RESUMO
Congenitally analbuminaemic individuals and rats (NARs) exhibit several metabolic abnormalities, including hypertriglyceridaemia and plasma free fatty acid deficiency. Our aim was to study glucose homeostasis and insulin secretion in NARs. Plasma concentrations of lipids, glucose and insulin and secretion of insulin from the pancreatic islets were measured in female NARs and control animals (Sprague-Dawley rats; SDRs). Glucose homeostasis tests were also performed. Plasma glucose levels were similar between NARs and SDRs, irrespective of feeding status. However, fed insulinaemia was â¼37% higher (P 0.05) in NARs than in SDRs. The NARs displayed a markedly increased glucose tolerance, i.e. the integrated glycaemic response was one-third that of the control animals. Enhanced glucose tolerance was associated with threefold higher insulinaemia at peak glycaemia after a glucose load than in the control animals. Similar peripheral insulin sensitivity was observed between groups. Isolated pancreatic islets from NARs secreted significantly more insulin than islets from SDRs in response to a wide range of glucose concentrations (2.8-33.3 mm). Despite having similar liver glycogen contents in the fully fed state, NARs had â¼40% (P 0.05) lower glycogen contents than SDRs after 6 h fasting. The injection of a gluconeogenic substrate, pyruvate, elicited a faster rise in glycaemia in NARs compared with SDRs. Overall, NARs displayed enhanced glucose tolerance, insulin secretion and gluconeogenic flux. The higher glucose tolerance in NARs compared with SDRs is attributed to enhanced islet responsiveness to secretagogues, while peripheral insulin sensitivity seems not to be involved in this alteration. We propose that the enhanced glucose metabolism is a chronic compensatory adaptation to decreased free fatty acid availability in NARs.
Assuntos
Glicemia/metabolismo , Ácidos Graxos não Esterificados/sangue , Hipertrigliceridemia/sangue , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Albumina Sérica/deficiência , Animais , Deficiências Nutricionais/sangue , Deficiências Nutricionais/complicações , Deficiências Nutricionais/diagnóstico , Feminino , Teste de Tolerância a Glucose/métodos , Hipertrigliceridemia/etiologia , Secreção de Insulina , Ratos , Ratos Sprague-DawleyRESUMO
Congenital analbuminemia is a rare autosomal recessive disorder characterized by a trace level of albumin in blood plasma and mild clinical symptoms. Analbuminemic patients generally present associated abnormalities, among which dyslipidemia is a hallmark. In this study, we show that mitochondria isolated from different tissues (liver, heart and brain) from 3-month-old analbuminemic rats (NAR) present a higher susceptibility to Ca(2+)-induced mitochondrial permeability transition (MPT), as assessed by either Ca(2+)-induced mitochondrial swelling, dissipation of membrane potential or mitochondrial Ca(2+) release. The Ca(2+) retention capacity of the liver mitochondria isolated from 3-month-old NAR was about 50% that of the control. Interestingly, the assessment of this variable in 21-day-old NAR indicated that the mitochondrial Ca(2+) retention capacity was preserved at this age, as compared to age-matched controls, which indicates that a reduced capacity for mitochondrial Ca(2+) retention is not a constitutive feature. The search for putative mediators of MPT sensitization in NAR revealed a 20% decrease in mitochondrial nitrosothiol content and a 30% increase in cyclophilin D expression. However, the evaluation of other variables related to mitochondrial redox status showed similar results between the controls and NAR, i.e., namely the contents of reduced mitochondrial membrane protein thiol groups and total glutathione, H(2)O(2) release rate, and NAD(P)H reduced state. We conclude that the higher expression of cyclophilin D, a major component of the MPT pore, and decreased nitrosothiol content in NAR mitochondria may underlie MPT sensitization in these animals.
Assuntos
Anormalidades Congênitas/metabolismo , Ciclofilinas/metabolismo , Mitocôndrias/metabolismo , S-Nitrosotióis/metabolismo , Albumina Sérica/deficiência , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Cálcio , Peptidil-Prolil Isomerase F , Ciclofilinas/genética , Feminino , Expressão Gênica , Fígado/metabolismo , Fígado/patologia , Masculino , Potencial da Membrana Mitocondrial , Dilatação Mitocondrial , Estresse Oxidativo , Permeabilidade , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Abnormalities in lipid metabolism and transport are hallmarks in analbuminemic Nagase rats (NAR) and humans. Triglyceridemia is nearly 3- to 5-fold higher in female NAR than in control Sprague-Dawley rats (SDR). Also, NAR present with a severe plasma free fatty acid (FFA) deficit. There are conflicting results regarding the mechanisms underlying NAR hypertriglyceridemia. OBJECTIVE: We aimed at investigating whether liver lipogenesis and triglyceride secretion rates into the plasma contribute to the hypertriglyceridemia in NAR. We also studied whether heparin or albumin administration would release the hypothesized lipolysis inhibition in NAR. METHODS: The incorporation of tritiated water into lipids and the linear accumulation rate of plasma triglycerides after Triton WR1339 injection were the measures of liver lipogenesis and triglyceride secretion rates. RESULTS: Lipogenesis (596 ± 40 vs. 929 ± 124 µmol 3H2O/g/h) and triglyceride (4.25 ± 1.00 vs. 7.04 ± 1.68 mg/dL/min) secretion rates were slower (P ≤ 0.05) in fasted NAR than in control SDR. The injection of either heparin or albumin elicited an increase in NAR plasma FFA levels over time. FFA levels reached control levels 90 min after the albumin administration, increasing from 0.36 ± 0.05 to 1.34 ± 0.16 mEq/L (P ≤ 0.05). These results indicate that the lack of plasma albumin inhibits intravascular lipolysis and causes the FFA deficit observed in NAR. CONCLUSION: NAR hepatic triglyceride synthesis and output do not contribute to NAR hypertriglyceridemia. We propose that the lack of albumin diminishes intravascular lipolysis which reduces the plasma triglyceride removal rate and explain both NAR hypertriglyceridemia and FFA deficiency.
Assuntos
Ácidos Graxos não Esterificados , Hipertrigliceridemia , Albumina Sérica , Triglicerídeos , Animais , Deficiências Nutricionais/sangue , Deficiências Nutricionais/genética , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/genética , Ácidos Graxos não Esterificados/metabolismo , Feminino , Heparina/administração & dosagem , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/genética , Hipertrigliceridemia/metabolismo , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Lipólise/efeitos dos fármacos , Lipólise/genética , Polietilenoglicóis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Albumina Sérica/deficiência , Albumina Sérica/genética , Triglicerídeos/sangue , Triglicerídeos/genética , Triglicerídeos/metabolismoRESUMO
Dyslipoproteinemia of the Nagase analbuminemic rat (NAR) is characterized by elevated concentrations of VLDL and LDL attributed to increased rates of liver lipoprotein synthesis. Increased lysophosphatidylcholine (LPC) in NAR HDL has been attributed to high plasma LCAT activity. We show here that, as compared with Sprague-Dawley rats (SDR), NAR plasma triacylglycerol (TAG), total cholesterol (TC), HDL TAG, protein, total phospholipids (PL), LPC, and PS are increased. These alterations rendered the NAR HDL particle more susceptible to the activity of the enzyme hepatic lipoprotein lipase (HL), which otherwise was unaltered in our study. Fractional catabolic rates in blood of the autologous 125I-apoHDL (median and lower quartile values), were, respectively, 0.231 and 1.645 (n = 10) in NAR as compared with 0.140 and 0.109 (n = 10) in SDR (P = 0.012), corresponding to synthesis rates of HDL protein of 89.8 +/- 33.7 mg/d in NAR and 17.4 +/- 6.5 mg/d in SDR (P = 0.0122). Furthermore, Swiss mouse macrophage free-cholesterol (FC) efflux rates, measured as the percent [14C]-cholesterol efflux/6 h, were 8.2 +/- 2.3 (n = 9) in NAR HDL and 11.2 +/- 3.2 (n = 10) in SDR HDL (P = 0.03). Therefore, in NAR the modification of the HDL composition slows down the cell FC efflux rate, and together with the increased rate of plasma HDL metabolism influences the reverse cholesterol transport system.
Assuntos
Apolipoproteínas/metabolismo , Colesterol/metabolismo , Hiperlipoproteinemias/metabolismo , Lipoproteínas HDL/metabolismo , Macrófagos/metabolismo , Albumina Sérica/deficiência , Animais , Apolipoproteínas/sangue , Apolipoproteínas/farmacocinética , Transporte Biológico/genética , Colesterol/sangue , Hiperlipoproteinemias/sangue , Hiperlipoproteinemias/genética , Radioisótopos do Iodo , Lipoproteínas HDL/sangue , Camundongos , Ratos , Ratos Mutantes , Ratos Sprague-Dawley , Triglicerídeos/sangueRESUMO
Plasma albumin restricts capillary water filtration. Accordingly, the glomerular ultrafiltration coefficient is higher in Nagase analbuminemic rats (NAR) than in Sprague-Dawley controls. We investigated whether the glomerular permeability to macromolecules is also enhanced in NAR. SDS-PAGE fractionation of urine proteins showed several bands with molecular masses between 60 and 90 kDa in NAR only. Acute administration of BSA to NAR led to nearly complete disappearance of these proteins from urine, an effect partially reversed when most of the exogenous albumin was cleared from circulation. The fractional clearance of 70-kDa dextran was increased in NAR, indicating a size defect. Binding of cationized ferritin to the glomerular basement membrane was decreased in NAR, suggesting associated depletion of fixed anions. The magnitude of cationic ferritin binding correlated negatively with the fractional clearance of 70-kDa dextran, suggesting that the two abnormalities may share a common pathogenic mechanism. Collectively, these results suggest enhanced glomerular permeability to macromolecules in NAR. Albumin may be necessary to maintain the normal glomerular permselectivity properties.
Assuntos
Acetilglucosaminidase/genética , Acetilglucosaminidase/metabolismo , Glomérulos Renais/metabolismo , Albumina Sérica/deficiência , Animais , Proteínas Sanguíneas/urina , Permeabilidade Capilar/fisiologia , Dextranos/farmacocinética , Eletroforese em Gel de Poliacrilamida , Ferritinas/análise , Testes de Função Renal , Glomérulos Renais/química , Glomérulos Renais/ultraestrutura , Substâncias Macromoleculares , Microscopia Eletrônica , Proteinúria/genética , Proteinúria/metabolismo , Ratos , Ratos Mutantes , Ratos Sprague-Dawley , Albumina Sérica/farmacocinéticaRESUMO
Hypoalbuminemia in dialysis is a highly prevalent condition associated with morbidity and mortality. Hypoalbuminemia, although not synonymous of malnutrition, is highly related to it. Poor nutrient intake, frequently observed in uremia, may cause malnutrition and subsequently hypoalbuminemia. In addition, it has been recently reported that a systemic inflammatory response may participate in developing hypoalbuminemia in chronic renal failure. Uremia per se, or through mechanisms stimulated by the use of current dialysis membranes and/or solutions, seems to trigger the inflammatory process, remarkably associated with hypoalbuminemia. Infections, to which patients on dialysis are particularly predisposed, stimulate production of the inflammatory response as well. Other conditions non-associated to inflammatory response, such as the protein losses through dialysis, may cause and increase malnutrition. Overhydration, frequently present in patients with renal failure, on the one hand causes dilution of serum albumin concentrations, and on the other hand, is cause of onset and/or enhancement of congestive cardiac failure, which in turn may be associate with malnutrition. Patients with chronic renal failure develop hypoalbuminemia due to a complex setting of conditions, with systemic inflammatory response as a major cause; notwithstanding, other factors such as malnutrition and overhydration can also play a relevant role. Therefore, diagnostic and therapeutic approaches should be individualized.
Assuntos
Inflamação/sangue , Diálise Peritoneal/efeitos adversos , Desnutrição Proteico-Calórica/sangue , Albumina Sérica/deficiência , Biomarcadores/sangue , Doenças Cardiovasculares/mortalidade , Humanos , Inflamação/mortalidade , Interleucina-1/sangue , Falência Renal Crônica/metabolismo , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Diálise Peritoneal/mortalidade , Prognóstico , Diálise Renal/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Owing to high diarrhoea and protein malnutrition frequencies in pellagra, we hypothesised that pellagra patients would have higher electrolyte disturbances than non-pellagra alcoholics. OBJECTIVE: To compare serum electrolytes of hospitalised alcoholics with or without pellagra. DESIGN: Retrospective and descriptive case-control study. SETTING: Internal Medicine wards at a University Hospital, Medical School of Uberaba, Brazil. SUBJECTS: Medical records were reviewed to obtain relevant clinical details, main diagnosis and laboratory data, including serum electrolytes on hospital admission of pellagra patients (n=33) and a randomly chosen control group of alcoholics (n=37), matched in age, gender and socio-economic status. Anaemia was ascertained by haemoglobin <12.5 g/dl (men) and 1.5 g/dl (women), and hypoalbuminemia by serum albumin <3.3 g/dl. RESULTS: Pellagra and controls showed similar age (39.4+/-13.1 vs 45.0+/-11.4 years) and a male predominance of gender (69.7 vs 78.4%), and similar associated diagnoses, including high blood pressure (21.2 vs 16.2%), peripheral neuropathy (12.1 vs 13. 5%), and pneumonia (9.1 vs 13.5%). Despite displaying similar serum sodium (136.6+/-6.1 vs 137.8+/-5.7 mEq/I), magnesium (1.72+/-0.74 vs 1.62+/-0.34 mg/dl), phosphorus (3.79+/-0.87 vs 3.87+/-0.78 mEq/1) than controls,in addition to higher hypoalbuminemia (76.2 vs 33%) and anaemia (60.6 vs 35.1%) frequencies. CONCLUSIONS: Higher anaemia and hypoalbuminemia frequencies associated with lower serum potassium levels suggest increased protein malnutrition prevalence among pellagrins.
Assuntos
Alcoolismo/sangue , Alcoolismo/complicações , Eletrólitos/sangue , Pelagra/sangue , Pelagra/complicações , Adulto , Anemia/complicações , Estudos de Casos e Controles , Feminino , Hospitalização , Humanos , Hipertensão/complicações , Magnésio/sangue , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/complicações , Fósforo/sangue , Pneumonia/complicações , Potássio/sangue , Estudos Retrospectivos , Albumina Sérica/deficiência , Sódio/sangueRESUMO
Hypoalbuminemia may cause interstitial edema and hemodilution, which we hypothesized may influence serum sodium levels. Our purpose was to compare serum sodium levels of hospitalized adults with or without hypoalbuminemia. All sodium and albumin serum levels of 142 adults hospitalized at general medical wards over a six-month period were searched at a University Hospital mainframe computer. Relevant laboratory data and clinical details were also registered. Hypoalbuminemia was defined by serum albumin concentration < 3.3 g/dl Fisher, Mann-Whitney, and Student's t tests were applied to compare groups with or without hypoalbuminemia. Ninety-nine patients, classified as hypoalbuminemic, had lower blood hemoglobin (10.68 +/- 2.62 vs. 13.54 +/- 2.41), and sodium (135.1 +/- 6.44 vs. 139.9 +/- 4.76 mEq/l) and albumin (2.74 +/- 0.35 vs. 3.58 +/- 0.28 g/dl) serum levels than non-hypoalbuminemic (n = 43). Pearson's coefficient showed a significant direct correlation between albumin and sodium serum levels (r = 0.40) and between serum albumin and blood hemoglobin concentration (r = 0.46). Our results suggest that hypoalbuminemic adults have lower serum sodium levels than those without hypoalbuminemia, a phenomenon that may be at least partially attributed to body water retention associated with acute phase response syndrome.
Assuntos
Albumina Sérica/deficiência , Sódio/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Albumina Sérica/metabolismoRESUMO
La albúmina es una proteína plasmática sintetizada por el hígado con múltiples funciones. La hipoalbuminemia es un dato de laboratorio frecuente en pacientes graves con diferentes patologías. La administración de albúmina exógena humana es una práctica clínica generalizada a pesar de no tener evidencia científica concluyente de su eficacia. Se estudiaron 14 pacientes pediátricos enfermos graves en la unidad de terapia intensiva (TTIP) del Hospital Central Militar (HCM) con hipoalbuminemia (< 3 g/dL). Se excluyeron aquellos pacientes con enfermedad renal, hepática o cáncer. Estudio prospectivo, abierto y aleatorio de la administración de albúmina humana exógena (1 g/kg/dosis), contra placebo (solución salina) hasta tener niveles normales de albúmina, monitorizando cada 4 días el nivel de albúmina. Se siguieron hasta su salida del hospital o su defunción, se determinaron PRISM y SNAP a su ingreso. Las variables clínicas estudiadas fueron los días de hospitalización, días de ventilación mecánica, días de estancia en la UTIP, total de días de ayuno y mortalidad. No se encontraron efectos clínicos benéficos en la tolerancia a la nutrición enteral, tiempo para cubrir requerimientos nutricionales totales, días de ventilación mecánica y día de nutrición parenteral total al administrar albúmina en el grupo de estudio vs. el control. No se encontró disminución de la morbilidad y mortalidad en los pacientes tratados con albúmina. El uso de la administración de albúmina exógena humana es una práctica cara
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Monitoramento de Medicamentos , Albumina Sérica/administração & dosagem , Albumina Sérica/deficiência , Estado Terminal , Doenças do Recém-Nascido/fisiopatologia , Doenças do Recém-Nascido/terapia , Unidades de Terapia Intensiva NeonatalRESUMO
This investigation examined how the nutritional status of rats fed a low-protein diet was affected when the animals were treated with the beta-2 selective agonist clenbuterol (CL). Males (4 weeks old) from an inbred, specific-pathogen-free strain of hooded rats maintained at the Dunn Nutritional Laboratory were used in the experiments (N = 6 rats per group). CL treatment (Ventipulmin, Boehringer-Ingelheim Ltd., 3.2 mg/kg diet for 2 weeks) caused an exacerbation of the symptoms associated with protein deficiency in rats. Plasma albumin concentrations, already low in rats fed a low-protein diet (group A), were further reduced in CL rats (A = 25.05 +/- 0.31 vs CL = 23.64 +/- 0.30 g/l, P < 0.05). Total liver protein decreased below the level seen in either pair-fed animals (group P) or animals with free access to the low-protein diet (A = 736.56 +/- 26 vs CL = 535.41 +/- 54 mg, P < 0.05), whereas gastrocnemius muscle protein was higher than the values normally described for control (C) animals (C = 210.88 +/- 3.2 vs CL = 227.14 +/- 1.7 mg/g, P < 0.05). Clenbuterol-treated rats also showed a reduction in growth when compared to P rats (P = 3.2 +/- 1.1 vs CL = -10.2 +/- 1.9 g, P < 0.05). This was associated with a marked decrease in fat stores (P = 5.35 +/- 0.81 vs CL = 2.02 +/- 0.16 g, P < 0.05). Brown adipose tissue (BAT) cytochrome oxidase activity, although slightly lower than in P rats (P = 469.96 +/- 16.20 vs CL = 414.48 +/- 11.32 U/BAT x kg body weight, P < 0.05), was still much higher than in control rats (C = 159.55 +/- 11.54 vs CL = 414.48 +/- 11.32 U/BAT x kg body weight, P < 0.05). The present findings support the hypothesis that an increased muscle protein content due to clenbuterol stimulation worsened amino acid availability to the liver and further reduced albumin synthesis causing exacerbation of hypoalbuminemia in rats fed a low-protein diet.