RESUMO
Ghrelin is a peptide secreted mainly by gastric parietal cells that may play a role in appetite regulation. Circulating ghrelin is abruptly lowered by food intake, but factors involved in ghrelin regulation remain unclear. The aim of this study was to determine whether intravenous glucose infusion lowers ghrelin, and to determine whether glucose, insulin or some measure of insulin action best predicts the effect of feeding on ghrelin. Rats were infused over 3 h with either A. saline (controls); B. dextrose to steady state blood glucose approximately 16.7 mM, or C. insulin 7.5 mU/kg x min, plus dextrose as needed to clamp to euglycemic basal concentrations. During 3 h of infusion, group B had significantly greater (P<0.01) glucose, 17.4+/-0.3 mM, than groups A (6.6+/-0.3) or C (6.1+/- 0.2). Groups B and C had hyperinsulinemia at the end of the 3 h infusion (894+/-246, 804+/-156 pM) compared with saline-infused (222+/-24 pM, P<0.01). Ghrelin concentrations were reduced (P<0.01) in both hyperinsulinemic groups (B=85+/-2; C=103+/-0.6 pM) versus controls (163+/-9). Ghrelin was strongly correlated with insulin (r=-0.68), glucose infusion rate (r=-0.75) and free fatty acids (r=0.67), when all 3 groups were combined, although only the 2 latter variables were independent predictors of ghrelin. In conclusion, neither a rise in blood glucose nor presence of nutrient in the stomach is required for the effect of feeding on ghrelin. The data suggest that whole body insulin responsiveness plays either a direct or indirect role in meal-related ghrelin inhibition.
Assuntos
Glucose/administração & dosagem , Insulina/fisiologia , Hormônios Peptídicos/sangue , Ração Animal , Animais , Glicemia/análise , Estudos Transversais , Grelina , Glucose/fisiologia , Infusões Intravenosas , Insulina/sangue , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
This study was designed to examine circulating and urine cytokine levels in patients receiving long-term home total parenteral nutrition (TPN) support. Twelve patients who had been receiving home TPN for more than 1 year (range, 1.3-19.5 years) were enrolled for study. To avoid the potential confounding effects of intercurrent infection, patients were studied during periods of clinical stability without clinical evidence of infection. Ten normal healthy volunteers served as controls. Serum levels of albumin and C-reactive protein, temperature, body weight, and blood white cell counts were determined. The levels of soluble tumor necrosis factor receptor II (sTNF-RII) and interleukin 6 (IL-6) were measured in serum and 24-hr urine. The results showed that the concentrations of sTNF-RII and IL-6 in 24-hr urine and serum were significantly higher in patients, indicating that long-term home TPN may be associated with a persistent low-grade inflammatory state.
Assuntos
Mediadores da Inflamação/metabolismo , Nutrição Parenteral Total no Domicílio , Adulto , Idoso , Estudos de Casos e Controles , Enterite/terapia , Feminino , Humanos , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores do Fator de Necrose Tumoral/metabolismo , Síndrome do Intestino Curto/terapia , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The bacterial lipopolysaccharide endotoxin induces a catabolic response characterized by resistance to multiple anabolic hormones. The objective of this study was to determine the effects of endotoxin on the GH signaling pathway in rat liver in vivo. After the iv injection of Escherichia coli endotoxin (1 mg/kg), there was a progressive decrease in liver STAT5 (signal transducer and activator of transcription-5) tyrosine phosphorylation in response to GH (40% decrease 6 h after endotoxin), which occurred in the absence of a change in abundance of the STAT5 protein. Endotoxin resulted in a rapid 40-fold increase in liver Janus family kinase-2 (JAK2) messenger RNA, followed by a 2-fold increase in JAK2 protein abundance. This was associated with a 50% decrease in phosphorylated/total JAK2 after GH stimulation. GH receptor abundance was unchanged, suggesting a postreceptor site of endotoxin-induced GH resistance. Rat complementary DNAs for three members of the suppressor of cytokine signaling gene family were cloned [cytokine-inducible sequence (CIS), suppressor of cytokine signaling-2 (SOCS-2), and SOCS-3] and, using these probes, messenger RNAs for SOCS-3 and CIS were shown to be increased 10- and 4-fold above control values, respectively, 2 h after endotoxin infusion. The finding of endotoxin inhibition of in vivo STAT5 tyrosine phosphorylation in response to a supramaximal dose of GH in the absence of a change in GH receptor abundance or total GH-stimulated JAK2 tyrosine phosphorylation provides the first demonstration of acquired postreceptor GH resistance. We hypothesize that this may occur through a specificity-spillover mechanism involving the induction of SOCS genes by cytokines released in response to endotoxin and subsequent SOCS inhibition of GH signaling.
Assuntos
Endotoxinas/farmacologia , Fígado/metabolismo , Proteínas do Leite , Proteínas Proto-Oncogênicas , Receptores da Somatotropina/fisiologia , Proteínas Repressoras , Transdução de Sinais , Fatores de Transcrição , Animais , Proteínas de Ligação a DNA/metabolismo , Escherichia coli , Expressão Gênica , Hormônio do Crescimento Humano/farmacologia , Janus Quinase 2 , Masculino , Fosforilação , Fosfotirosina/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT5 , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina , Transativadores/metabolismoRESUMO
BACKGROUND: This study examined whether adding arachidonic acid (AA) to a fish oil diet would alter certain of the anti-inflammatory effects of fish oil in response to tumor necrosis factor (TNF) infusion in rats. METHODS: AA was given at 0.08 wt% of diet for 6 weeks. The total fat in each diet provided 20% of dietary energy. Four groups were pair-fed sunflower oil (S), S+AA, fish oil (F), or F+AA for 6 weeks. At the end of feeding, each animal received TNF-alpha (20 microg/kg) infusion for 3 hours. After 1 hour of TNF infusion, a euglycemic and hyperinsulinemic clamp (10 mU/min per kilogram of insulin) was used to determine the actions of insulin. The insulin-stimulated glucose utilization in liver, muscle, and fat was determined by using 14C-deoxyglucose. The plasma glucose, insulin, and corticosterone levels were determined at basal, 60 minutes, and the end of the experiment (180 minutes). The fatty acid composition of plasma phospholipids also was determined. RESULTS: Fish oil significantly increased omega-3 fatty acids in phospholipids in both F and F+AA and decreased AA in F, compared with S. AA significantly restored the level of AA and reduced the increase of omega-3 fatty acids in phospholipids in F+AA compared with F, but had no impact on fatty acid composition when added to S. Corticosterone level was significantly lower with fish oil feeding but higher in both F and S containing AA compared with F and S, respectively. The highest glucose uptake in tissues was in F, followed by F+AA, and then S and S+AA. CONCLUSIONS: These results suggest that fish oil is anti-inflammatory principally through a reduction in the AA content of phospholipids.
Assuntos
Ácido Araquidônico/farmacologia , Óleos de Peixe/uso terapêutico , Inflamação/prevenção & controle , Fator de Necrose Tumoral alfa , Tecido Adiposo/metabolismo , Animais , Ácido Araquidônico/administração & dosagem , Glicemia/metabolismo , Ácidos Graxos Ômega-3/sangue , Glucose/metabolismo , Técnica Clamp de Glucose , Inflamação/etiologia , Insulina/sangue , Fígado/metabolismo , Masculino , Músculos/metabolismo , Fosfolipídeos/sangue , Ratos , Ratos Sprague-DawleyRESUMO
Intestinal cell growth is markedly affected by nutrient intake and the presence of cytokines. Since insulin-like growth factor-I (IGF-I) is an important hormone regulator of intestinal proliferation, this study examined the effects of dietary protein content and tumor necrosis factor (TNF) on mRNA levels of IGF-I, IGF-I receptor, IGF binding protein-3 (IGFBP-3), and IGFBP-4 and on the histology of the colon, jejunum, and ileum in protein-malnourished rats. After 2 weeks of feeding a 2% casein diet, rats continued on the 2% casein diet or were refed with a 20% casein diet and received daily intraperitoneal injections of either TNF (50 microg/kg) or saline for 4 days. The abundance of mRNA in the intestine was determined by RNA dot-blot analysis, and morphology measurements were performed by light microscopy. Simultaneous refeeding with the 20% casein diet and administration of TNF led to a modest increase in IGF-I and IGFBP-4 mRNA abundance in the colon. However, in the jejunum and ileum, refeeding had no effect but TNF caused a decrease in IGF-I and IGFBP-3 mRNA levels in malnourished rats. Refeeding with the 20% casein diet resulted in relatively modest histologic changes, which were greater in the colon versus the small intestine. The decreased magnitude of histologic changes in the order of the colon, ileum, and jejunum may reflect a response to a gradient of amino acid availability from intraluminal nutrients. These data demonstrate that TNF has distinct effects on colon and small intestine mRNA, but these mild changes had only a slight impact in the colon and did not translate into identifiable histologic changes in the small intestine. Combined protein restriction and TNF administration had only a modest effect on intestinal mRNA levels and mucosal histology.
Assuntos
Colo/metabolismo , Proteínas Alimentares/farmacologia , Fator de Crescimento Insulin-Like I/genética , Intestino Delgado/metabolismo , Deficiência de Proteína/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Animais , Caseínas/administração & dosagem , Colo/patologia , Íleo/metabolismo , Íleo/patologia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Fator de Crescimento Insulin-Like I/metabolismo , Jejuno/metabolismo , Jejuno/patologia , Masculino , Deficiência de Proteína/patologia , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor IGF Tipo 1/genéticaRESUMO
The purpose of this study was to determine the effects of insulin-like growth factor-I (IGF-I) on glucose metabolism in normal and tumor necrosis factor (TNF)-treated rats under euglycemic and hyperinsulinemic conditions. During a hyperinsulinemic clamp (10 mU/kg.min), rats further received either saline or IGF-I (3.33 micrograms/kg.min) infusion for 2 hours. Glucose kinetics were determined with [3H-3]-glucose. Glucose utilization in peripheral tissues was examined by glucose uptake using [14C-2]-deoxyglucose (14C-DG) and by glycogen content in select tissues. The results showed that TNF infusion significantly decreased the rate of glucose infusion required to maintain euglycemia. TNF decreased glycogen content significantly in liver and marginally in abdominis muscle. TNF also decreased glucose uptake in muscle, although the decrease was only statistically significant compared with IGF-I infusion. In addition, TNF significantly reduced plasma IGF-I concentration. However, during hyperinsulinemic and euglycemic conditions, exogenous IGF-I significantly increased glucose uptake in muscle and glycogen storage in the liver and abdominis muscle in both saline- and TNF-treated groups. IGF-I normalized each of the effects of TNF in the rats, including those on plasma IGF-I, glucose uptake in muscle, and glycogen content in liver and abdominis muscle. These data suggest that under hyperinsulinemic and euglycemic conditions, TNF-treated rats, although resistant to insulin, have a normal response to IGF-I, indicating that the TNF-induced defect in the insulin pathway may not be a step in the IGF-I pathway.
Assuntos
Glucose/metabolismo , Hiperinsulinismo/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Glicemia/análise , Técnica Clamp de Glucose , Insulina/sangue , Fígado/metabolismo , Masculino , Músculo Esquelético/metabolismo , Ratos , Ratos Sprague-Dawley , Valores de ReferênciaRESUMO
This study determined the effects of chronic administration of the two principal proximate cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), on host wasting in rats. The effects were compared with those observed in a matched pair-fed group to distinguish the contribution from anorexia. Both TNF and IL-1 produced weight loss, net nitrogen loss, and skeletal muscle catabolism and increased liver weight. Such effects were independent from and additive to those resulting from semistarvation. However, under equivalent nutritional conditions, TNF infusion led to a greater effect on muscle protein catabolism and liver weight and caused liver protein anabolism, whereas only the group receiving IL-1 had altered glucose metabolism in the postabsorptive state. Tachyphylaxis was seen in the response of food intake over time after administration of IL-1. These actions define the two principal mechanisms for the development of protein calorie malnutrition that occur because of cytokine action, anorexia producing semistarvation and an increased net protein catabolic rate reducing anabolic efficiency.
Assuntos
Caquexia/fisiopatologia , Proteínas/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Metabolismo Energético , Jejum , Leucina/metabolismo , Fígado/anatomia & histologia , Fígado/metabolismo , Masculino , Proteínas Musculares/metabolismo , Nitrogênio/urina , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: This study was designed to determine the consequences of acute hyperglycemia on the immune function of peripheral neutrophils, peritoneal macrophages, and alveolar macrophages in nondiabetic rats. METHODS: The animals were randomly divided into nonsurgical (normal) and surgical groups. The postoperative rats were further divided into normoglycemic (control) and hyperglycemic (glucose) groups. The hyperglycemic condition was maintained by constant infusion of glucose to raise plasma glucose concentration to 300 mg/dL for 3 hours. The immune cells were then harvested to determine their phagocytic and oxidative capacities via flow cytometry. RESULTS: The results showed that hyperglycemia significantly decreased the respiratory burst of alveolar macrophages (p < .05). In contrast, hyperglycemia enhanced phagocytosis in these cells (p < .002). There was a significant activation of the respiratory burst in peripheral neutrophils by surgery (p < .002), but no effect of hyperglycemia. CONCLUSIONS: We conclude that hyperglycemia itself can influence immune function in some phagocytic cells, which may be an important factor in postsurgical infection.
Assuntos
Hiperglicemia/imunologia , Sistema Imunitário/fisiologia , Doença Aguda , Análise de Variância , Animais , Glicemia/análise , Glicemia/metabolismo , Células Cultivadas , Citometria de Fluxo , Glucose/farmacologia , Hiperglicemia/fisiopatologia , Sistema Imunitário/citologia , Sistema Imunitário/metabolismo , Insulina/sangue , Macrófagos Alveolares/citologia , Macrófagos Alveolares/fisiologia , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/fisiologia , Neutrófilos/citologia , Neutrófilos/fisiologia , Oxirredução , Fagocitose/fisiologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Explosão Respiratória/fisiologiaRESUMO
Protein restriction decreases plasma concentrations of albumin and insulin-like growth factor-I (IGF-I) by reducing their hepatic mRNA levels, whereas protein restriction increases IGF-I binding protein-2 (IGFBP-2) gene expression in the liver. Tumor necrosis factor (TNF), as an inducer of the injury response, decreases plasma albumin concentration and albumin mRNA in the liver. The present study was designed to evaluate the effects of protein repletion and TNF on plasma albumin and IGF-I and their mRNAs and IGFBP-2 mRNA in the liver of protein-restricted rats. After 2 weeks of feeding a 2% casein diet, rats were assigned to four groups according to either being refed with a 2% or 20% casein diet or receiving saline or TNF by intraperitoneal injection (50 microg/kg x d) for 4 days. Plasma IGF-I and albumin were assayed. Hepatic mRNAs of IGF-I, albumin, and IGFBP-2 were determined. Protein repletion increased plasma concentrations of IGF-I and albumin and their mRNA content in the liver, but decreased IGFBP-2 mRNA. TNF did not alter plasma IGF-I concentration but did increase hepatic IGF-I mRNA in protein-repleted animals, and plasma albumin concentration was significantly decreased with unaltered hepatic albumin mRNA. Thus, protein repletion of malnourished rats increased plasma IGF-I and albumin concentrations in association with increased expression of their mRNAs in the liver. However, plasma albumin but not IGF-I decreased following TNF in protein-restricted rats, whereas TNF increased hepatic IGF-I mRNA in protein-repleted rats. Thus, only plasma albumin concentration responds to both principal determinants, diet and injury, in the development of malnutrition.
Assuntos
Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Fígado/metabolismo , RNA Mensageiro/metabolismo , Albumina Sérica/genética , Albumina Sérica/metabolismo , Animais , Peso Corporal , Proteínas Alimentares/metabolismo , Ingestão de Energia , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Masculino , Distúrbios Nutricionais/metabolismo , Concentração Osmolar , Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismoRESUMO
GH has been shown to stimulate tyrosine phosphorylation of JAK2, several STAT proteins, insulin receptor substrate-1 (IRS-1), and SHC proteins in cultured cells. The goal of this study was to determine GH effects on protein tyrosine phosphorylation in liver and skeletal muscle of normal rats in vivo. Nonfasted male Sprague-Dawley rats (225-250 g) were injected with GH iv, and tissues were obtained after 5, 15, 30, or 60 min. At a maximally effective GH dose (1.5 mg/kg body weight), phosphotyrosine antibody immunoblots demonstrated marked stimulation of the tyrosine phosphorylation of JAK2 (maximal at 5 min) and a 95,000 Mr protein (maximal at 15 min) in both liver and skeletal muscle. The 95,000 Mr protein was recognized and immunodepleted by STAT5 antibody, but not by other STAT protein antibodies. Although basal tyrosine phosphorylation of IRS-1 and SHC was evident, GH did not stimulate tyrosine phosphorylation of either of these proteins in liver or skeletal muscle. In conclusion, GH stimulates the tyrosine phosphorylation of JAK2 and STAT5, but not IRS-1, SHC, or other STAT proteins in liver and skeletal muscle of normal rats. These results differ from findings in cultured cells and support the concept that selectivity for tyrosine kinase substrates is an important determinant of postreceptor signaling specificity in vivo.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas Adaptadoras de Transporte Vesicular , Proteínas de Ligação a DNA/metabolismo , Hormônio do Crescimento/farmacologia , Fígado/metabolismo , Proteínas do Leite , Músculo Esquelético/metabolismo , Fosfoproteínas/metabolismo , Fosfotirosina/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogênicas , Transativadores/metabolismo , Animais , Proteínas de Ligação a DNA/isolamento & purificação , Fator de Crescimento Epidérmico/farmacologia , Humanos , Proteínas Substratos do Receptor de Insulina , Janus Quinase 2 , Cinética , Fígado/efeitos dos fármacos , Masculino , Peso Molecular , Músculo Esquelético/efeitos dos fármacos , Fosfoproteínas/isolamento & purificação , Fosforilação , Proteínas Tirosina Quinases/isolamento & purificação , Proteínas/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Fator de Transcrição STAT5 , Proteínas Adaptadoras da Sinalização Shc , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src , Fatores de Tempo , Transativadores/isolamento & purificaçãoRESUMO
The effects of recombinant interleukin-1 (IL-1), given as a continuous infusion for 6 days, on host responses were determined in rats. The development of fever, change in food intake and body weight, and key components of the acute-phase response in energy and protein metabolism were assessed. The effects of IL-1 were compared with those observed in a matched pair-fed group (semistarved), to distinguish the contribution from anorexia, and in a group that received IL-1 for 4 h acutely. IL-1 significantly increased core temperature, plasma levels of IL-6, and acute-phase protein production and decreased food intake and the circulating zinc level. The catabolic effects of IL-1 on nitrogen loss and muscle protein breakdown were independent of, and additive to those from malnutrition. The changes in energy expenditure, cumulative urinary nitrogen, and hydroxyproline excretion in the chronic IL-1 group were increased over semistarved animals. Finally, changes in muscle protein kinetics were only seen with chronic IL-1 infusion, and the changes in acute-phase protein were greater.
Assuntos
Metabolismo Energético/efeitos dos fármacos , Interleucina-1/farmacologia , Proteínas/metabolismo , Proteínas de Fase Aguda/metabolismo , Animais , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Jejum , Humanos , Hidroxiprolina/urina , Interleucina-6/sangue , Cinética , Masculino , Metilistidinas/urina , Nitrogênio/urina , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes , Valores de ReferênciaRESUMO
This study was conducted to characterize the effects of fish oil and sunflower oil on hepatic glucose production and peripheral glucose utilization during infusion of saline or tumor necrosis factor (TNF), using the euglycemic-hyperinsulinemic clamp technique combined with a primed-constant tracer infusion of high-performance liquid chromatography-purified 3H-3-glucose for estimation of whole-body glucose appearance and utilization rates. Insulin 10 mU/kg.min was infused to reach a plasma insulin level of 200 microU/mL. 14C-1-deoxyglucose (14C-DG) uptake was also measured in specific tissues following intravenous bolus administration. The results showed that during a hyperinsulinemic-euglycemic clamp, infusion of TNF 20 micrograms/kg for 3 hours resulted in a significant reduction of glucose infusion and a significant increase of hepatic glucose production in both dietary groups as compared with saline infusion, indicating a state of insulin resistance induced by TNF. The results also showed that TNF infusion significantly decreased the rate of 14C-DG uptake in muscle in the sunflower oil group but not in the fish oil group, suggesting that fish oil is able to restore to normal the glucose utilization impaired by TNF. These observations suggest that in hyperinsulinemic and euglycemic conditions, prefeeding with fish oil significantly improves glucose uptake in muscle tissue, but does not alter the increase in hepatic glucose production during TNF infusion.
Assuntos
Óleos de Peixe/farmacologia , Glucose/farmacocinética , Músculo Esquelético/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Animais , Glicemia/análise , Cromatografia Líquida de Alta Pressão , Desoxiglucose/metabolismo , Ácidos Graxos/análise , Ácidos Graxos/farmacologia , Glucose/metabolismo , Teste de Tolerância a Glucose , Helianthus , Insulina/sangue , Insulina/farmacologia , Masculino , Músculo Esquelético/química , Óleos de Plantas/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Óleo de Girassol , TrítioRESUMO
Previous studies have demonstrated that the administration of the cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF)(20 micrograms/kg) to rats in a fasting state can produce many and perhaps most of the metabolic alterations found in patients with sepsis and injury. The purposes of the present study were 1) to define the metabolic effects of IL-1 and TNF during a fed state provided by continuous intravenous feeding for 20 h and 2) to characterize the unique effects of IL-1 among the overall response to cytokines by using IL-1 receptor antagonist (IL-1RA; 5 mg/kg). The effects were also explored during the endotoxemic condition induced by infusion of 200 micrograms/kg of endotoxin into rats. The results showed that during feeding IL-1 is responsible for the increase in glucose flux and plasma insulin, the development of insulin resistance, and plasma zinc depression during condition mimicking sepsis and injury, similar to effects observed in the fasting state. The changes in energy expenditure have a more complex mechanism. The results also suggested that certain host responses to cytokines or endotoxin, particularly related to protein metabolism, differed between the fed and fasting states. These data may have a special clinical relevance for the insulin-resistant state that develops during severe infection, since using IL-1RA in conjunction with nutritional therapy may offer additional advantages in the treatment of these severe metabolic disorders.
Assuntos
Endotoxinas/farmacologia , Interleucina-1/farmacologia , Receptores de Interleucina-1/antagonistas & inibidores , Fator de Necrose Tumoral alfa/farmacologia , Animais , Glicemia/metabolismo , Metabolismo Energético/efeitos dos fármacos , Hormônios/sangue , Insulina/sangue , Resistência à Insulina , Masculino , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes , Respiração/efeitos dos fármacos , Zinco/sangueRESUMO
This study was performed to characterize and compare the actions of insulin on hepatic glucose production and peripheral glucose utilization during infusions of endotoxin, tumor necrosis factor (TNF), interleukin-1 (IL-1), and a combination of IL-1 and TNF in the rat. The euglycemic hyperinsulinemic clamp technique was combined with a primed-constant tracer infusion of high-performance liquid chromatography (HPLC)-purified 3H-3-glucose for estimation of whole-body glucose appearance and utilization rates; 14C-deoxyglucose (14C-DG) uptake was also measured in specific tissues following intravenous bolus administration. As expected, acute endotoxemia resulted in a significant reduction of glucose infusion during the clamp procedure (insulin concentration, 100 microU/mL), suggesting decreased insulin action. Similarly, infusion of TNF decreased the rate of glucose infusion necessary to maintain euglycemia. However, differences between endotoxin- and cytokine-treated rats were noted in whole-body glucose appearance (or disappearance) rates. Whereas endotoxin infusion predominantly decreased whole-body glucose uptake, suggesting diminished utilization in skeletal muscles, cytokine infusions were associated with a measurable hepatic glucose output despite hyperinsulinemia. In contrast, both cytokine and endotoxin administration decreased the rate of 14C-DG uptake by muscle tissue. These results demonstrate that TNF, IL-1, and endotoxin can induce a state of insulin resistance when infused continuously; the results also emphasize the complexity of regulation of glucose homeostasis during infection and sepsis.
Assuntos
Endotoxinas/farmacologia , Glucose/metabolismo , Glucose/farmacocinética , Interleucina-1/farmacologia , Músculos/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Animais , Cromatografia Líquida de Alta Pressão , Desoxiglucose/administração & dosagem , Endotoxinas/administração & dosagem , Infusões Intravenosas , Injeções Intravenosas , Insulina/fisiologia , Resistência à Insulina/fisiologia , Interleucina-1/administração & dosagem , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Trítio , Fator de Necrose Tumoral alfa/administração & dosagemRESUMO
Fish oil has been demonstrated to ameliorate many of the responses to infection. This study was conducted to determine whether fish oil feeding could modify the alterations of glucose metabolism induced by interleukin-1 alpha (IL-1 alpha) infusion in the rat. Male Sprague-Dawley rats were pair-fed for 5 weeks on two experimental diets in which the source of fat was either fish oil or soybean oil and provided 20% of calories; the diets were isonitrogenous and isocaloric. After 5 weeks of feeding, rats from both diet regimens were further divided into two subgroups to receive a 3-hour infusion of either 0.1% albumin in saline or 0.1% albumin in saline containing IL-1 alpha. A total of 20 micrograms/kg IL-1 alpha was administered, and half the dose of IL-1 alpha was given as a bolus and the remaining portion (10 micrograms/kg) was continuously infused into the jugular vein. During the last 2 hours of IL-1 alpha infusion, a primed constant infusion of D-(6-3H)glucose and D-(U-14C)glucose was combined to determine the effects of IL-1 alpha and diet on glucose kinetics. Plasma levels of glucose and insulin, energy expenditure, and respiratory quotient were also measured. IL-1 alpha significantly increased concentrations of plasma insulin and the percentage of glucose carbon recycling, confirming previous findings. Concentrations of glucose and insulin with IL-1 alpha treatment were significantly higher in soybean oil- fed animals compared with fish oil-fed animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Óleos de Peixe/farmacologia , Glucose/metabolismo , Interleucina-1/farmacologia , Análise de Variância , Animais , Glicemia/análise , Calorimetria Indireta , Metabolismo Energético/efeitos dos fármacos , Insulina/sangue , Cinética , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
This study examined the short-term effects of three total parenteral nutrition solutions, each containing a different lipid source, on host and tumor protein metabolism in a rat cancer model. Each diet contained 220 kcal/kg per day, including 2 g of nitrogen/kg per day and 50% of nonprotein calories as either a structured lipid of medium-chain triglycerides and fish oil, a physical mix of medium-chain triglycerides and fish oil, or Liposyn II, a long-chain triglyceride. A 3-day intravenous feeding infusion began on day 7 after tumor implantation. Tumor growth rate, nitrogen balance, energy expenditure, and plasma albumin, glucose, and free fatty acids were measured, and whole body protein kinetics and fractional synthetic rates in liver, muscle, and tumor tissues were assessed using a constant infusion of 14C-leucine. The results revealed that tumor growth rate was slowed in structured lipid-fed animals (p = .06, one-way analysis of variance) with significant increases in rates of tumor protein synthesis and tumor protein breakdown (p < .001, one-way analysis of variance). Although muscle fractional synthetic rates were significantly decreased in tumor-bearing animals (p < .05, two-way analysis of variance), the rates in structured lipid-fed animals were restored. Nitrogen balance improved significantly in structured lipid-fed animals. The results demonstrate that the source of lipid in total parenteral nutrition solutions can influence tumor and host protein metabolism, and that a structured lipid composed of medium-chain triglycerides and fish oil seems to improve protein metabolism in host tissue without stimulating tumor growth.
Assuntos
Proteínas de Neoplasias/metabolismo , Nutrição Parenteral Total , Sarcoma de Yoshida/metabolismo , Triglicerídeos/administração & dosagem , Animais , Emulsões , Emulsões Gordurosas Intravenosas/administração & dosagem , Óleos de Peixe/administração & dosagem , Cinética , Masculino , Modelos Biológicos , Transplante de Neoplasias , Fosfolipídeos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Óleo de Cártamo , Sarcoma de Yoshida/patologia , Óleo de Soja , Fatores de TempoRESUMO
To evaluate the accuracy of in vivo estimates of protein synthesis and breakdown, measurements of plasma and tissue leucine kinetics were made in rat tumor tissues at different conditions of growth by use of constant intravenous infusion of [14C]leucine. These measurements were made in Yoshida sarcoma tumors on days 10 and 13 after implantation, with and without tumor necrosis factor (TNF) infusion and on day 10 in Walker-256 carcinosarcoma. Expressed as micromoles of leucine per gram tissue, tumor protein breakdown increased (P less than 0.01) from 0.32 +/- 0.02 to 0.52 +/- 0.09 (SE) mumol/h, with progress of the Yoshida sarcoma tumor between days 10 and 13 after implantation. Similarly, TNF increased tumor proteolysis on day 10 (0.43 +/- 0.03 mumol.h-1.g-1, P less than 0.05 vs. day 10 control) but not on day 13 after implantation of the Yoshida tumor. Estimates of growth derived from the difference between protein synthesis and breakdown rates were not statistically different from those based on actual tumor volume changes in both tumor models. However, estimates of "whole body" protein metabolism (plasma leucine flux) were not affected either by tumor aging or by treatment with TNF. This study shows that in vivo estimates of tissue protein metabolism based on our [14C]leucine constant infusion model closely reflect the growth characteristic of that tissue. A cytotoxic perfusion-independent effect for intravenous TNF on growing tumor tissue is demonstrable as increased protein breakdown. Furthermore, the commonly used concept of whole body protein metabolism, derived solely from tracer dilution in plasma, is an oversimplification.
Assuntos
Peptídeo Hidrolases/metabolismo , Sarcoma Experimental/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Análise de Variância , Animais , Radioisótopos de Carbono , Leucina/metabolismo , Fígado/metabolismo , Masculino , Músculos/metabolismo , Transplante de Neoplasias , Ratos , Ratos Endogâmicos , Sarcoma Experimental/patologia , Fatores de TempoRESUMO
The effects of structured lipid composed of fish oil and medium-chain triglycerides (Fish/MCT) on tumor and the host metabolism was compared with conventional long-chain triglycerides (LCTs) in Yoshida-sarcoma-bearing rats receiving TPN for 3 d. The two parenterally fed groups were divided into two treatments, saline or tumor necrosis factor (TNF), given intravenously at 20 micrograms/kg body wt. Changes in tumor volume, body weight, urinary nitrogen, whole-body and tissue protein kinetics, and fatty acid composition were measured. The study revealed that Fish/MCT feeding inhibited tumor growth, which could be attributed to decreased tumor protein synthesis. Body weight and nitrogen were better maintained by Fish/MCT feeding. In addition, the effects of Fish/MCT on tumor growth were synergistic with TNF treatment. The results demonstrate that dietary fat composition can influence fatty acid compositions of tumor tissue as well as tumor protein kinetics after a short period of TPN feeding.
Assuntos
Gorduras na Dieta/farmacologia , Óleos de Peixe/farmacologia , Sarcoma de Yoshida/metabolismo , Triglicerídeos/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Gorduras na Dieta/administração & dosagem , Ácidos Graxos/análise , Óleos de Peixe/administração & dosagem , Masculino , Nutrição Parenteral Total , Proteínas/metabolismo , Ratos , Ratos Endogâmicos , Sarcoma de Yoshida/química , Triglicerídeos/administração & dosagem , Redução de PesoRESUMO
We have studied the ability of branched chain amino-acid enriched total parenteral nutrition solutions to improve nutritional status without stimulating tumor growth. Protein kinetics, nitrogen balance, tumor kinetics, fractional synthetic rates of individual tissues, and albumin synthesis were compared in male Sprague-Dawley rats (125-145 g) that had either s.c. Yoshida sarcoma (n = 15) or sham implantations (n = 18). Ten days postinjection, rats were randomly assigned to 2 diet groups and given parenteral infusions of 4 days at 170 kcal/kg.body wt.day as dextrose and 2 g N/kg.body wt.day as either 19 or 50% branched chain amino acid-enriched diet. During the last 4 h of feeding, protein kinetic values were studied using a constant infusion of [14C]tyrosine. Plasma tyrosine appearance, synthesis, and breakdown were unchanged by branched chain amino acid infusion. Percentage of tyrosine flux oxidized and tyrosine oxidation decreased (P less than 0.05) and net tyrosine balance improved (P less than 0.05) in rats receiving the branched chain amino acid-enriched diet. Greater nitrogen balance and lower tumor growth rates were also found in branched chain amino acid-infused rats although not statistically significant. Tumor intracellular specific activity was significantly higher in tumor animals receiving crystalline infusions, suggesting greater tumor protein breakdown with branched chain amino acid-enriched infusion. Fractional synthetic rates of liver, muscle, and tumor were unchanged. Hence, branched chain amino acid-enriched total parenteral nutrition increases amino acid utilization for net protein synthesis principally by reducing oxidation without stimulating tumor growth.