESULTS: In the patients presenting with MetS, the standardized diurnal and nocturnal cortisol excretion rates were 210.7 ± 145.5 and 173.7 ± 118.1 (mean ± standard deviation) µg/g creatinine/12 h; in those without MetS, the standardized diurnal and nocturnal cortisol excretion rates were 188.7 ± 92.7 and 144.1 ± 82.3 µg/g creatinine/12 h, respectively (nocturnal urinary cortisol in patients with MetS versus those without MetS p = 0.05, female patients with MetS vs female patients without MetS, p < 0.025). A significant positive correlation was found between the CRP levels and both the diurnal and nocturnal urinary cortisol levels with r = 0.187 (p < 0.025) and r = 0.411 (p < 0.00000001), respectively. DISCUSSION: The elderly patients with MetS showed a trend towards increased standardized nocturnal cortisol excretions, with particular regard to the female subjects. CONCLUSION: The positive correlation between cortisol excretion and low-grade inflammation suggests a common mechanism driving both hormonal and inflammatory changes.
Asunto(s)
Hidrocortisona/metabolismo , Inflamación/metabolismo , Síndrome Metabólico/metabolismo , Anciano , Anciano de 80 o más Años , Ecocardiografía , Femenino , Humanos , Inflamación/complicaciones , Masculino , Síndrome Metabólico/complicacionesRESUMEN
BACKGROUND: Several indexes based on clinical and laboratory tests to identify frailty and to predict mortality have been produced. Only two studies, mixing clinical and laboratory parameters were made about a frailty index made of laboratory tests (FI-Lab) and mortality in older patients hospitalized for COVID-19. The aim of this study was to explore the accuracy and precision of an FI-Lab constructed with some common bio-humoral tests and mortality in a cohort of patients hospitalized for COVID-19. METHODS: The FI-Lab was constructed using 40 different bio-humoral tests during the first four days of hospitalization, with a score from 0 to 1. The association between FI-Lab and mortality was assessed using a multivariate Cox's regression analysis, reported as hazard ratios (HRs) and 95% confidence intervals (CIs). The accuracy of the FI-Lab was reported as area under the curve (AUC) and the precision with the C-Index. RESULTS: 376 patients (mean age: 65 years; 53.7% males) were initially included. During the follow-up period, 41 deceased. After adjusting for five different factors, an FI-Lab value >0.54, the median value of our cohort, was associated with a relative risk about five times greater than lower values. Modeling FI-LAB as a continous variable, each increase in 0.01 points was associated with an increased risk in mortality of 8.4% (HR=1.084; 95%CI: 1.039-2.044). The FI-Lab was highly accurate (AUC=0.91; 95%CI: 0.87-0.95) and precise (C-Index=0.81) in predicting death. CONCLUSIONS: A simple index based on common laboratory tests can be used to predict mortality among older people hospitalized for COVID-19.
Asunto(s)
COVID-19 , Fragilidad , Hospitalización , Humanos , COVID-19/mortalidad , COVID-19/diagnóstico , COVID-19/epidemiología , Anciano , Femenino , Masculino , Fragilidad/diagnóstico , Fragilidad/epidemiología , Pronóstico , Hospitalización/estadística & datos numéricos , Evaluación Geriátrica/métodos , Anciano Frágil/estadística & datos numéricos , Anciano de 80 o más Años , SARS-CoV-2 , Persona de Mediana EdadRESUMEN
BACKGROUND AND AIM: Accumulated evidence supports the effectiveness of Mediterranean-type diets (MeDiet) in reducing mortality and preventing several chronic diseases. Widely used scores to assess adherence to MeDiet are based on specific sample characteristics; alternatively, they might be built according to absolute/normative cut-off points for the consumption of specific food groups (pre-defined servings/day or/week). The aim of this study was to compare sample-specific MeDiet adherence scores (MDS) versus absolute-normative scores (Mediterranean Diet Adherence Screener - MEDAS) on their association with macronutrient intake, total mortality and incidence of chronic diseases. DESIGN: SUN (Seguimiento Universidad de Navarra) dynamic prospective cohort study (60.5% women; mean age 38.4 years). METHODS AND RESULTS: In cross-sectional analyses (n=20,155) we evaluated macronutrient distribution according to MDS (based on 136-item FFQ), MEDAS (based on 13 questions), and variants of both. In prospective analyses (n=9109; mean follow-up: 6.2 years), we evaluated disease incidence or mortality. Adherence to MeDiet increased with age and, as expected, was associated with higher fiber intake, lower total fat intake but higher monounsaturated/saturated fat ratio, using all scores. Among subjects initially free of cancer, diabetes, and cardiovascular disease (CVD), adherence to MeDiet appraised with an absolute-normative score (MEDAS) similarly predicted macronutrient distribution and disease incidence or mortality (diabetes incidence, CVD or all-cause mortality), when compared to a sample-specific score based on 136-item FFQ (MDS). CONCLUSIONS: Adherence to MeDiet was associated with a decreased incidence of a composite outcome including diabetes incidence, cardiovascular events incidence or all-cause mortality.
Asunto(s)
Enfermedades Cardiovasculares/mortalidad , Diabetes Mellitus Tipo 2/mortalidad , Dieta Mediterránea , Conducta Alimentaria , Adulto , Índice de Masa Corporal , Enfermedades Cardiovasculares/dietoterapia , Enfermedades Cardiovasculares/prevención & control , Estudios Transversales , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/prevención & control , Fibras de la Dieta/administración & dosificación , Ácidos Grasos Monoinsaturados/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Modelos Logísticos , Estudios Longitudinales , Masculino , Actividad Motora , Evaluación Nutricional , Cooperación del Paciente , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Optimal nutritional and hormonal statuses are determinants of successful ageing. The age associated decline in anabolic hormones such as testosterone and insulin-like growth factor 1 (IGF-1) is a strong predictor of metabolic syndrome, diabetes and mortality in older men. Studies have shown that magnesium intake affects the secretion of total IGF-1 and increase testosterone bioactivity. This observation suggests that magnesium can be a modulator of the anabolic/catabolic equilibrium disrupted in the elderly people. However, the relationship between magnesium and anabolic hormones in men has not been investigated. We evaluated 399 ≥65-year-old men of CHIANTI in a study population representative of two municipalities of Tuscany (Italy) with complete data on testosterone, total IGF-1, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEAS) and serum magnesium levels. Linear regression models were used to test the relationship between magnesium and testosterone and IGF-1. Mean age of the population was 74.18 ± 6.43 (years ± SD, age range 65.2-92.4). After adjusting for age, magnesium was positively associated with total testosterone (ß ± SE, 34.9 ± 10.3; p = 0.001) and with total IGF-1 (ß ± SE, 15.9 ± 4.8; p = 0.001). After further adjustment for body mass index (BMI), log (IL-6), log (DHEAS), log (SHBG), log (insulin), total IGF-1, grip strength, Parkinson's disease and chronic heart failure, the relationship between magnesium and total testosterone remained strong and highly significant (ß ± SE, 48.72 ± 12.61; p = 0.001). In the multivariate analysis adjusted for age, BMI, log (IL-6), liver function, energy intake, log (insulin), log (DHEAS), selenium, magnesium levels were also still significantly associated with IGF-1 (ß ± SE, 16.43 ± 4.90; p = 0.001) and remained significant after adjusting for total testosterone (ß ± SE, 14.4 ± 4.9; p = 0.01). In a cohort of older men, magnesium levels are strongly and independently associated with the anabolic hormones testosterone and IGF-1.
Asunto(s)
Anabolizantes/sangre , Hormonas Esteroides Gonadales/sangre , Magnesio/sangre , Anciano , Humanos , Italia , MasculinoRESUMEN
BACKGROUND: Pharmacological treatment for diabetic polyneuropathy (DP) has shown limited benefit; frequency-modulated electrical stimulation (FREMS) has shown positive results in pain control and nerve conduction velocity in DP. OBJECTIVE: To investigate the effects of FREMS vs transcutaneous electrical nerve stimulation (TENS) on the release of vascular endothelial growth factor (VEGF) in Type 2 diabetic and in non-diabetic subjects. METHODS: 10 non-diabetic [mean age 37+/-5 yr; females (F)/males (M): 6/4] and 10 Type 2 diabetic subjects (mean age 52+/-6 yr; F/M: 5/5) with DP underwent TENS (for 10 min) followed by 30 min interval without electrical stimulation, and then FREMS (for 10 min) over the forearm volar surface. Blood samples for VEGF measurements were obtained from the contra-lateral arm every 2 min during TENS/FREMS application and every 10 min during the intervals. RESULTS: We observed a significant rise in plasma VEGF during FREMS in both non-diabetic and diabetic subjects (maximal response 89.4+/-80.3 pg/ml and 48.5+/-18.3 pg/ml, respectively; p<0.01 vs basal) with a lower, but still significant response in diabetics. No changes in VEGF were observed during TENS application. CONCLUSION: VEGF release during FREMS may help explain the positive effects on nerve conduction velocity in DP, possibly mediated by favorable effects on vasa nervorum microangiopathy.
Asunto(s)
Neuropatías Diabéticas/sangre , Terapia por Estimulación Eléctrica/métodos , Estimulación Eléctrica Transcutánea del Nervio/métodos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Potenciales de Acción/fisiología , Adulto , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuronas Motoras/fisiología , Conducción Nerviosa/fisiología , Dolor/etiología , Dolor/fisiopatología , Manejo del Dolor , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
Developing countries face the double menace of still prevalent infectious diseases and increasing cardiovascular disease (CVD) with epidemic proportions in the near future, linked to demographic changes (expansion and ageing), and to urbanisation and lifestyle modifications. It is estimated that the elderly population will increase globally (over 80% during the next 25 years), with a large share of this rise in the developing world because of expanding populations. Increasing longevity prolongs the time exposure to risk factors, resulting in a greater probability of CVD. As a paradox, increased longevity due to improved social and economical conditions associated with lifestyle changes in the direction of a rich diet and sedentary habits in the last century, is one of the main contributors to the incremental trend in CVD. The variable increase rate of CVD in different nations may reflect different stages of "epidemiological transition" and it is probable that the relatively slow changes seen in developing populations through the epidemiological transition may occur at an accelerated pace in individuals migrating from nations in need to affluent societies (i.e. Hispanics to the USA, Africans to Europe). Because of restrained economic conditions in the developing world, the greatest gains in controlling the CVD epidemic lies in its prevention. Healthy foods should be widely available and affordable, and healthy dietary practices such as increased consumption of fresh fruits and vegetables, reduced consumption of saturated fat, salt, and simple sugars, may be promoted in all populations. Specific strategies for smoking and overweight control may be regulation of marketed tobacco and unhealthy fast food and promotion of an active lifestyle. Greater longevity and economic progress are accompanied by an increasing burden of CVD and other chronic diseases with an important decrease in quality of life, which should question the benefit of these additional years without quality.
Asunto(s)
Envejecimiento/patología , Enfermedades Cardiovasculares/epidemiología , Estilo de Vida , Adolescente , Adulto , Anciano , Enfermedades Cardiovasculares/etiología , Niño , Preescolar , Países en Desarrollo , Emigración e Inmigración , Femenino , Promoción de la Salud , Humanos , Lactante , Recién Nacido , Esperanza de Vida , Masculino , Persona de Mediana Edad , Crecimiento Demográfico , Factores de RiesgoRESUMEN
Diabetes is associated with impaired cardiac diastolic dysfunction. Isolated ventricular myocytes from diabetic animals demonstrate impaired relaxation concomitant with prolonged intracellular Ca2+ transients. We have recently shown that maintaining normal adult rat ventricular myocytes in a "diabetic-like" culture medium (low insulin and high glucose) produces abnormalities in excitation-contraction coupling similar to in vivo diabetes. Troglitazone (TRO), a novel insulin-sensitizing agent, significantly lowers blood pressure and modestly increases cardiac output in vivo, but its direct impact on cardiac function is unknown. To determine whether TRO could prevent high-glucose-induced dysfunction, normal myocytes were maintained in culture for 1-2 days in either normal medium containing 5 mmol/l glucose or high-glucose medium containing 25 mmol/l glucose. TRO (5 micromol/l) was added to both normal and high-glucose media. Mechanical properties were evaluated using a high-resolution video-edge detection system, and Ca2+ transients were recorded in fura-2-loaded myocytes. Relaxation from peak contraction was significantly longer in myocytes cultured in high glucose. Treating cells with TRO either attenuated or prevented the high-glucose effects, without changing the mechanical properties of myocytes cultured in normal medium. TRO also prevented the abnormally slow rates of Ca2+ transient decay induced by high glucose. Collectively, these data demonstrate that TRO can protect against the high-glucose-induced relaxation defects, perhaps through changes in intracellular Ca2+ handling. If TRO has both vasodilatory actions and beneficial cardiac properties (e.g., improvement of diastolic function) in the presence of hyperglycemia, this antidiabetic agent may prove to have significant salutary cardiovascular effects in type II diabetes.
Asunto(s)
Calcio/metabolismo , Cromanos/farmacología , Glucosa/administración & dosificación , Corazón/efectos de los fármacos , Hipoglucemiantes/farmacología , Miocardio/metabolismo , Tiazoles/farmacología , Tiazolidinedionas , Animales , Fenómenos Biomecánicos , Células Cultivadas , Medios de Cultivo , Corazón/fisiología , Ventrículos Cardíacos/efectos de los fármacos , Masculino , Contracción Miocárdica , Ratas , Ratas Sprague-Dawley , Troglitazona , Función VentricularRESUMEN
We have recently demonstrated that adult rat ventricular myocytes maintained in a high glucose (HG) culture medium exhibit abnormalities in excitation-contraction coupling similar to myocytes from diabetic rats. Metformin, an insulin-sensitizing biguanide, enhances peripheral insulin action and lowers blood pressure in hyperinsulinemic animals, but its direct impact on cardiac function is not fully understood. To examine the role of metformin on HG-induced cardiac dysfunction at the cellular level, normal adult ventricular myocytes were cultured for 1 day in a serum-free insulin-containing medium with either normal glucose (5.5 mmol/l glucose) or HG (25.5 mmol/l glucose) in the presence or absence of metformin or the sulfonylurea glyburide. Mechanical properties were evaluated using a high-speed video-edge detection system, and intracellular Ca2+ transients were recorded in fura-2-loaded myocytes. As previously reported, culturing myocytes in HG depresses peak shortening, prolongs time to 90% relengthening, and slows Ca2+ transient decay. Culturing cells with metformin (50 micromol/l) prevented the HG-induced abnormalities in relaxation without ameliorating depressed peak-shortening amplitudes. Incubation of the cells with metformin also prevented slower intracellular Ca2+ clearing induced by HG. However, the HG-induced relaxation defects were not improved by glyburide (50-300 micromol/l). Interestingly, metformin also improved HG-induced relaxation abnormalities in the absence of insulin, whereas it failed to protect against HG in the presence of the tyrosine kinase inhibitor genistein (50 micromol/l). These data demonstrate that, unlike glyburide, metformin provides cardioprotection against HG-induced abnormalities in myocyte relaxation, perhaps through tyrosine kinase-dependent changes in intracellular Ca2+ handling, independent of its insulin sensitizing action.
Asunto(s)
Glucemia/metabolismo , Calcio/metabolismo , Gliburida/farmacología , Hipoglucemiantes/farmacología , Metformina/farmacología , Miocardio/metabolismo , Animales , Inhibidores Enzimáticos , Genisteína/farmacología , Corazón/efectos de los fármacos , Insulina/metabolismo , Masculino , Proteínas Quinasas/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
The insulin-sensitizing compound troglitazone has evolved into a promising therapeutic agent for type II diabetes. It improves insulin sensitivity and lipoprotein metabolic profiles and lowers blood pressure in humans and rodents. Because troglitazone has insulin-like effects on a number of tissues, we hypothesized that it may reduce vascular tone through stimulation of endothelial-derived nitric oxide (NO) production or by diminution of vascular smooth muscle cell (VSMC) intracellular calcium ([Ca2+]i). Our results show that troglitazone decreases norepinephrine-induced contractile responses in the rat tail artery, an effect not reversed by the NO inhibitor L-nitroarginine methyl ester (L-NAME). In contrast, troglitazone significantly inhibited L-type Ca2+ currents in freshly dissociated rat tail artery and aortic VSMCs and in cultured VSMCs. The data suggest that troglitazone attenuates vascular contractility via a mechanism involving VSMC [Ca2+]i but independent from endothelial generation of NO. Because insulin has been shown to affect vascular tone by both of these mechanisms, troglitazone only partially mimics insulin action in this tissue.
Asunto(s)
Canales de Calcio/metabolismo , Cromanos/farmacología , Hipoglucemiantes/farmacología , Músculo Liso Vascular/efectos de los fármacos , Tiazoles/farmacología , Tiazolidinedionas , Análisis de Varianza , Animales , Arterias/efectos de los fármacos , Arterias/fisiología , Canales de Calcio/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Músculo Liso Vascular/metabolismo , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , TroglitazonaRESUMEN
Metformin enhances peripheral insulin action and reduces blood pressure in hypertensive rats. Our group has previously reported that insulin and insulin-like growth factor I (IGF-1) attenuate both agonist-induced vascular smooth muscle cell (VSMC) contraction and associated increases in cytosolic free calcium ([Ca]i). Thus, changes in insulin actions may explain in part metformin's vascular effects. However, metformin's mechanism of action at the vasculature had not been elucidated. Therefore, the purpose of this study was to determine whether metformin evokes alterations in VSMC insulin and IGF-I receptors, glucose transport, and/or [Ca]i. We quantitated hormone binding and tyrosine kinase (TK) activity in partially purified insulin and IGF-I receptors prepared from metformin-treated (100 microM) and control rat aortic VSMC in culture. Glucose transport was assessed by 2-deoxyglucose uptake. Metformin exposure for 24 h 1) increased basal TK activity (metformin, 3.49 +/- 0.39; control, 1.77 +/- 0.39 pmol 32P incorporated/mg protein; P < 0.01) without changes in insulin-or IGF-I stimulated TK activity, 2) increased 2-deoxyglucose transport in a dose-dependent manner, 3) decreased thrombin-induced elevation in [Ca]i (metformin, 10.3%; control, 35.3% over basal; P < 0.05), These insulin/IGF-I-like effects of metformin may help explain some of its vascular actions.
Asunto(s)
Calcio/metabolismo , Glucosa/metabolismo , Membranas Intracelulares/metabolismo , Metformina/farmacología , Músculo Liso Vascular/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Células Cultivadas , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Músculo Liso Vascular/citología , Concentración Osmolar , Ratas , Ratas Sprague-DawleyRESUMEN
Magnesium (Mg) deficiency enhances tissue sensitivity to ischemic damage, an effect reversed not only by Mg, but also by sulfhydryl (SH)-containing compounds. We therefore created an in vitro model of red blood cell ischemia to investigate whether the protective effects of these compounds might be related to effects on intracellular free Mg (Mg(i)) content. (31)P-nuclear magnetic resonance (NMR) spectroscopy was used to measure the high-energy metabolites ATP and 2,3-diphosphoglycerate (DPG) and Mg(i) and inorganic phosphate (P(i)) levels in erythrocytes before and for 6 hours after progressive oxygen depletion in the presence or absence of SH-compounds, including captopril, N-acetyl-L-cysteine (NAC), penicillamine, and N-(2-mercaptopropionyl)-glycine (MPG). Under basal aerobic conditions, captopril increased Mg(i) in a dose- and time-dependent fashion (174.5+/-5.3 to 217.1+/-5.1 micromol/L, P<0. 05 at 100 micromol/L, 60 minutes). The SH compounds NAC, penicillamine, and MPG but not the non-SH compound enalaprilat also significantly raised Mg(i) in erythrocytes (P<0.05). With oxygen deprivation, a consistent decrease occurred in both ATP and 2,3-DPG levels associated with a rise in P(i) and in the P(i)/2,3-DPG ratio used as an index of high-energy metabolite depletion. Captopril, compared with control, retarded the rise in P(i) and reduced the P(i)/2,3-DPG ratio (P<0.008 and P<0.025 at 4 and 6 hours, respectively). Furthermore, the higher the initial Mg(i) and the greater the captopril-induced rise in Mg(i), the greater the metabolite-protective effect (r=0.799 and r=0.823, respectively; P<0. 01 for both). Altogether, the data suggest that Mg influences the cellular response to ischemia and that the ability of SH compounds such as captopril to ameliorate ischemic injury may at least in part be attributable to the ability of such compounds to increase cytosolic free Mg levels.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Captopril/farmacología , Eritrocitos/metabolismo , Eritrocitos/patología , Magnesio/metabolismo , Estrés Oxidativo , Adulto , Femenino , Humanos , Isquemia/metabolismo , Isquemia/prevención & control , MasculinoRESUMEN
Elevated cytosolic free calcium (Ca(i)) and reciprocally reduced, extracellular ionized calcium (Ca-ion) levels are observed in both hypertension and non-insulin-dependent diabetes mellitus (NIDDM). Because the changes of vascular function and insulin sensitivity in these conditions resemble the changes associated with "normal" aging, we wondered to what extent similar alterations in calcium metabolism occur with aging per se in the absence of overt hypertension or diabetes. We therefore measured platelet Ca(i) levels by spectrofluorometry and serum Ca-ion levels in normotensive, nondiabetic, healthy, normal, elderly (>65 years old) subjects, mean age +/-SEM, 72.2+/-1.5 years old (n=11); in healthy, normal, young (<65 years old) adults, 46.1+/-2.3 years old (n=12); in 10 young adult hypertensives, 48.6+/-1.9 years old; and in 10 normotensive NIDDM subjects, 49.2+/-1.6 years old. Platelet Ca(i) levels were higher (104.5+/-4.9 versus 80.2+/-1.8 nmol/L, P<0.01) and Ca-ion levels lower (1.212+/-0.010 versus 1.236+/-0.011 mmol/L, P<0.05) in normal elderly compared with young control subjects, but normal elderly Ca(i) and Ca-ion levels were indistinguishable from those in hypertensive (Ca(i) 107.5+/-3.6 nmol/L, Ca-ion 1.210+/-0.009 mmol/L) and NIDDM (Ca(i) 110.7+/-4.7 nmol/L, Ca-ion 1.204+/-0.014 mmol/L) subjects. In normal subjects, significant correlations were found between platelet Ca(i) levels and age (r=0.655, P<0.01) and between Ca(i) levels and systolic blood pressure (r=0.733, P<0.001). We conclude that aging is associated with alterations of Ca(i) and Ca-ion levels resembling those changes present at any age in hypertension and type 2 diabetes. We hypothesize that these alterations of calcium metabolism underlie the predisposition to the alterations of blood pressure and insulin sensitivity characteristic of "normal" aging. The data also suggest that studies of the aging process should be limited to subjects with normal blood pressure and glucose tolerance.
Asunto(s)
Envejecimiento/sangre , Calcio/sangre , Diabetes Mellitus Tipo 2/metabolismo , Hipertensión/metabolismo , Adolescente , Adulto , Anciano , Plaquetas/metabolismo , Citosol/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Hipertensión/fisiopatología , Persona de Mediana EdadRESUMEN
Depletion of intracellular free magnesium (Mg(i)) is a characteristic feature of insulin resistance in essential hypertension, but it is not clear to what extent low Mg(i) levels contribute to insulin resistance, result from it, or both. As insulin-like growth factor I (IGF-I) may improve insulin resistance, we investigated whether this peptide could similarly improve Mg(i) responsiveness to insulin in hypertension, and whether this effect was related to any direct IGF-I effect on Mg(i). 31P-Nuclear magnetic resonance spectroscopy was used to measure Mg(i) in erythrocytes from 13 fasting normotensive and 10 essential hypertensive subjects before and 30, 60, and 120 min after incubation with a physiologically maximal dose of insulin (200 microU/mL) and with different doses of recombinant human IGF-I (0.1-100 nmol/L). In normotensive subjects, IGF-I elevated Mg(i) (P < 0.05) in a dose- and time-dependent fashion, as did insulin (P < 0.05). However, in hypertensive subjects, maximal Mg(i) responses to insulin, but not to IGF-I, were blunted [insulin, 163+/-11 to 177+/-10 micromol/L (P=NS); IGF-I, 164+/-6 to 190+/-11.7 micromol/L (P < 0.05)]. Furthermore, for insulin, but not for IGF-I, cellular Mg(i) responsiveness was closely and directly related to basal Mg(i) levels (insulin: r=0.72; P < 0.01; IGF-I: r=0.18; P=NS). Lastly, blunted Mg(i) responses to insulin could be reversed by preincubation of hypertensive cells with IGF-I. We conclude that 1) both IGF-I and insulin stimulate erythrocyte Mg(i) levels; 2) cellular Mg(i) responses to insulin, but not to IGF-I, depend on basal Mg(i) levels, i.e. the higher the Mg(i) the greater the sensitivity to insulin; and 3) IGF-I potentiates insulin-induced stimulation of Mg(i) at doses that themselves do not raise Mg(i). These effects of IGF-I may underlie at least in part its ability to improve insulin sensitivity clinically. Together, these data support a role for IGF-I in cellular magnesium metabolism and emphasize the importance of magnesium as a determinant of insulin action.
Asunto(s)
Eritrocitos/metabolismo , Hipertensión/sangre , Factor I del Crecimiento Similar a la Insulina/farmacología , Insulina/farmacología , Magnesio/sangre , Adulto , Relación Dosis-Respuesta a Droga , Eritrocitos/efectos de los fármacos , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Valores de ReferenciaRESUMEN
Recent evidence suggests that the endogenous antioxidant glutathione may play a protective role in cardiovascular disease. To directly investigate the role of glutathione in the regulation of glucose metabolism in hypertension, we studied the acute effects of in vivo infusions of this antioxidant (alone or in combination with insulin) on whole body glucose disposal (WBGD) using euglycemic glucose clamp and the effects on total red blood cell intracellular magnesium (RBC-Mg) in hypertensive (n=20) and normotensive (n=30) subjects. The relationships among WBGD, circulating reduced/oxidized glutathione (GSH/GSSG) levels, and RBC-Mg in both groups were evaluated. The in vitro effects of glutathione (100 micromol/L) on RBC free cytosolic magnesium (Mg(i)) were also studied. In vivo infusions of glutathione (15 mg/minx120 minutes) increased RBC-Mg in both normotensives and hypertensives (1.99+/-0.02 to 2.13+/-0.03 mmol/L, P<0.01, and 1.69+/-0.03 to 1.81+/-0.03 mmol/L, P<0.01, respectively). In vitro GSH but not GSSG increased Mg(i) (179+/-3 to 214+/-5 micromol/L, P<0.01). In basal conditions, RBC-Mg values were related to GSH/GSSG ratios (r=0.84, P<0.0001), and WBGD was directly, significantly, and independently related to both GSH/GSSG ratios (r=0.79, P<0.0001) and RBC-Mg (r=0.89, P<0.0001). This was also true when hypertensive and control groups were analyzed separately. On multivariate analysis, basal RBC-Mg (t=6.81, P<0.001), GSH/GSSG (t=3. 67, P<0.02), and blood pressure (t=2.89, P<0.05) were each independent determinants of WBGD, with RBC-Mg explaining 31% of the variability of WBGD. These data demonstrate a direct action of glutathione both in vivo and in vitro to enhance intracellular magnesium and a clinical linkage between cellular magnesium, GSH/GSSG ratios, and tissue glucose metabolism.
Asunto(s)
Antioxidantes/farmacología , Eritrocitos/metabolismo , Glucosa/metabolismo , Glutatión/farmacología , Membranas Intracelulares/metabolismo , Magnesio/sangre , Adulto , Antioxidantes/metabolismo , Femenino , Técnica de Clampeo de la Glucosa , Glutatión/sangre , Disulfuro de Glutatión/farmacología , Humanos , Hipertensión/sangre , Hipertensión/metabolismo , Hipoglucemiantes/farmacología , Insulina/farmacología , Masculino , Persona de Mediana Edad , Valores de ReferenciaRESUMEN
Vitamin E is an antioxidant that has been demonstrated to improve insulin action. Glutathione, another natural antioxidant, may also be important in blood pressure and glucose homeostasis, consistent with the involvement of free radicals in both essential hypertension and diabetes mellitus. Our group has recently suggested that the effects of reduced glutathione on glucose metabolism may be mediated, at least in part, by intracellular magnesium levels (Mg([i])). Recent evidence suggests that vitamin E enhances glutathione levels and may play a protective role in magnesium deficiency-induced cardiac lesions. To directly investigate the effects of vitamin E supplementation on insulin sensitivity in hypertension, in relation to the effects on circulating levels of reduced (GSH) and oxidized (GSSG) glutathione and on Mg([i]), we performed a 4-week, double-blind, randomized study of vitamin E administration (600 mg/d) versus placebo in 24 hypertensive patients and measured whole-body glucose disposal (WBGD) by euglycemic glucose clamp, GSH/GSSG ratios, and Mg([i]) before and after intervention. The relationships among WBGD, GSH/GSSG, and Mg([i]) in both groups were evaluated. In hypertensive subjects, vitamin E administration significantly increased WBGD (25.56+/-0.61 to 31.75+/-0.53 micromol/kg of fat-free mass per minute; P<0.01), GSH/GSSG ratio (1.10+/-0.07 to 1.65+/-0.11; P<0.01), and Mg([i]) (1.71+/-0.042 to 1.99+/-0.049 mmol/L; P<0.01). In basal conditions, WBGD was significantly related to both GSH/GSSG ratios (r=0.58, P=0.047) and Mg([i]) (r=0.78, P=0.003). These data show a clinical link between vitamin E administration, cellular magnesium, GSH/GSSG ratio, and tissue glucose metabolism. Further studies are needed to explore the cellular mechanism(s) of this association.
Asunto(s)
Glucosa/metabolismo , Glutatión/administración & dosificación , Hipertensión/tratamiento farmacológico , Magnesio/metabolismo , Vitamina E/administración & dosificación , Método Doble Ciego , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Hipertensión/metabolismo , Resistencia a la Insulina , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Cytosolic free calcium (Cai) and magnesium (Mgi) are vital to cellular homeostasis and function. OBJECTIVE: To evaluate cellular divalent cations in normal subjects at different ages and their relationship to ion levels in essential hypertension and diabetes. DESIGN: A cross-sectional study. SETTING: A university hospital in New York. PARTICIPANTS: A total of 103 subjects (32 older, 71.1 +/- 1.2 y/o, and 71 young/middle aged subjects, 51.1 +/- 2.3 y/o). INTERVENTION: Oral glucose tolerance test. MEASUREMENTS: 19F and 31P NMR spectroscopy were used to measure Cai and Mgi levels in erythrocytes from normal (>65 y/o, n = 11; <65 y/o, n = 26), hypertensive (EH) (>65 y/o, n = 9; <65 y/o, n = 30), and type 2 diabetic (DM) (>65 y/o, n = 12; <65 y/o, n = 15) subjects; these levels were also compared with glucose and insulin levels before and after oral glucose loading. RESULTS: Fasting Mgi levels were lower (207 +/- 7.8 vs 236 +/- 7.5 microM; P < .05) and Cai higher (32.2 +/- 3.0 vs 20.3 +/- 1.8 nM; P < .05) in older than in younger normal subjects. For all normal subjects, the greater the age, the higher the Cai (r = 0.622, P = .004) and the lower the Mgi (r = -0.423; P = .011). However, no significant (P = NS) differences in Mgi or Cai levels were observed between older normal and young/middle-aged subjects with EH (Mgi = 189.7 +/- 5.9 vs 182.6 +/- 9.8 microM; Cai = 33.8 +/- 4.9 vs 35.6 +/- 4.0 nM) or DM (Mgi = 182.8 +/- 10.9 vs 180.8 +/- 8.1 microM; Cai = 33.6 +/- 4.3 vs 39.7 +/- 5.9 nM). Significant relationships were also found between cellular ion content, blood pressure, and glycemic indices. CONCLUSIONS: Aging is associated with the onset of altered Cai and Mgi levels, indistinguishable from those observed in hypertension and diabetes, independent of age. We suggest that these ionic changes may be clinically significant, underlying the predisposition of older subjects to cardiovascular and metabolic diseases.
Asunto(s)
Envejecimiento/metabolismo , Calcio/análisis , Citosol/química , Diabetes Mellitus Tipo 2/metabolismo , Eritrocitos/química , Hipertensión/metabolismo , Magnesio/análisis , Factores de Edad , Anciano , Anciano de 80 o más Años , Glucemia/análisis , Estudios de Casos y Controles , Causalidad , Estudios Transversales , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
Left ventricular hypertrophy (LVH) in hypertensive subjects is associated with an increased prevalence of ventricular arrhythmias. To evaluate the effect of antihypertensive treatment on cardiac arrhythmias (CA) and transient episodes of myocardial ischemia (TEMI), we studied 46 hypertensive patients with LVH, divided into four groups randomly treated with enalapril, hydrochlorothiazide (HCTZ), atenolol, or verapamil (SR-V) for 6 months. Office blood pressure and office heart rate values were recorded, in basal conditions, after 1 and 6 months of treatment, and all patients underwent echocardiography, electrocardiographic Holter monitoring, and stress testing. All drugs significantly lowered blood pressure, whereas left ventricular mass index was reduced by atenolol, enalapril, and SR-V, but not by HCTZ. Treatment induced a significant reduction in the number of patients with supraventricular arrhythmias (35 v 15, P < .034, and 28 v 8, excluding patients treated with HCTZ, P < .008). The number of patients with ventricular arrhythmias was also reduced (32 v 16 considering all groups, P < .08, and 24 v 9, excluding patients treated with HCTZ, P < .04). The number of TEMI during Holter monitoring significantly decreased from 47 to 23 (P = .043) in all patients, and from 39 to 14 (P = .013) excluding patients treated with HCTZ. In all groups, irrespective of treatment, a reduction of blood pressure, heart rate, and systolic blood pressure/heart rate product measured by exercise stress test was observed. The present study shows that in hypertensive patients with LVH, antihypertensive treatment with atenolol, enalapril and SR-V reduces LVH and decreases the prevalence of CA and TEMI. Treatment with HCTZ during the 6-month study did not alter LVH and did not appear to reduce CA and TEMI.
Asunto(s)
Antihipertensivos/administración & dosificación , Arritmias Cardíacas/tratamiento farmacológico , Enalapril/administración & dosificación , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Isquemia Miocárdica/tratamiento farmacológico , Adulto , Anciano , Antiarrítmicos/administración & dosificación , Arritmias Cardíacas/etiología , Atenolol/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Electrocardiografía Ambulatoria , Femenino , Humanos , Hidroclorotiazida/administración & dosificación , Hipertensión/complicaciones , Hipertrofia Ventricular Izquierda/complicaciones , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/etiología , Resultado del Tratamiento , Verapamilo/administración & dosificaciónRESUMEN
Angiotension converting enzyme (ACE) inhibitors and beta-blockers have been reported to possess disparate effects on insulin sensitivity. The aim of this study was to study the effects of the selective beta-1 blocker bisoprolol and of the ACE inhibitor captopril on cellular insulin action in hypertensive individuals. After washout, 12 mild to moderate essential hypertensives were randomized in a double-blind manner to 5 mg bisoprolol daily or 25 mg captopril twice daily for 8 weeks. Erythrocyte insulin binding and insulin-stimulated tyrosine kinase (TK) activity were measured before and after therapy. Both agents decreased diastolic blood pressure significantly (bisoprolol 96.5+/-0.9 to 87.8+/-3.1 mm Hg; captopril 96.5+/-0.9 to 91.5+/-1.8 mm Hg; P < .05). Fasting plasma glucose, insulin, and insulin/glucose indices remained unchanged after both therapies, as did lipid profiles. Maximal insulin-stimulated TK activity, assessed by phosphorylation of the exogenous substrate poly-Glu80Tyr20, was significantly higher (P < .05) after bisoprolol treatment, but not after captopril treatment, when compared to placebo (bisoprolol 8.5+/-1.8; captopril 7.3+/-1.5; placebo: 6.4+/-1.3 pmol 32P-ATP/fmol bound insulin). However, captopril, but not bisoprolol, increased the sensitivity of the receptor TK activity, as measured by the half-maximal activity concentration (ED50). Specific insulin binding was not affected by these two agents. Thus, both captopril and bisoprolol may have favorable but different effects on TK activity and insulin action at the cellular level.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Bisoprolol/farmacología , Captopril/farmacología , Hipertensión/tratamiento farmacológico , Receptor de Insulina/efectos de los fármacos , Anciano , Método Doble Ciego , Humanos , Hipertensión/enzimología , Resistencia a la Insulina , Persona de Mediana Edad , Receptor de Insulina/metabolismoRESUMEN
To investigate the metabolic and renal effects of the nonsulfhydryl, tissue-active ACE inhibitor quinapril in diabetes and in hypertension, we studied 30 essential hypertensives and 24 non-insulin-dependent (type II) diabetic (NIDDM) subjects with hypertension. Systolic and diastolic blood pressures, plasma glucose, and insulin responses to an oral glucose load (75 g), lipid profile, and urinary albumin excretion were evaluated before and after 8 weeks' administration of quinapril (10 to 40 mg/day). Quinapril produced a significant and comparable reduction of arterial blood pressure in both groups. Mean arterial pressure decreased from 114.8 +/- 0.9 to 94.2 +/- 1.1 (-17.9 +/- 1.5%) in the essential hypertensive group and from 118.4 +/- 1.6 to 96.2 +/- 1.4 (-18.4 +/- 1.6%) in the diabetic hypertensive group. In both essential hypertensives and diabetic-hypertensive subjects with microalbuminuria, quinapril significantly and comparably reduced the urinary albumin excretion rate (UAE); UAE decreased from 32.5 +/- 5.5 micrograms/min to 14.7 +/- 3.7 micrograms/min (P < .05 v baseline) in the diabetic-hypertensive group and from 27.5 +/- 3.0 micrograms/min to 11.6 +/- 2.7 micrograms/min (P < .05 v baseline) in the essential hypertensives. Altogether, a direct correlation was found between the initial level of UAE and the UAE reduction after quinapril (delta UAE) (r = 0.706, p < .05). Insulin and glucose responses to an oral glucose tolerance test and the lipid profiles were not modified by quinapril treatment. The results confirm that quinapril is an effective antihypertensive agent that additionally reduces microalbuminuria in both hypertensive diabetics and in patients with essential hypertension, without altering insulin sensitivity and lipid profiles.
Asunto(s)
Albuminuria/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Hipertensión/tratamiento farmacológico , Isoquinolinas/uso terapéutico , Tetrahidroisoquinolinas , Albuminuria/etiología , Albuminuria/metabolismo , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Insulina/sangre , Masculino , Persona de Mediana Edad , QuinaprilRESUMEN
alpha-Adrenergic blockers have shown favorable metabolic effects. We evaluated the glucose and insulin responses to a glucose load and lipid profiles in 36 diabetic hypertensive patients before and after 8 weeks of doxazosin administration. To evaluate insulin action at the cellular level, erythrocyte insulin binding and tyrosine kinase (TK) activity were measured in 12 of these patients. Systolic and diastolic blood pressures decreased significantly (P < .0001) after 8 weeks of doxazosin therapy. Doxazosin administration significantly reduced the integrated insulin response (area under the curve [AUC]-insulin: 6093 +/- 894 to 5260 +/- 807; P = .04) and the insulin/glucose index (I/G) at 90 and 120 min after a glucose load (at 90 min, 0.230 +/- 0.055 v 0.180 +/- 0.04, P < .05; at 120 min, 0.275 +/- 0.071 v 0.173 +/- 0.036, P < .05). HDL3 level increased from 31.1 +/- 1.5 mg% to 34 +/- 1.6 mg% (P < .05) after doxazosin. Erythrocyte insulin binding and tyrosine kinase activity were not significantly altered after doxazosin. No significant correlation was found between the insulin or glucose responses and the insulin receptor binding or tyrosine kinase activity before and after treatment.