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C H Lang

Publications and source records attributed to C H Lang.

At least 145 records · Page 8Linked to original sources
PubMed1991

Gram-negative infection increases noninsulin-mediated glucose disposal.

Peripheral glucose uptake can occur by either insulin- or noninsulin-mediated mechanisms, and the two pathways appear to be regulated independently. Using the euglycemic hyperinsulinemic clamp technique, we have previously demonstrated that sepsis induces whole body insulin resistance. The purpose of the present study was to determine whether infection also alters noninsulin-mediated glucose uptake (NIMGU) and, if so, which tissues are affected. Studies were performed in chronically catheterized conscious rats under either basal (6 mM glucose, 30 microU/ml insulin) or insulinopenic conditions to determine NIMGU. Hypermetabolic sepsis was induced by sc injections of live Escherichia coli, and 24 h later a tracer amount of [U-14C]deoxy-2-glucose was injected for the determination of the in vivo glucose metabolic rate (Rg) in selected tissues. Our results indicate that NIMGU is the predominant route of glucose disposal in both septic and nonseptic rats, accounting for 79-83% of the total rate of glucose disposal. Because the rate of whole body glucose disposal was increased by sepsis, the absolute rate of NIMGU was 46% higher in septic rats than in nonseptic animals. This increase was the result of the elevated Rg in liver, spleen, ileum, and lung. Sepsis also increased whole body insulin-mediated glucose uptake by 88% under basal conditions, and this was due to an enhanced glucose uptake by muscle and skin. In insulinopenic animals in which the plasma glucose concentration was elevated to 17 mM, whole body glucose disposal increased by 107% in nonseptic animals, but by only 32% in septic rats. The hyperglycemic-induced increment in organ Rg was smaller in all tissues examined from septic animals. However, the absolute rate of whole body and tissue glucose utilization was not different between the two groups. These results indicate that gram-negative infection increases whole body NIMGU, which results from an enhanced rate of glucose utilization by tissues rich in mononuclear phagocytes, including the liver, spleen, ileum, and lung, but not by muscle.

Animals↗
PubMed1990

The effect of ethanol infusion on the altered glucose turnover during bacterial infection.

The increased glucose turnover seen during the hypermetabolic, hyperdynamic phase of sepsis is part of the body's defense mechanisms. In contrast, the metabolism of ethanol (ETOH) is known to compromise hepatic gluconeogenesis under certain conditions. This study tested the hypothesis that acute infusion of ETOH inhibits the elevated glucose production that is manifested during infection and thereby alters the normal responses to sepsis. In catheterized conscious rats, ETOH or saline infusion was started 24 hours before the induction of sepsis, and continued throughout the experiment. In vivo glucose kinetics were assessed by the infusion of [6-3H, U-14C]-glucose 24 hours after the induction of sepsis. The characteristic sepsis-induced hyperthermia was prevented in ETOH-infused animals. Sepsis increased the plasma lactate concentration (100%), as well as the rates of glucose appearance ([Ra] 77%), recycling (213%), and metabolic clearance ([MCR] 82%) in saline-infused control animals. In contrast, ETOH infusion prevented the sepsis-induced increase in glucose Ra and markedly attenuated the increase in plasma lactate (49%) and glucose recycling (97%). The infusion of ETOH increased the lactate/pyruvate and beta-hydroxybutyrate (BHBA)/acetoacetate (AcAc) ratio in both septic and nonseptic rats. These results indicate that ETOH administration attenuates the increased glucose production, utilization, and elevated arterial lactate, and prevents the hyperthermic response seen during the hypermetabolic phase of sepsis. Thus, ethanol intoxication alters the normal metabolic responses to sepsis, thereby contributing to the compromised host defenses against the challenging bacteria.

3-Hydroxybutyric Acid↗
PubMed1990

Role of insulin in the blunted glucose metabolic response of septic rats to epinephrine.

Epinephrine produces smaller incremental increases in plasma glucose concentration and rate of glucose appearance (Ra) in septic rats compared with nonseptic animals. In the present study, we investigated the role of insulin in the diminished response of septic rats to epinephrine-induced increases in glucose turnover. Glucose kinetics were assessed by the infusion of [6-3H]-glucose in conscious catheterized rats made septic by subcutaneous injections of live Escherichia coli. Epinephrine was infused at 1 micrograms/min/kg for 2 hours in the presence and absence of somatostatin and mannoheptulose (SRIF + MH). In comparison to nonseptic control animals, epinephrine-induced increases in plasma glucose concentration and glucose Ra were blunted by more than 50% in the septic rats. Infusion of SRIF + MH with epinephrine restored the blunted response to normal. During the infusion of epinephrine alone, the plasma insulin concentration in the septic rats was 2.8-fold higher than the nonseptic controls. SRIF + MH lowered the plasma insulin concentrations in both the nonseptic and septic rats to less than 10 microU/mL. SRIF + MH reversed the sepsis-induced hyperglucagonemia, but did not prevent a slight increase in glucagon levels during the epinephrine infusion in the nonseptic rats. In a second study, septic rats infused with SRIF + MH and replacement insulin showed a smaller increase in glucose concentration and glucose production in response to epinephrine than did septic animals administered SRIF + MH and no insulin. These results indicate that insulin plays an important role in the diminished response of septic rats to epinephrine.

Animals↗
PubMed1990

Insulin-mediated glucose uptake by individual tissues during sepsis.

Gram-negative hypermetabolic sepsis has been previously reported to produce whole body insulin resistance. The present study was performed to determine in vivo which tissues are responsible for the sepsis-induced decrease in insulin-mediated glucose uptake (IMGU), and whether that decrease was related to a change in regional blood flow. Vascular catheters were placed in rats and sepsis was induced by subcutaneous injections of Escherichia coli. Insulin action was assessed 20 hours after the first injection of bacteria by the combined use of the euglycemic hyperinsulinemic clamp and the tracer 2-deoxyglucose (dGlc) technique. Insulin was infused at various rates in separate groups of septic and nonseptic rats for 3 hours to produce steady-state insulin levels between 70 and 20,000 microU/mL. Rats were injected with [U-14C]-dGlc 140 minutes after the start of the euglycemic hyperinsulinemic clamp for the determination of the glucose metabolic rate (Rg) in selected tissues. The maximal response to insulin was decreased 30% to 40% in the gastrocnemius, and in the red and white quadriceps. The former two muscles also showed a decrease in insulin sensitivity. However, the insulin resistance seen in hindlimb muscles was not evident in all muscles of the body, since IMGU by abdominal muscle, diaphragm, and heart was not impaired by sepsis. The basal Rg by skin, spleen, ileum, and lung was increased by sepsis, and was higher than the insulin-stimulated increases in Rg by these tissues in nonseptic animals. Cardiac output was similar in septic and nonseptic rats and did not change during the infusion of insulin. Under basal conditions, sepsis appeared to redistribute blood flow away from the red quadriceps and skin, and increased flow to the liver (arterial), lung, and small intestine. When plasma insulin levels were elevated, hepatic arterial blood flow was increased, and flow to the red quadriceps and skin was decreased in nonseptic animals. Hyperinsulinemia did not produce any consistent change in regional blood flow in septic animals. The results of this study indicate that a decrease rate of IMGU in muscle is primarily responsible for the whole body insulin resistance seen during hypermetabolic sepsis, and that the impairment of insulin action in skeletal muscle is not dependent on fiber type or to changes in blood flow.

Animals↗
PubMed1990

Ethanol attenuates endotoxin-enhanced glucose utilization.

Ethanol (EtOH) is known to alter various aspects of cellular metabolism. Among these, the blunting of the increased rate of glucose production and utilization by the host after the administration of endotoxin may be an important factor in the increased susceptibility to infections. Therefore the present study was conducted to determine which tissues are responsible for the attenuation of the endotoxin-induced increase in whole body glucose utilization after acute EtOH administration. In vivo glucose metabolic rate (Rg) of different organs was investigated in conscious rats by the tracer 2-deoxy-D-glucose technique. Rats received a slow intravenous bolus injection of EtOH (275 mg/100 g body wt of a 20% wt/vol solution) followed by a continuous infusion (25 mg/100 g body wt) that was maintained throughout the experimental period. Thirty minutes after initiation of the EtOH treatment, Escherichia coli endotoxin (100 micrograms/100 g body wt) was administered intravenously. Time-matched control animals received an equal volume of saline. EtOH alone affected Rg only in gastrocnemius muscle (30% decrease) and adipose tissue (twofold increase). Endotoxin alone increased Rg in all tissues examined except in heart and brain. Prior administration of EtOH inhibited the endotoxin-induced increased Rg in skeletal muscle (regardless of fiber type), ileum, liver, adipose tissue, and kidney, blunted the increase in spleen and lung, and did not alter the increased Rg in skin. Brain showed a 20% decrease in Rg in response to EtOH and endotoxin administration. The EtOH-attenuated increase in glucose utilization in the macrophage-rich tissues of endotoxin-treated rats may be a reflection of an impaired capacity of these tissues to respond to infection.

Animals↗
PubMed1989

Interleukin-1 induced increases in glucose utilization are insulin mediated.

Interleukin-1 (IL-1) is known to modulate a variety of the acute-phase responses to infection. Since an enhanced rate of whole-body glucose utilization is a consistent feature of the hypermetabolic phase of infection, the purpose of the present study was to determine whether IL-1 could increase glucose uptake and whether that increase was dependent on the concomitant elevation in plasma insulin. Glucose utilization (Rg) of different tissues was investigated in vivo by the 2-deoxyglucose tracer technique. Human purified IL-1 was administered to chronically, catheterized conscious rats and increased the plasma insulin levels and the Rg in macrophage-rich tissues, including the lung, spleen, liver and skin. IL-1 also increased Rg in skeletal muscle and diaphragm. To eliminate the insulin-stimulated increase in Rg, somatostatin (SRIF) was infused 1 h prior to IL-1. SRIF prevented the IL-1 induced increase in insulin and tissue glucose utilization. IL-1 administration to streptozotocin-induced diabetic rats also failed to increase Rg in any tissue examined. These data suggest that the administration of IL-1 increases organ glucose utilization by insulin-dependent mechanisms.

Animals↗
PubMed1989

Epinephrine-induced increase in glucose turnover is diminished during sepsis.

The responsiveness of septic rats to epinephrine-induced alterations in carbohydrate metabolism was studied. Nonlethal sepsis was produced by subcutaneous injections of live Escherichia coli over 18 hours in conscious catheterized rats. Glucose kinetics were assessed by IV infusion of [6-3H]-glucose. After two hours of tracer infusion, blood samples were taken for basal values. Thereafter, epinephrine was infused at 0, 0.05, 0.2, or 1.0 microgram/min/kg for an additional four hours. Compared with nonseptic rats, septic animals had increased basal values for glucose rate of appearance (Ra, 63%), glucose clearance (86%), and plasma lactate concentration (133%). Infusion of epinephrine resulted in dose-dependent increases in glucose Ra, as well as plasma glucose and lactate concentrations, and decreases in glucose clearance and muscle glycogen content. At each dose of epinephrine, the increases in response from basal of plasma glucose and glucose Ra in septic rats were 50% or less of that observed in nonseptic animals. There were no differences between septic and nonseptic rats in plasma lactate and glucose clearance responses from basal or in circulating levels of catecholamines achieved during the epinephrine infusion. The present results indicate that septic rats are less responsive than control animals to epinephrine-induced increases in glucose turnover.

Animals↗
PubMed1989

Acute alcohol infusion suppresses endotoxin-induced serum tumor necrosis factor.

Tumor necrosis factor (TNF) is suggested to play an important role in host defense as well as in eliciting some of the metabolic alterations in endotoxemia. Bacteria and their products are involved in triggering the production and release of TNF. Alcohol consumption is known to suppress the immune system and increase susceptibility to infections. The present study was undertaken to investigate the effect of acute ethanol administration on the ability of endotoxin to increase circulating TNF levels and to determine the relationship between blood ethanol levels and endotoxin-induced serum TNF. A 50% decrease in serum TNF levels was seen 1-1.5 h after endotoxin challenge in conscious rats with blood alcohol levels between 75-175 mg/dl. A dose-related depression of serum TNF was observed with increasing blood alcohol levels. This was accompanied by a markedly diminished hyperlactacidemia seen following endotoxin administration. These data suggest that impaired TNF release may have a role in the altered immune response of alcoholics to infection.

Animals↗
PubMed1989

Ethanol administration diminishes the endotoxin-induced increase in glucose metabolism.

The metabolism of ethanol (ETOH) is known to increase the cytosolic NADH/NAD ratio and consequently impairs hepatic glucose output in the fasted state. In contrast, one of the characteristic alterations in glucose metabolism produced by the administration of endotoxin is an increase in the de novo synthesis of glucose. Therefore, the present study tests the hypothesis that the acute administration of ETOH will prevent the endotoxin-induced increase in glucose production. In vivo glucose kinetics were determined by the infusion of [6-3H, U-14C]glucose in catheterized conscious rats. The intravenous infusion of tracer glucose, and ETOH (100 mg/100 g b.w./hr) or saline were started at the same time and both continued throughout the experiment. Two hours later the ETOH infusion rate was decreased to maintain the blood ETOH levels between 100 and 160 mg/dl. At 140 min, endotoxin (100 micrograms/100 g b.w.) was injected. ETOH alone did not alter basal values of plasma glucose (5 mM), glucose rate of appearance (Ra; 35 mumols/min/kg) or metabolic clearance (MCR; 7 ml/min/kg). Endotoxin alone increased plasma glucose (80%) and lactate (140%) concentrations, glucose Ra (60%) and recycling (40%) in saline-infused rats, whereas in ETOH-infused animals, plasma glucose and lactate levels were only elevated 40% and glucose Ra and recycling were unchanged. The results show that acute ETOH administration diminishes the increased glucose production and utilization seen in endotoxemia. The attenuation of the endotoxin effect by ethanol is due to inhibition of hepatic glucose production and peripheral glucose utilization.

Animals↗
PubMed1989

Sepsis-induced changes in in vivo insulin action in diabetic rats.

The present study examined whether sepsis exacerbates the diabetes-induced peripheral and hepatic insulin resistance. Vascular catheters were placed in diabetic (70 mg/kg streptozotocin, 4-wk duration) and nondiabetic rats, and sepsis was produced by subcutaneous injections of live Escherichia coli. Basal glucose metabolism was determined with the use of [3-3H]glucose initiated 18 h after the first injection of bacteria. Thereafter, in vivo insulin action was assessed with the use of the euglycemic hyperinsulinemic clamp technique. Sepsis in nondiabetic rats produced a 57% reduction in the maximal responsiveness for the insulin-induced increase in total glucose utilization compared with nondiabetic nonseptic animals. Diabetes alone decreased both insulin sensitivity and responsiveness. When the septic insult was superimposed on the diabetic condition, the maximum responsiveness was unchanged compared with non-septic diabetic rats, but the 50% maximally efficient dose was reduced from 817 to 190 microU/ml, suggesting an improvement in insulin sensitivity. Sepsis did not alter the insulin-induced suppression of hepatic glucose output in either nondiabetic or diabetic animals. Sepsis increased the plasma concentrations of epinephrine, norepinephrine, glucagon, and corticosterone in both nondiabetic and diabetic rats; however, the elevation in catecholamines and glucagon was 65 to 250% greater in the diabetic animals. These results indicate that hypermetabolic sepsis produces peripheral insulin resistance in nondiabetic rats but does not worsen the preexisting insulin resistance in diabetic animals, despite the higher prevailing blood levels of glucagon and catecholamines.

Animals↗
PubMed1989

Tissue glucose utilization during epinephrine-induced hyperglycemia.

The aim of this study was to investigate glucose utilization by individual tissues during epinephrine infusion. First, the applicability of the 2-deoxyglucose (2-DG) tracer technique during in vivo hyperglycemia was investigated in model systems in vitro. Epitrochlearis muscle and spleen cells were incubated with 1.25-20 mM glucose. The discrimination against 2-[14C]DG in glucose metabolic pathways, expressed by the lumped constant, remained unchanged over this wide range of glucose concentrations. It was concluded that in vivo hyperglycemia does not preclude the application of the 2-DG method. In a series of in vivo experiments, chronically catheterized conscious rats fasted for 24 h and were infused with epinephrine (0.2 microgram.kg-1.min-1), which produced a two-fold increase in plasma glucose concentration. 2-[14C]DG was injected 30 min after starting the epinephrine infusion and glucose utilization rates of individual tissues were calculated based on the concentration of phosphorylated 2-DG in samples excised at 70 min. The epinephrine infusion increased glucose utilization rates by 40-160% in hindlimb muscles, skin, ileum, liver, spleen, lung, epididymal fat, and kidney, although no change was found in the brain. Mass action of the increased plasma glucose is likely to play an important role in the enhanced rate of glucose utilization.

Animals↗
PubMed1989

Importance of hyperglucagonemia in eliciting the sepsis-induced increase in glucose production.

The plasma concentration of various catabolic hormones, including glucagon and catecholamines, is elevated in sepsis. Furthermore, the infusion of these hormones into control animals increases the rate of glucose production. Previous studies by our laboratory have demonstrated that adrenergic blockade alone is not able to reverse or prevent the sepsis-induced increase in glucose metabolism. Therefore, the purpose of the present study was to determine whether the sepsis-induced hyperglucagonemia was important to maintain the elevation in glucose metabolism. Hypermetabolic sepsis was produced in chronically catheterized conscious rats by repeated subcutaneous injections of Escherichia coli. Glucose kinetics, assessed by the constant i.v. infusion of [6-3H]- and [U-14C]-glucose, were determined in septic and nonseptic rats prior to and for 3-4 hr after the infusion of somatostatin with or without insulin replacement. Sepsis increased the rate of glucose appearance (80%), recycling (276%), and metabolic clearance (88%), as well as the plasma lactate concentration (140%), compared to nonseptic rats. Lowering both the insulin and glucagon concentration with somatostatin did not attenuate the sepsis-induced increases in glucose metabolism. However, when the hyperglucagonemia was selectively reduced by replacing insulin, and euglycemia was maintained by a glucose infusion, the elevated rate of endogenous glucose production returned to levels not different from nonseptic animals. In contrast, the sepsis-induced elevation of glucose clearance was unaltered under these conditions. These results indicate that during hypermetabolic sepsis the elevated glucagon level is an important mediator of the enhanced rate of gluconeogenesis.

Animals↗
PubMed1989

Altered control of carbohydrate metabolism in endotoxemia.

Based on our data, we envisage the following sequence of events to occur after the administration of a moderately severe dose of endotoxin: Sympathetic stimulation due to hypotension, and possibly other factors, increases plasma concentration of catecholamines. Increased hepatic phosphorylase a activity depletes existing glycogen stores and causes transient hyperglycemia. Lactate release from skeletal muscle is also enhanced, due to the more sustained activation of muscle phosphorylase a and increased uptake of plasma glucose. Stimulation of the immunologically active tissues by endotoxin with the participation of mononuclear phagocytes and TNF results in elevated glycolysis in these tissues as well, thus further enhancing the hyperlactacidemia. The increased precursor concentration and their delivery to the liver stimulate gluconeogenesis, in spite of endotoxin-induced suppression of PEPCK activity. Thus, an elevated precursor supply accelerates gluconeogenesis which is primarily responsible for the increased glucose Ra when hepatic glycogen stores are depleted. It appears that both an increase in blood lactate and catecholamines are important in maintaining the increased gluconeogenesis. This is illustrated schematically in Fig. 4. We postulate that in the fasted nutritionally nonsupported rat, endotoxin enhances glucose utilization in immunologically active tissues as well as in muscle. The presence of catecholamines and the glycolytically produced lactate stimulates gluconeogenesis. These events support the mounting of an effective immune response and aid the body to maintain the immune response by conserving glucose carbon.

Animals↗
PubMed1989

In vivo insulin resistance during nonlethal hypermetabolic sepsis.

The present study was performed to determine whether hypermetabolic sepsis alters peripheral and hepatic insulin sensitivity and/or responsiveness. Nonlethal sepsis was produced in chronically catheterized conscious rats by repeated subcutaneous injections of live Escherichia coli. Basal glucose metabolism was determined using a primed-constant infusion of [3-3H]glucose initiated 20 hr after the first injection of bacteria. Thereafter, in vivo insulin action was assessed using the euglycemic hyperinsulinemic clamp technique. Insulin was infused at various rates in separate groups of animals for 3 hr to produce steady-state insulin levels of approximately 60, 120, 400, 2,500, and 25,000 microU/ml, and euglycemia was maintained by varying the glucose infusion rate. The sepsis-induced hyperglucagonemia was not significantly altered by the infusion of insulin and glucose. In septic rats, the dose-response curve for the insulin-induced increment in glucose utilization was shifted downward and to the right. As a result, septic rats showed a twofold increase in the ED50 value (380 vs. 190 microU/ml) and a 50% reduction in the maximal responsiveness compared with control animals, indicating peripheral insulin resistance. Septic and nonseptic animals, however, had a similar reduction in the endogenous glucose production rate as the plasma insulin concentration was increased, suggesting that there was no hepatic insulin resistance. The plasma lactate concentration increased in a dose-dependent manner in both septic and nonseptic rats as the plasma insulin concentration was raised. However, the increment in steady-state lactate concentration was consistently higher (75-220%) in septic animals at each insulin infusion rate. These results indicate that nonlethal hypermetabolic sepsis in the rat is associated with peripheral insulin resistance.

Animals↗
PubMed1989

Early changes in glucose utilization of individual tissues after endotoxin administration.

Administration of Escherichia coli endotoxin (100 micrograms/100 g, i.v.) to conscious rats induces transient hyperglycemia and a sustained increase in whole body glucose turnover. To identify the tissues responsible for the increase in glucose utilization, the glucose metabolic rate (Rg) of peripheral tissues was determined in vivo by the 2-deoxyglucose tracer technique during and after the hyperglycemic phase. Rg was markedly increased in spleen, liver, intestine, epidydimal fat, gastrocnemius muscle, and skin during the early hyperglycemic period (80 min after endotoxin) and remained elevated in the subsequent euglycemic period (220 min). Combined alpha- and beta-adrenergic blockade, achieved by the primed continuous infusion of phentolamine and propranolol, prevented the transient hyperglycemia that followed endotoxin injection. Adrenergic blockade also prevented or considerably attenuated the early increases in tissue glucose utilization that were induced by endotoxin. The results indicate that the early increase in Rg can be mainly attributed to adrenergic stimulation and the resultant hyperglycemia, while the sustained elevation is due to mechanisms independent of hyperglycemia.

Animals↗
PubMed1988

Lipoxygenase and cyclooxygenase blockade by BW755C prevents endotoxin-induced hypotension but not changes in glucose metabolism.

Arachidonic acid metabolites are mediators of various pathophysiologic events following endotoxin administration. However, their role in the endotoxin-induced increase in glucose metabolism has not been examined. Rats were administered either saline or BW755C (an inhibitor of both the cyclooxygenase and lipoxygenase pathways) 30 min prior to injection of E. coli endotoxin and whole body glucose kinetics assessed using a constant iv infusion of [6-3H] glucose. Treatment with BW755C prevented the endotoxin-induced hypotension and tachycardia. Endotoxin produced characteristic increases in the plasma glucose (23-70%) and lactate (2- to 9-fold) concentrations, as well as elevations in the rate of glucose appearance (34-63%) and metabolic clearance (40-92%). In contrast to the amelioration in hemodynamics, pretreatment with BW755C did not prevent these alterations in glucose metabolism normally seen after endotoxin. BW755C markedly reduced the endotoxin-induced increase in plasma catecholamine concentrations, but levels were still elevated 2- to 4-fold compared to control values. The results suggest that arachidonic acid metabolites mediate the early hypotensive response following endotoxin, but are not by themselves responsible for the elevated rates of glucose production and utilization.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗