Biomedical subjects

C H Lang

Publications and source records attributed to C H Lang.

At least 109 records · Page 6Linked to original sources

PubMed1993

Granulocyte colony-stimulating factor prevents ethanol-induced impairment in host defense in septic rats.

Ethanol is a potent immunosuppressive agent that impairs neutrophil effector function. The purpose of this study was to determine whether granulocyte colony-stimulating factor (G-CSF), a cytokine that increases neutrophil number and functional activity, could prevent the ethanol-induced impairment of antibacterial host defense. Rats were injected with human recombinant G-CSF for 2 days. Eight hr after the last injection of G-CSF, animals were infused with ethanol (or saline) for 1 hr before the subcutaneous injection of live Escherichia coli. The infusion of alcohol was continued after the bacterial challenge and produced blood alcohol levels of 275-300 mg/dl. In control animals, the injection of E. coli resulted in a marked leukopenia. There was an influx of leukocytes into the subcutaneous space where the bacteria were injected, and neutrophil accumulation in tissues adjacent to the focus of infection (i.e., dorsal skin and muscle). Based on myeloperoxidase activity, there was no detectable accumulation of neutrophils in other soft tissues. In acutely intoxicated rats, leukocyte migration to the inflammatory site was impaired, and the number of viable bacteria isolated from the subcutaneous pocket was markedly increased. G-CSF prevented the sepsis-induced leukopenia, increased the influx of neutrophils in to the infection site, reduced the number of bacteria in the subcutaneous lavage fluid, and decreased the incidence of bacteremia in ethanol-treated rats when compared with rats not receiving G-CSF. These results demonstrate that G-CSF is a potent immunomodulator that stimulates neutrophil recruitment selectively to the site of infection and that can be used to ameliorate the ethanol-induced impairment in bacterial host defense.

Alcoholism↗

PubMed1993

Beta-adrenergic blockade attenuates insulin resistance induced by tumor necrosis factor.

The macrophage secretory product tumor necrosis factor (TNF) impairs insulin action on peripheral glucose uptake and hepatic glucose output. Because circulating catecholamines are also elevated by TNF, the present study was performed to determine the role of the adrenergic system in eliciting the insulin resistance. Human recombinant TNF (1 microgram.h-1.kg-1) was infused intravenously into chronically catheterized fasted rats for approximately 18 h. Before TNF, an infusion of either saline, propranolol (nonselective beta-antagonist), atenolol (selective beta 1-antagonist), or phentolamine (alpha-antagonist) was started and continued throughout the experimental protocol. Infusion of either the alpha- or beta-receptor antagonist failed to prevent the TNF-induced increase in basal glucose uptake or hepatic glucose output. Under euglycemic hyperinsulinemic conditions, whole body glucose disposal was lower in TNF-infused rats than in control animals. This resulted from a decreased rate of insulin-stimulated glucose uptake by skeletal muscle, skin, and intestine. In propranolol-infused rats, but not in those receiving atenolol or phentolamine, the TNF-induced decrease in whole body glucose uptake was partially prevented. Propranolol attenuated the development of peripheral insulin resistance by selectively preventing the decrease in glucose uptake by skeletal muscle but not by skin and ileum. Propranolol was also able to ameliorate the hepatic insulin resistance produced by TNF. These results suggest that beta-adrenergic stimulation, probably mediated by a beta 2-adrenergic mechanism, is partially responsible for the development of both peripheral and hepatic insulin resistance in animals infused with TNF.

Adrenergic beta-Antagonists↗

PubMed1993

Impairment of insulin action on peripheral glucose uptake and hepatic glucose production in tumor-bearing rats.

The present study was performed to determine the time-course for the development of peripheral and hepatic insulin resistance in rats as a result of an increasing tumor burden. Animals were inoculated with Yoshida ascites hepatoma, and studies were conducted during the early phase of tumor growth (day 4) at which time there was no change in food intake and at a later time point (day 8) when the tumor burden was increased and rats demonstrated anorexia. In vivo insulin action was accessed under euglycemic hyperinsulinemic conditions, in which insulin was infused at rates sufficient to produce arterial insulin levels that represent high physiological (3.5 ng/ml) or maximally stimulating values (180 ng/ml). On day 4, tumor-bearing (TB) rats were euglycemic, and whole body glucose turnover was elevated 32%. Insulin-mediated glucose uptake (IMGU) in TB rats was similar to control values at the low insulin infusion rate but reduced by 53% under maximally stimulating conditions. The insulin-induced suppression of glucose production was similar in TB and control animals at this time point. In contrast, on day 8, TB rats were hypoglycemic and glucose turnover was reduced 35%. The impairment in IMGU was more severe than seen earlier, with glucose uptake being reduced 39 and 61% at both levels of hyperinsulinemia. At this time point, the ability of insulin to inhibit glucose production was also impaired. These results indicate that the insulin resistance induced by the Yoshida hepatoma was manifested initially by a reduction in IMGU by peripheral tissues. As the tumor burden increased peripheral insulin resistance became more severe and an impairment in hepatic insulin action was observed.

Animals↗

PubMed1993

Effect of subcutaneous Escherichia coli-induced hypermetabolic sepsis on hepatic gluconeogenesis and its hormonal responsiveness in the rat.

In hypermetabolic sepsis, gluconeogenesis is markedly elevated during fasting, and is manifested as an increased rate of glucose appearance (Ra). The likely causes of such a change are alterations in 1) concentration of systemic hormones, 2) concentration of glucose precursors, especially lactate, 3) activity of the key enzymes of the pathway, and 4) hormone receptors and/or transmembrane signalling mechanisms, involved in the hormonal regulation of the pathway. In this study, we investigated the importance of the latter two factors in the increase of gluconeogenesis during hypermetabolic sepsis. Rats were rendered septic by repeated subcutaneous administration of live Escherichia coli. The livers were perfused in vitro in a nonrecirculating mode to measure the rate of gluconeogenesis from saturating concentrations of lactate (5 mM) or lactate (5 mM) + pyruvate (0.5 mM), and the response of gluconeogenesis to vasopressin (VP, 0.1 and 1.0 nM), glucagon (Glc, 0.1 and 1.0 nM), and prostaglandin (PG) F2 alpha (5 microM). The rate of gluconeogenesis without precursor supply was approximately 20-30 mumoles/100 g b w/hr during the first 4-6 min of perfusion, followed by a continuous decline to very low levels. Infusion of lactate (5 mM) or lactate (5 mM) + pyruvate (0.5 mM) increased glucose output, and maintained it at approximately 100-110 and approximately 130-140 mumoles/100 g b w/hr, respectively. VP, Glc, and PGF2 alpha stimulated the rate of gluconeogenesis in a dose-dependent manner (VP and Glc). No differences were observed between control and septic rats using these stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Gram-negative bacterial lipopolysaccharide impairs hyaluronan clearance in vivo and its uptake by the isolated, perfused rat liver.

The purpose of this investigation was to examine the effect of gram-negative bacterial lipopolysaccharide on hyaluronan concentration in blood plasma, hyaluronan removal from the blood and hyaluronan uptake by isolated, perfused rat liver. Intravenous administration of Escherichia coli lipopolysaccharide to rats markedly increased plasma hyaluronan concentration in a dose-dependent manner. One day after lipopolysaccharide challenge (0.1 or 1.0 mg per 100 gm body wt), plasma hyaluronan levels were 570.7 +/- 66.8 ng x ml-1 and 1,951.0 +/- 120.3 ng x ml-1, respectively, as compared with 94.2 +/- 12.2 ng x ml-1 in the time-matched control animals. Removal of intravenously injected hyaluronan (30 micrograms per 100 gm body wt) was suppressed 32% by lipopolysaccharide administration (100 micrograms per 100 gm body wt). At the same dose, lipopolysaccharide induced a severe inhibition (60% to 80%) of hyaluronan uptake by perfused livers isolated 3 or 24 hr after lipopolysaccharide administration. The inhibitory effect of lipopolysaccharide on hyaluronan uptake by the isolated, perfused liver was not abolished by pretreatment with either antibodies to tumor necrosis factor-alpha IgG or indomethacin, an inhibitor of the cyclooxygenase pathway. Continuous intravenous infusion of recombinant murine tumor necrosis factor-alpha for 18 to 20 hr did not affect plasma hyaluronan concentration. These data suggest that neither tumor necrosis factor-alpha, an early cytokine induced by lipopolysaccharide, nor prostaglandins are involved in the mechanism of lipopolysaccharide-induced inhibition of hyaluronan uptake by the perfused rat liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Hyaluronic acid uptake by the isolated, perfused rat liver: an index of hepatic sinusoidal endothelial cell function.

Previous studies indicate that sinusoidal endothelial cells bind and internalize hyaluronic acid at much greater rates than do other liver cells. Thus hepatic hyaluronic acid removal rate may be indicative of sinusoidal endothelial cell function. In these studies the uptake of hyaluronic acid (molecular weight 1.3 x 10(6)) was measured in isolated perfused rat liver under a variety of conditions. Uptake was dependent on hyaluronic acid concentration. At all concentrations tested, the rate of hyaluronic acid uptake stabilized at a steady-state level 2 to 3 min after development of a high rate of apparent uptake. At saturating hyaluronic acid concentration (150 ng.ml-1), the steady-state uptake rate was 10.4 +/- 1.0 micrograms.gm-1 liver wet wt.hr-1, which is as high as or higher than the rates reported for isolated rat liver sinusoidal endothelial cells. The half-maximal rate of uptake was attained at a hyaluronic acid concentration of 80 ng.ml-1. Hyaluronic acid uptake was inhibited by heparin (80%), a competitive ligand for the hyaluronic acid receptor on sinusoidal endothelial cells; 4 beta-phorbol 12 beta-O-myristoyl 13 alpha-acetate (25% to 50%), a tumor promoter and activator of protein kinase C; prostaglandin F2 alpha (24% to 52%), an eicosanoid secreted in the liver by Kupffer cells; A23187 (33% to 66%), a Ca2+ ionophore; and Escherichia coli lipopolysaccharide (16% to 43%). Platelet activating factor did not affect hyaluronic acid uptake by the perfused liver. Hyaluronic acid uptake was increased by 50% after a 24-hr fast.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Regulation of glucose metabolism after endotoxin and during infection is largely independent of endogenous tumor necrosis factor.

Increased hepatic glucose production and glucose utilization involving multiple tissues occur in response to administration of bacterial lipopolysaccharide (LPS) and are metabolic hallmarks of hypermetabolic sepsis. As a proximal mediator in the host response to infection-like challenges, tumor necrosis factor (TNF) may enhance glucose metabolism by directly interacting with cells or by initiating a cascade of events leading to changes in glucose production and utilization. To determine if endogenous TNF is an important mediator in LPS- or sepsis-induced changes in glucose metabolism, rats were pretreated with a neutralizing goat anti-TNF IgG antibody prior to intravenous LPS or subcutaneous live Escherichia coli administration. Whereas high levels of plasma TNF were observed in rats not pretreated with anti-TNF, TNF was not detected 90 min after LPS in rats receiving the antibody. Pretreatment with anti-TNF attenuated the increase in plasma lactate and glucagon levels in LPS-challenged rats but failed to ameliorate the LPS-induced hyperglycemia and increase in glucose rate of appearance (Ra). The LPS-stimulated increase of in vivo glucose metabolic rate (Rg) of examined tissues, measured with [14C]-2-deoxyglucose, was not altered by anti-TNF. Likewise, rats treated with anti-TNF prior to induction of hypermetabolic infection exhibited usual increases in whole-body glucose Ra and metabolic clearance rate. Although neutralizing TNF failed to prevent the sepsis-induced augmentation of Rg in any tissue examined, it reduced the increase in the lung (P < 0.05) and tended to decrease it in other barrier tissues as well as in the spleen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Adrenergic blockade attenuates endotoxin-induced hepatic glucose uptake.

The purpose of the present study was to elucidate the role of catecholamines in mediating the endotoxin-induced increase in glucose uptake of individual tissues. In vivo glucose utilization by selected tissues, assessed by the 2-deoxyglucose (2dGlc) tracer technique, was determined 3 hr following the i.v. injection of Escherichia coli lipopolysaccharide (LPS; 100 micrograms/100 g bw) or saline. Catecholamine action was inhibited by the combined administration of alpha and beta receptor antagonists, phentolamine and propranolol. Adrenergic antagonists alone did not change plasma glucose levels or the glucose metabolic rate (Rg) of the investigated tissues; however, adrenergic blockage resulted in mild hypoglycemia in endotoxemic animals. LPS administration increased in vivo Rg by the liver (571%), lung (229%), spleen (210%), intestine (76%), skin (82%), fat (181%), gastrocnemius muscle (70%), and kidney (61%). There was a significant elevation in the glucose metabolic clearance rate (MCR) by these tissues as well. LPS did not increase Rg by brain and testis. Adrenergic blockade completely prevented the LPS-induced Rg increase in the liver and partially inhibited the elevation in other tissues. The LPS-induced increase in the MCR in spleen, lung, intestine, skin, fat, muscle, and kidney was not altered by adrenergic blockade, indicating that the attenuated Rg in these tissues was the consequence of the decreased plasma glucose concentration observed under this condition. However, in the liver, adrenergic antagonists markedly inhibited the LPS-induced increase in both Rg and MCR. Thus our data indicate that the glucose metabolic response to LPS is partially mediated by catecholamines through the accompanying changes in plasma glucose concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Effects of acute alcohol intoxication on gluconeogenesis and its hormonal responsiveness in isolated, perfused rat liver.

Rats were acutely administered ethanol as a primed constant infusion in order to produce sustained blood ethanol levels of 8-12 or 55-65 mM. At the end of ethanol infusion the livers were either freeze-clamped in vivo or isolated and perfused for metabolic studies. The rate of gluconeogenesis and its responsiveness to phenylephrine (10 microM), prostaglandin F2 alpha (5 microM) and glucagon (10 nM), as well as the redox state of the cytosolic NAD(+)-NADH system were assessed in livers isolated from acutely ethanol-treated rats, and subsequently perfused without ethanol. For liver clamped in vivo, high- but not low-ethanol treatment decreased the ATP content by 31% and slightly increased ADP and AMP content, resulting in a decreased energy charge (11%). Glutamate and aspartate content was also increased in high-dose ethanol-infused rats with no changes in malate and 2-oxoglutarate content. Gluconeogenesis with saturating concentrations of lactate (4 mM)+pyruvate (0.4 mM) was delayed in reaching a plateau in the livers of high-dose ethanol-treated rats and its response to all three stimulators was impaired. Low-dose ethanol treatment only decreased the liver response to phenylephrine. While the perfused livers of low-dose ethanol-treated rats displayed no changes in adenine nucleotide content, the livers of high-dose ethanol-treated rats had a decreased ATP (35%) and an increased AMP (77%) content, paralleled by a fall in the total adenine nucleotides (14%) and energy charge (14%). No differences were observed between the saline- and ethanol-treated rats with respect to malate-aspartate shuttle intermediate concentration in perfused livers. Also, the livers of high-, but not low-dose ethanol-treated rats had a more negative value of NAD(+)-NADH redox state as compared to the livers of control rats. The data suggest that acute ethanol intoxication produces changes in liver metabolism and its responsiveness to hormones/agonists that are demonstrable for at least 2 hr after isolation and perfusion of the liver.

Adenine Nucleotides↗

PubMed1992

Kupffer cells play a major role in insulin-mediated hepatic glucose uptake in vivo.

The effect of insulin on the in vivo glucose utilization by different hepatic cells was investigated using the euglycemic, hyperinsulinemic clamp, combined with the 2-deoxyglucose tracer technique. Rats were infused with insulin at a rate of 2.8 or 9.0 mU/min/kg for 220 min, resulting in plasma concentrations of the hormone of about 80 microU/ml and 340 microU/ml, respectively. Glucose use by the whole liver was elevated by more than 200% following insulin. However, glucose uptake by the parenchymal cells was only elevated by 50-60%. By contrast nonparenchymal cells were more responsive to insulin. Glucose uptake by endothelial cells was increased 100% and Kupffer cells displayed the most marked response to insulin showing a 3- to 6-fold increase in glucose uptake. These data indicate that the sinusoidal nonparenchymal cells are the major sites of the insulin-mediated increased glucose utilization by the liver.

Analysis of Variance↗

PubMed1992

Differential regulation of glucose transporter gene expression in adipose tissue or septic rats.

To understand the molecular mechanisms responsible for the sepsis-induced enhanced glucose uptake, we have examined the levels of GLUT4 and GLUT1 mRNA and protein in the adipose tissue of septic animals. Rats were challenged with a nonlethal septic insult where euglycemia was maintained and hexose uptake in adipose tissue was markedly elevated. Northern blot analysis of total RNA isolated from epididymal fat pads indicated differential regulation of the mRNA content for the two transporters: GLUT1 mRNA was increased 2.6 to 4.6-fold, while GLUT4 mRNA was decreased by 2.5 to 2.9-fold. Despite the difference in mRNA levels, both GLUT1 and GLUT4 protein were down regulated in plasma membranes (40% and 25%, respectively) and microsomal membranes (42% and 25%, respectively) of the septic animals. The increased glucose uptake cannot be explained by the membrane content of GLUT1 and GLUT4 protein. Thus, during hypermetabolic sepsis, increased glucose utilization by adipose tissue is dependent on alternative processes.

Adipose Tissue↗

PubMed1992

In vivo metabolic response of hepatic nonparenchymal cells and leukocytes to granulocyte-macrophage colony-stimulating factor.

This study investigates the in vivo glucose utilization of various immune-competent cells after an intra-arterial injection of a nonlethal dose (30 micrograms/kg body weight) of murine recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF). Injection of GM-CSF resulted in a rapid but transient reduction in the number of circulating neutrophils. After 20 min the number of neutrophils returned to normal values, and by 4 h it was about 80% greater than in time-matched saline-injected controls. One hour after the treatment, neutrophils were accumulated in the livers of GM-CSF-injected animals but not in control livers. In vivo glucose utilization by circulating neutrophils and mononuclear cells and various liver cell types was investigated by combining the 2-deoxyglucose tracer technique with cell isolation procedures. GM-CSF increased the in vivo glucose utilization of circulating and infiltrating neutrophils by more than 200%. Glucose utilization by circulating mononuclear cells was also doubled. After GM-CSF injection, glucose utilization by Kupffer cells was increased by 130% and by hepatic endothelial cells was increased by 60%. Indomethacin pretreatment blunted the hyperglycemia caused by GM-CSF injection; however, it did not inhibit the increased glucose utilization by immune-competent cells. This suggests that the effect of GM-CSF on glucose utilization by these cells is not mediated by prostanoids and is at least partially independent of the mass action of elevated glucose concentration. These findings indicate that GM-CSF may be an important member of the cytokine cascade that mediates the acute in vivo metabolic response of immune-competent cells in sepsis or endotoxemia.

Animals↗

PubMed1992

Effect of granulocyte colony-stimulating factor on sepsis-induced changes in neutrophil accumulation and organ glucose uptake.

Neutropenia was seen in rats made septic by subcutaneous (sc) injection of Escherichia coli. The sepsis-induced increase in glucose uptake by tissues distant from the site of infection was not associated with increased myeloperoxidase (MPO) activity. Only the skin and muscle at the site of infection demonstrated an increase in both glucose uptake and MPO activity. Granulocyte colony-stimulating factor (G-CSF) attenuated the sepsis-induced decrease in circulating neutrophils. Both glucose uptake and MPO activity of skin and muscle adjacent to the infection site showed a smaller increase in G-CSF treated rats. In contrast, septic rats injected with G-CSF exhibited a greater number of leukocytes and a larger reduction in the number of bacteria in the sc lavage fluid. These results demonstrate that G-CSF is a potent immunomodulator that stimulates neutrophil function and also increases their recruitment to the site of infection, resulting in improved bacterial killing and host defense.

Animals↗

PubMed1992

Acute ethanol intoxication prevents lipopolysaccharide-induced down regulation of protein kinase C in rat Kupffer cells.

Protein kinase (PK) C has been implicated in a number of cellular events, many of which are also known to be affected by ethanol (ETOH). ETOH intoxication is also known to impair immune function, thereby increasing the host's susceptibility to infection. The purpose of this study was to assess the effect of acute ETOH intoxication on PKC activity and its intracellular distribution in nonparenchymal liver cells following an E. coli lipopolysaccharide (LPS) challenge. The liver was chosen for the study because it is the primary site both for metabolism of ETOH and detoxification of gut derived bacterial products. Catheterized conscious rats were administered saline or ETOH (175 mg/100 g body weight as a bolus followed by a continuous, 7 hr infusion of 28 mg/100 body weight/hr). LPS was injected intravenously (100 micrograms/100 g body weight) 3 hr before the end of the saline or ETOH infusion. Kupffer and endothelial cells were isolated by collagenase-pronase digestion followed by centrifugal elutriation. PKC was assayed after extraction with digitonin containing buffer and partial purification on DE-52 cellulose minicolumns. LPS decreased PKC activity by 69% from control values. Although ETOH infusion alone did not affect PKC activity in Kupffer cells, it completely abrogated the LPS effect. A similar trend was observed for the endothelial cells. No significant differences were observed between groups with respect to the intracellular distribution of PKC. The down-regulation of PKC by LPS may represent a mechanism of functional adaptation of the immunocompetent cells to one of the cytokines, i.e., TNF, whose receptors are down regulated by activation of PKC.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholic Intoxication↗

PubMed1992

Modulation of f-met-leu-phe induced chemotactic activity and superoxide production by neutrophils during chronic ethanol intoxication.

Chronic alcohol consumption has been associated with increased migration of neutrophils into liver that could contribute to the development of alcoholic liver disease. Mild endotoxemia may be at least partially responsible for this condition since endotoxemia was shown to be present in virtually all chronic alcoholics. This study examines the release of superoxide anion and chemotactic activity by Kupffer cells and sequestered hepatic as well as blood neutrophils during chronic alcohol intoxication (16 weeks) alone, and following an intravenous injection of Escherichia coli lipopolysaccharide (LPS) (1 mg/kg) 3 hr before cell isolation. Chronic ethanol consumption increased the total neutrophil yield per liver, but did not change the f-met-leu-phe induced chemotactic activity by both hepatic and blood neutrophils. However, the combined insults of ethanol and LPS increased the chemotactic activity and superoxide anion generation by these cells. Plasma from ethanol-fed rats was highly chemotactic to syngeneic normal rat neutrophils. This activity was increased 1.75-fold in the plasma obtained from chronic ethanol plus endotoxin-injected rats. The chemotactic activity of Kupffer cells was not significantly modulated during ethanol intoxication plus endotoxin treatment. The f-met-leu-phe-induced superoxide anion release by Kupffer cells was enhanced after LPS treatment. Chronic ethanol consumption did not induce any effect on this parameter. These observations suggest that functional alterations in neutrophils during chronic ethanol intoxication may contribute to hepatic injury.

Alcoholic Intoxication↗

PubMed1992

Effect of acute alcohol administration on TNF-alpha binding to neutrophils and isolated liver plasma membranes.

The mechanisms underlying the effects of alcohol (ethanol, ETOH) on host defense are poorly understood. ETOH modulation of the cytokine regulatory network is one possible way by which ETOH could alter nonspecific immune function. In this study we examined the ability of acute alcohol intoxication to alter lipopolysaccharide (LPS)-induced changes in tumor necrosis factor (TNF)-alpha binding to neutrophils and isolated liver plasma membranes. Rats were injected intravenously with a primed constant infusion of ETOH for 7 hr to maintain blood ETOH concentration at approximately 35 mM. Four hours after the start of ETOH infusion, the animals received intravenously either sterile saline or LPS (100 micrograms/100 g body weight) and were sacrificed at the end of ETOH infusion. Blood neutrophils and liver plasma membranes were isolated, and TNF-alpha binding characteristics determined using recombinant human [125I]TNF-alpha. ETOH treatment alone induced a significant decrease (51%) of neutrophil Bmax for TNF-alpha, without affecting the cytokine binding to plasma membranes. LPS, with or without ETOH, significantly decreased (61%) neutrophil Bmax for TNF-alpha and increased (115%) its binding to liver plasma membranes. The KD values of binding to either neutrophils or liver plasma membranes were not altered by ETOH or LPS treatment of animals. By decreasing the cytokine binding to neutrophils, ETOH may impair the control exerted by TNF-alpha on cell function, thus damaging host defense.

Alcoholic Intoxication↗

PubMed1992

Sepsis-induced insulin resistance in rats is mediated by a beta-adrenergic mechanism.

Bacterial infection decreases insulin-mediated glucose uptake (IMGU) by skeletal muscle and produces whole body insulin resistance. Because circulating catecholamines are elevated by the septic insult, the present study was performed to determine the potential role of the beta-adrenergic system in eliciting these changes. Before induction of sepsis, an infusion containing saline, propranolol, or atenolol was started and continued throughout the experimental protocol. Sepsis increased the basal rate of glucose production and utilization and impaired IMGU by peripheral tissues. The peripheral insulin resistance in septic rats was manifested by an increase in the dose producing 50% of maximal response and a decrease in the maximal responsiveness. Infusion of propranolol, a nonselective beta-adrenergic antagonist, attenuated the sepsis-induced increase in basal glucose turnover by 70% and completely prevented the decrease in IMGU by the whole body. In contrast, atenolol, a selective beta 1-antagonist, did not alter the glucose metabolic response to infection. Under basal conditions, propranolol prevented or attenuated the increase in glucose uptake by the gastrocnemius, diaphragm, skin, liver, lung, spleen, and ileum normally observed in septic rats. In addition, propranolol prevented the decrease in IMGU by various muscles and skin in septic animals. These results suggest that adrenergic stimulation, probably mediated by a beta 2-adrenergic mechanism, is partially responsible for the sepsis-induced increases in basal whole body glucose turnover and plays a prominent role in the development of peripheral insulin resistance in this condition.

Animals↗

PubMed1992

Attenuation of glucose metabolic changes resulting from TNF-alpha administration by adrenergic blockade.

Administration of tumor necrosis factor (TNF-alpha) increases whole body glucose kinetics and stimulates in vivo glucose uptake by several tissues. Because circulating catecholamines are also increased after TNF-alpha administration, the present study was conducted to examine the potential role of the adrenergic system in eliciting these changes. Rats given 150 micrograms TNF-alpha/kg by intravenous infusion over a 30-min period exhibited an increased rate of glucose appearance (glucose Ra). Combined alpha- and beta-adrenergic blockade (phentolamine and propranolol infusion) prevented the TNF-alpha-induced increase in glucose Ra without influencing plasma glucagon or corticosterone levels. TNF-alpha infusion also increased in vivo glucose utilization (Rg), measured with 2-deoxy-[14C]glucose, in spleen (86%), liver (80%), skin (47%), ileum (71%), lung (53%), and heart (112%). Adrenergic blockade prevented the tissue Rg increase in the spleen, liver, and skin; partially reduced it in the ileum; but did not abrogate it in the lung or heart. The effect of blockade was primarily due to inhibition of the TNF-alpha-induced increase in hepatic glucose output. Whereas the adrenergic system plays a major role on the effect of TNF-alpha on whole body glucose production, its importance in directly mediating TNF-alpha's effect on tissue glucose uptake is minimal.

Animals↗