RESUMEN
We evaluated the delivery of 14C-cytosine arabinoside (AraC) to rat brain by: 1) intravenous (IV) bolus, by 2) intrathecal (IT) and 3) intraventricular (IVT) infusion, and by 4) convection-enhanced delivery (CED) into the caudate nucleus. Plasma and brain AraC metabolites were measured with HPLC, and distribution and concentration of 14C-AraC in brain sections were measured by quantitative autoradiography. After IV administration, the alpha and beta plasma half-lives were 1.9 and 46.5 min, respectively. The blood-to-brain transfer constant of AraC was 2.5+/-1.4 microliter g(-1) min(-1), compatible with high water solubility. After IT and IVT administration, tissue levels were high at the brain and ventricular surfaces, but declined exponentially into brain. After CED, maximum brain levels were up to 10,000 times higher than the IV group, and the distribution pattern was one of high 14C-AraC concentration in the convective component, with exponentially declining concentrations outside this region. The rate loss constant from brain was 0.002+/-0.0004 min(-1), suggesting that AraC was accumulating in brain cells. AraC was metabolized into uracil arabinoside within the brain. 14C-AraC was infused into 1 dog and distributed widely in the ipsilateral hemisphere. These studies suggest that delivery of AraC to brain parenchyma by the IV, IT or IVT routes will be subtherapeutic. Delivery by CED can achieve, and maintain, therapeutic levels of AraC in the brain, and should be further evaluated as a potential method of drug delivery.
Asunto(s)
Encéfalo/metabolismo , Núcleo Caudado/metabolismo , Citarabina/administración & dosificación , Citarabina/farmacocinética , Animales , Radioisótopos de Carbono , Citarabina/sangre , Perros , Semivida , Infusiones Parenterales , Inyecciones Intravenosas , Inyecciones Intraventriculares , Inyecciones Espinales , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
OBJECT: The authors evaluated convection-enhanced delivery (CED) of 14C-sucrose to the rat brain as a method of enhancing cerebral drug delivery and compared it with intravenous (i.v.) and intraventricular (i.v.t.) routes of administration. METHODS: Groups of rats received 14C-sucrose by bolus i.v. infusion, i.v.t. infusion for 1, 2, or 7 days at 0.17 microl/minute, or CED at rates from 0.01 to 0.5 microl/minute for periods from 1 hour to 7 days. Radioisotope distribution and concentration in tissue were analyzed using quantitative autoradiography. Intravenously administered sucrose reached the entire brain, but levels in tissue were low. After i.v.t. administration, sucrose levels in tissue were high at, and declined exponentially away from, the ventricular surface. Chronic CED administration maintained high levels of sucrose in tissue that focally were up to 10,000 times higher than in the i.v. group. The isotope distribution pattern after chronic CED infusions indicated a central component that resulted from convention and a peripheral component in gray matter that was the result of diffusion. The brain influx (0.42 microl/g/min) and diffusion constants of sucrose (2.8 x 10(-6) cm2/second) were similar to reported values. The total brain efflux constant was 0.0044 minute, whereas the blood-brain barrier (BBB) efflux constant was 0.0016 minute. There were no pathological changes in the brains after CED except those associated with cannula insertion. Sucrose, which was thought to be inert, was found to interact with brain tissue; up to 25% was bound to an unidentified tissue component. CONCLUSIONS: Chronic CED appears to be a potentially useful method for significantly circumventing the BBB and increasing delivery of water-soluble drugs to the brain.
Asunto(s)
Encéfalo , Sacarosa/administración & dosificación , Animales , Autorradiografía , Barrera Hematoencefálica/fisiología , Encéfalo/metabolismo , Radioisótopos de Carbono , Convección , Infusiones Intravenosas , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Sprague-Dawley , Sacarosa/metabolismo , Sacarosa/farmacocinéticaRESUMEN
The rate of glucose utilization (Rg) of various tissues including lung and bronchoalveolar lavage (BAL) fluids cells was measured, using the 2-deoxyglucose technique in Sprague-Dawley rats 4 h after challenge with either 1 mg/kg intravenous or 0.3 mg/kg intratracheal lipopolysaccharide (LPS). After intravenous LPS, Rg increased in whole lung and nonrespiratory tissues, but was unaltered in BAL cells. After intratracheal LPS, the Rg of nonrespiratory tissues was unchanged, but the Rg of BAL cells increased from 3.7 +/- 0.3 to 71.5 +/- 16.0 nmol/min. This increase in the Rg of BAL cells was explained by a doubling of the macrophage specific Rg, by a 100-fold increase in polymorphonuclear leukocytes (PMN) number, and by a higher Rg in PMN than in macrophages. These results demonstrate that increased glucose utilization after intratracheal LPS is confined to the respiratory system and that intra-alveolar phagocytes participate in this increase.
Asunto(s)
Glucosa/metabolismo , Lipopolisacáridos/administración & dosificación , Pulmón/metabolismo , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Desoxiglucosa/metabolismo , Glucólisis/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Intravenosas , Intubación Intratraqueal , Lactatos/sangre , Lipopolisacáridos/farmacología , Pulmón/efectos de los fármacos , Macrófagos Alveolares/citología , Macrófagos Alveolares/efectos de los fármacos , Masculino , Neutrófilos/citología , Neutrófilos/efectos de los fármacos , Especificidad de Órganos , Ratas , Ratas Sprague-DawleyRESUMEN
The aim of the present work was to test the effect of acute in vivo alcohol administration (180-190 mg/dl plasma for 3 h) on glucose utilization by tissues under basal conditions or after a hyperinsulinemic (100-130 microU/ml) euglycemic clamp in fasted rats. In vivo glucose use by individual tissues was assessed by the tracer 2-deoxy-D-glucose technique. Alcohol administration to saline-infused rats markedly inhibited glucose use by skeletal muscles, including the soleus, white and red quadriceps, and gastrocnemius, as well as by the heart. Ethanol infusion, however, had no effect on glucose use by the diaphragm, lung, liver, skin, ileum, brain, and adipose tissue. The insulin-stimulated glucose use was also inhibited by alcohol selectively in the muscles, with no effect on other tissues tested, except a moderate inhibition in the brain. Ethanol inhibited muscle glucose use by an average of approximately 50% under both basal and insulin-stimulated conditions. However, because insulin treatment more than doubled basal glucose use by these muscles, the 50% inhibition by ethanol treatment represents a greater inhibition of absolute glucose use under insulin-stimulated rather than under basal conditions. Our data demonstrate that acute alcohol intake attenuates basal and hormone-induced glucose utilization in a tissue-specific fashion. The inhibitory effect of alcohol on skeletal muscle glucose use could contribute to the previously observed decreased glucose recycling in humans after acute alcohol intake.
Asunto(s)
Etanol/toxicidad , Glucosa/metabolismo , Insulina/farmacología , Proteínas Musculares , Músculo Esquelético/metabolismo , Animales , Transportador de Glucosa de Tipo 4 , Masculino , Proteínas de Transporte de Monosacáridos/análisis , Ratas , Ratas Sprague-DawleyRESUMEN
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.
Asunto(s)
Glucosa/metabolismo , Insulina/farmacología , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas/metabolismo , Hígado/metabolismo , Animales , Peso Corporal , Ingestión de Alimentos , Hemodinámica , Cinética , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/patología , Neoplasias Hepáticas Experimentales/sangre , Neoplasias Hepáticas Experimentales/patología , Masculino , Trasplante de Neoplasias , Ratas , Ratas Sprague-DawleyRESUMEN
Both gram-negative infection and bacterial endotoxin (lipopolysaccharide, LPS) produce a marked neutropenia and increase glucose disposal by peripheral tissues. The purpose of the present study was to determine whether leukocyte depletion before these insults would diminish the commonly observed increases in tissue glucose uptake. Rats were depleted of circulating and marginated leukocytes with cyclophosphamide (CPA). Under basal postabsorptive conditions the subcutaneous injection of live Escherichia coli into control animals enhanced whole body glucose disposal that resulted in part from a stimulation of glucose uptake by the liver, spleen, intestine, and lung. These increases in tissue glucose uptake were not associated with an increase in neutrophil number, as assessed by myeloperoxidase (MPO) activity. CPA-induced leukopenia did not alter the sepsis-induced increase in glucose uptake by these tissues and whole body glucose use remained elevated. In contrast, skin and muscle proximal to the site of infection showed an increase in both glucose uptake and MPO activity. Furthermore, leukocyte depletion attenuated the elevated glucose uptake by skin and muscle near the inflammatory focus. The intravenous injection of LPS also increased whole body glucose disposal and enhanced glucose uptake by the lung, liver, spleen, intestine, and skin in saline-treated rats. Of these tissues the lung, liver, and spleen had a corresponding increase in neutrophil number. The LPS-induced increases in tissue glucose uptake in leukopenic rats were comparable, with the exception of liver and lung. In these tissues the incremental increase in glucose uptake after LPS was reduced 40-50% in leukopenic animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Endotoxinas/farmacología , Infecciones por Escherichia coli/metabolismo , Escherichia coli , Glucosa/farmacocinética , Leucopenia/metabolismo , Animales , Glucemia/análisis , Presión Sanguínea/efectos de los fármacos , Desoxiglucosa , Infecciones por Escherichia coli/sangre , Inyecciones Intravenosas , Leucopenia/sangre , Lipopolisacáridos/farmacología , Masculino , Tasa de Depuración Metabólica , Peroxidasa/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/análisisRESUMEN
The present study examines whether in vivo administration of granulocyte colony-stimulating factor (G-CSF) and the resultant neutrophilia alters basal glucose metabolism or modulates the glucose metabolic response to a subsequent endotoxin [lipopolysaccharide (LPS)] challenge. Rats were injected with human recombinant G-CSF (50 micrograms/kg sc) twice daily for 2 days preceding an injection of LPS. Animals treated with G-CSF showed an eightfold increase in blood polymorphonuclear leukocytes (PMNs) but no detectable changes in hemodynamics or glucose metabolism. In control animals, LPS transiently decreased circulating PMN number, but by 4 h neutrophils had returned to control levels. LPS produced a greater reduction in circulating neutrophils in G-CSF-treated animals, which did not return to pretreatment levels by 4 h. G-CSF also produced marked changes in the glucose metabolic response to LPS. Rates of whole body glucose production and utilization in both control and G-CSF-treated rats were rapidly increased by LPS; however, the increment in glucose flux was 55-100% greater in the latter group. The enhanced rate of hepatic glucose production in this group occurred despite lower plasma levels of lactate and glucagon. The elevated rate of whole body glucose utilization was attributable to the G-CSF-enhanced LPS-induced increase in glucose uptake by the ileum, spleen, liver, and lung. Furthermore, LPS increased glucose uptake by skeletal muscle in G-CSF-treated rats but not in control animals. The enhanced glucose disposal in G-CSF-treated rats was not mediated by increases in plasma glucose or insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Endotoxinas/farmacología , Escherichia coli , Glucosa/metabolismo , Factor Estimulante de Colonias de Granulocitos/farmacología , Animales , Ciclo Celular , División Celular/efectos de los fármacos , Glucagón/sangre , Hemodinámica/efectos de los fármacos , Insulina/sangre , Leucocitos/citología , Masculino , Peroxidasa/metabolismo , Ratas , Ratas Sprague-Dawley , Distribución Tisular , Factor de Necrosis Tumoral alfa/análisisRESUMEN
An inhibitory effect of fatty acid oxidation on glucose uptake and oxidation has been demonstrated in heart and skeletal muscle under certain experimental conditions. This reciprocal relationship has been termed the glucose-fatty acid cycle. The purpose of the present study was to determine under in vivo conditions whether this interaction was operational in various nonmuscle tissues, and whether infection altered the activity of this cycle. Oral administration of alpha-methylpalmoxirate (MPA; 75 mg/kg), a known inhibitor of long-chain fatty acid oxidation, suppressed hepatic glucose production by 54% and increased whole body glucose disappearance by 15% in nonseptic rats. In contrast, MPA produced a larger reduction of glucose output in septic rats, but did not enhance glucose disposal. In vivo glucose uptake (Rg) by individual tissues was determined using the tracer 2-deoxyglucose technique. In nonseptic animals, MPA increased Rg in "working" muscles (heart and diaphragm; 12-fold and two-fold respectively), but not in "resting" skeletal muscles. MPA increased the Rg of heart and diaphragm to the same level in septic animals. Inhibition of fatty acid oxidation in nonseptic rats also enhanced Rg in liver (174%), spleen (158%), lung (153%), ileum (52%), skin (28%), kidney (115%), and epididymal fat (135%). In septic rats, MPA only increased Rg in the ileum (23%) and kidney (50%). This increased glucose uptake was independent of increases in plasma glucose and insulin concentrations. The infusion of heparin and intralipid, which increased circulating levels of fatty acids, failed to produce consistent changes in either the whole body glucose turnover or glucose uptake by individual tissues. We conclude that under basal in vivo conditions the inhibition of fatty acid oxidation suppresses glucose production and increases peripheral glucose disposal in nonseptic animals. These data support the presence of the glucose-fatty acid cycle in nonmuscle tissues and emphasizes its importance in whole body glucose homeostasis in situations where fatty acid oxidation is impaired. Infection increases glucose uptake by nonmuscle tissues which, for the most part, cannot be further enhanced by the inhibition of lipid oxidation.
Asunto(s)
Ácidos Grasos no Esterificados/metabolismo , Glucosa/metabolismo , Riñón/metabolismo , Sepsis/metabolismo , Tejido Adiposo/metabolismo , Animales , Carnitina O-Palmitoiltransferasa/antagonistas & inhibidores , Compuestos Epoxi/metabolismo , Íleon/metabolismo , Masculino , Tasa de Depuración Metabólica , Propionatos/metabolismo , Ratas , Ratas Sprague-Dawley , Piel/metabolismoRESUMEN
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.
Asunto(s)
Infecciones por Escherichia coli/inmunología , Glucosa/metabolismo , Factor Estimulante de Colonias de Granulocitos/farmacología , Neutrófilos/inmunología , Animales , Temperatura Corporal/efectos de los fármacos , Epinefrina/farmacología , Infecciones por Escherichia coli/sangre , Infecciones por Escherichia coli/metabolismo , Hemodinámica/efectos de los fármacos , Recuento de Leucocitos , Leucocitos/efectos de los fármacos , Masculino , Músculos/metabolismo , Peroxidasa/análisis , Ratas , Ratas Endogámicas , Piel/metabolismoRESUMEN
The present study examined whether a prolonged infusion of tumor necrosis factor (TNF) into rats could sustain the increased rate of whole body glucose metabolism observed with short term exposure, and whether TNF produced hepatic or peripheral insulin resistance. Basal glucose metabolism was determined with the use of [3-3H]glucose 18 h after initiating a constant infusion of recombinant human TNF (1 microgram/kg.h). Thereafter, a two-step euglycemic hyperinsulinemic clamp was performed to determine whether TNF impaired insulin action. The overnight infusion of TNF minimally elevated plasma glucose concentrations (17%), but produced large increases in the whole body rate of glucose production and utilization (133%). Under hyperinsulinemic conditions, the glucose infusion rate necessary to maintain euglycemia was 30% lower in TNF-treated rats, indicating an insulin-resistant condition. This resulted from an impaired ability of insulin to both suppress hepatic glucose production and stimulate peripheral glucose utilization in TNF-infused animals. A second series of experiments was performed, using the in vivo tracer [U-14C]2-deoxyglucose technique, to elucidate which tissues were responsible for the TNF-induced increase in basal (no exogenous insulin) glucose disposal and peripheral insulin resistance. Under basal conditions, TNF increased glucose uptake by various muscles (gastrocnemius, heart, and diaphragm) as well as nonmuscle tissues (liver, lung, spleen, gut, skin and fat). Because of their relatively large mass and/or high rate of glucose uptake, the increased uptake by skin (25%), intestine (24%), muscle (23%), and liver (15%) accounted for the majority of the TNF-induced increment in whole body glucose disposal. Under euglycemic hyperinsulinemic conditions, the increment in glucose uptake by muscle and skin (85%) accounted for the majority of the glucose disposal in control rats. However, in TNF-infused animals, hyperinsulinemia failed to increase glucose uptake by skin and blunted the insulin-mediated increase in muscle by 73%. These results suggest that sustained elevations of TNF during chronic therapy and prolonged production of TNF by patients and experimental animals with malignancies or infectious diseases may be an important mechanism for the enhanced glucose flux as well as the insulin resistance seen in these conditions.
Asunto(s)
Glucosa/metabolismo , Antagonistas de Insulina/farmacología , Hígado/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Animales , Resistencia a la Insulina , Masculino , Ratas , Ratas Endogámicas , Factor de Necrosis Tumoral alfa/análisisRESUMEN
The purpose of the present study was to determine how hypoglycemia alters glucose uptake by individual tissues and whether this response is altered by gram-negative infection. A hypermetabolic septic state was produced in catheterized rats by subcutaneous injections of live Escherichia coli. The next morning, animals were infused with saline, somatostatin to produce a euglycemic insulinopenic state (6 mmol/L glucose, 5 microU/mL insulin), or 3-mercaptopicolinate (3-MP) to inhibit gluconeogenesis and produce a hypoglycemic insulinopenic (4.5 or 2 mmol/L glucose, 5 microU/mL insulin) condition. After 140 minutes, [14C]2-deoxyglucose was injected intravenously (IV) to determine in vivo glucose uptake by individual tissues. Sepsis increased whole body glucose disposal (Rd) by 53% under basal euglycemic conditions and this increase resulted from an enhanced rate of glucose removal by liver, spleen, lung, ileum, and skin. Under euglycemic insulinopenic conditions, total glucose Rd decreased in both septic and nonseptic rats as a result of a decreased rate of glucose uptake by muscle. However, because the absolute rate of glucose uptake was still elevated by sepsis, the rate of non-insulin-mediated glucose uptake (NIMGU) was 46% higher in septic rats than in nonseptic animals. Severe hypoglycemia (2 mmol/L) produced a relative insulin deficiency and decreased whole body Rd in both septic and nonseptic animals by 53% to 58%, compared with euglycemic insulinopenic animals. The decrease in blood glucose decreased glucose uptake by all tissues examined, except brain and heart. However, sepsis still increased glucose uptake by liver, spleen, lung, ileum, and skin (25% to 90%), compared with hypoglycemic nonseptic rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Glucemia/metabolismo , Desoxiglucosa/metabolismo , Infecciones por Escherichia coli/metabolismo , Glucosa/metabolismo , Hipoglucemia/metabolismo , Insulina/sangre , Sepsis/metabolismo , Animales , Infecciones por Escherichia coli/complicaciones , Glucagón/sangre , Gluconeogénesis/efectos de los fármacos , Técnica de Clampeo de la Glucosa , Hipoglucemia/complicaciones , Cinética , Lactatos/sangre , Masculino , Especificidad de Órganos , Ácidos Picolínicos/farmacología , Ratas , Ratas Endogámicas , Valores de Referencia , Sepsis/complicaciones , Somatostatina/farmacologíaRESUMEN
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.
Asunto(s)
Infecciones Bacterianas/metabolismo , Glucemia/metabolismo , Glucosa/metabolismo , Bacterias Gramnegativas , Animales , Infecciones Bacterianas/fisiopatología , Temperatura Corporal , Infecciones por Escherichia coli/metabolismo , Infecciones por Escherichia coli/fisiopatología , Hemodinámica , Hormonas/sangre , Masculino , Ratas , Ratas EndogámicasRESUMEN
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.
Asunto(s)
Infecciones Bacterianas/metabolismo , Glucosa/metabolismo , Insulina/farmacología , Animales , Hemodinámica , Insulina/sangre , Resistencia a la Insulina , Masculino , Músculos/efectos de los fármacos , Músculos/metabolismo , Ratas , Ratas Endogámicas , Flujo Sanguíneo RegionalRESUMEN
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.
Asunto(s)
Infecciones Bacterianas/fisiopatología , Diabetes Mellitus Experimental/metabolismo , Infecciones por Escherichia coli/fisiopatología , Insulina/fisiología , Animales , Infecciones Bacterianas/complicaciones , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/fisiopatología , Relación Dosis-Respuesta a Droga , Infecciones por Escherichia coli/complicaciones , Glucosa/metabolismo , Bacterias Gramnegativas , Hemodinámica , Insulina/metabolismo , Insulina/farmacología , Resistencia a la Insulina , Masculino , Ratas , Ratas EndogámicasRESUMEN
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.
Asunto(s)
Infecciones por Escherichia coli , Resistencia a la Insulina , Sepsis/metabolismo , Animales , Glucemia/metabolismo , Ayuno , Glucagón/sangre , Glucosa/administración & dosificación , Glucosa/metabolismo , Insulina/administración & dosificación , Insulina/sangre , Insulina/farmacología , Lactatos/sangre , Ácido Láctico , Hígado/efectos de los fármacos , Masculino , Ratas , Ratas EndogámicasRESUMEN
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.
Asunto(s)
Glucosa/metabolismo , Insulina/fisiología , Interleucina-1/farmacología , Animales , Diabetes Mellitus Experimental/metabolismo , Insulina/farmacología , Hígado/metabolismo , Pulmón/metabolismo , Masculino , Músculos/metabolismo , Ratas , Ratas Endogámicas , Piel/metabolismo , Bazo/metabolismoRESUMEN
The importance of platelet-activating factor (PAF) in producing hypotension, hemoconcentration and alterations in carbohydrate metabolism following thermal injury was investigated in chronically catheterized rats. Animals were fasted overnight, anesthetized with pentobarbital, and then injected with saline or the PAF antagonist SRI 63-675 prior to a 25% body surface area scald injury. Burned animals showed a sustained 20-30% fall in mean arterial pressure that was attenuated by the PAF antagonist. Burn also produced a prolonged increase in hematocrit. Animals pretreated with SRI 63-675 showed a similar degree of polycythemia after 1 h, but thereafter hematocrit fell and was not different from sham-burned animals. Burn increased the plasma glucose (45-52%) and lactate (5-6 fold) concentrations, and tended to produce an early increase and a later decrease in the rate of glucose appearance (Ra). These metabolic changes were associated with elevated plasma levels of glucagon and catecholamines. The PAF antagonist prevented the hyperglycemia, reduced the hyperlactacidemia, and prevented the late fall of glucose Ra. Treated animals still showed increased levels of glucagon, while catecholamine concentrations were reduced by 50%. Short-term survival (4 h) was markedly improved (86 vs. 43%). These results suggest that PAF produced following thermal injury is responsible, at least in part, for the early hemodynamic changes and hemoconcentration. However, the role of PAF as a mediator of burn-induced glucose dyshomeostasis appears secondary to its hemodynamic effects.
Asunto(s)
Glucemia/análisis , Quemaduras/sangre , Catecolaminas/sangre , Hemodinámica/efectos de los fármacos , Factor de Activación Plaquetaria/fisiología , Quinolinas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Quemaduras/complicaciones , Quemaduras/mortalidad , Glucagón/sangre , Frecuencia Cardíaca/efectos de los fármacos , Hematócrito , Hipotensión/sangre , Hipotensión/etiología , Insulina/sangre , Factor de Activación Plaquetaria/antagonistas & inhibidores , Ratas , Ratas EndogámicasRESUMEN
Platelet-activating factor (PAF) is a postulated mediator of many of the early hemodynamic effects of endotoxin. The aim of the present study was to determine whether in vivo administration of PAF could produce alterations in whole-body glucose metabolism that would mimic those seen during endotoxemia. Glucose kinetics were assessed in chronically catheterized conscious rats by the constant infusion of [6-3H]- and [U-14C]glucose before and for 4 h after either a bolus injection (300 ng/kg) or a constant infusion (20 or 220 ng.min-1.kg-1) of PAF. The bolus injection of PAF produced a 30% decrease in blood pressure by 5 min that returned to control levels by 30 min. Increased plasma glucose (40%) and lactate (150%) levels after injection of PAF were also transient. In contrast, the bolus injection of PAF elevated the rate of glucose appearance (Ra; 44%) for 1.5 h. The lower PAF infusion rate decreased blood pressure 11% to 104 mmHg, whereas the higher infusion rate decreased pressure 34% to 77 mmHg. Both PAF infusion rates produced elevations in plasma glucose (28, 150%) and glucose Ra (20, 60%) throughout the 4-h infusion period in a dose-related manner. The PAF infusions also induced dose-related increases in plasma glucagon and catecholamine levels throughout the infusion period. In a separate group of experiments a complete adrenergic blockade, produced by the constant infusion of propranolol and phentolamine, completely prevented PAF-induced increases in glucose kinetics and the hyperglucagonemia.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Glucosa/farmacocinética , Factor de Activación Plaquetaria/farmacología , Animales , Glucemia/análisis , Hemodinámica/efectos de los fármacos , Hormonas/sangre , Infusiones Intravenosas , Masculino , Concentración Osmolar , Ratas , Ratas Endogámicas , Simpaticolíticos/farmacologíaRESUMEN
The present study examined the purported exacerbating effect of sepsis on glucose metabolism in diabetes. Diabetes was induced in rats by an intravenous injection of 70 or 45 mg/kg streptozotocin. The higher dose produced "severe" diabetes, whereas the lower dose of streptozotocin produced a milder, "latent" diabetes. After a chronic diabetic state had developed for 4 wk, rats had catheters implanted and sepsis induced by intraperitoneal injections of live Escherichia coli. After 24 h of sepsis the blood glucose concentration was unchanged in nondiabetics and latent diabetics, but glucose decreased from 15 to 8 mM in the septic severe diabetic group. This decrease in blood glucose was not accompanied by alterations in the plasma insulin concentration. Glucose turnover, assessed by the constant intravenous infusion of [6-3H]- and [U-14C]glucose, was elevated in the severe diabetic group, compared with either latent diabetics or nondiabetics. Induction of sepsis produced a slight decrease in the glucose turnover in the severe diabetic group but did not alter turnover in the latent diabetics. The rate of glucose disappearance, used to quantitate the alterations in plasma glucose after an intravenous glucose tolerance test, was decreased in both groups of diabetics and was proportional to the severity of the diabetic state. Sepsis increased the rate of glucose disappearance in nondiabetic rats but had no effect in either group of diabetic animals. Sepsis also failed to alter the insulinogenic index, used to estimate the insulin secretory capacity, in diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Infecciones Bacterianas/complicaciones , Diabetes Mellitus Experimental/complicaciones , Glucosa/metabolismo , Animales , Infecciones Bacterianas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Prueba de Tolerancia a la Glucosa/métodos , Bacterias Gramnegativas , Hemodinámica , Inyecciones Intravenosas , Cinética , Masculino , Ratas , Ratas Endogámicas , EstreptozocinaRESUMEN
The aim of this study was to determine whether diabetes enhanced the sensitivity of the myocardium to the deleterious effects of in vivo-administered Escherichia coli. Diabetes was induced in two groups of animals. One group received 70 mg/kg streptozotocin (iv) and exhibited a severe diabetes with elevated fasting and fed blood glucose concentrations and a markedly abnormal response to an oral glucose load. The second group received 45 mg/kg streptozotocin, was mildly diabetic (termed "latent" diabetes), and was characterized by normal fasting blood glucose but slightly elevated fed blood glucose and an abnormal response to a glucose load. A third group of rats received vehicle and served as time-matched control animals. Four weeks after induction of diabetes, all animals were catheterized under ether anesthesia and some received intraperitoneal injections of live E. coli. In vitro myocardial performance was assessed using the isolated, perfused working heart preparation. Ventricular function curves were generated by changing left atrial filling pressure and measuring changes in heart rate, cardiac output, and aortic peak systolic pressure. Cardiac performance in the severe diabetic group was depressed at the highest preload but was unchanged at lower preloads. Function in the latent diabetic group was not different from control. Sepsis induced a slight decrease in cardiac performance in the control group and resulted in larger reductions in the latent and severe diabetic groups. A depression in aortic flow was the major consequence of sepsis in the latent diabetic group, whereas decreased coronary flow was the primary change in the severe diabetic group.(ABSTRACT TRUNCATED AT 250 WORDS)