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J P Filkins

Publications and source records attributed to J P Filkins.

At least 37 records · Page 2Linked to original sources
PubMed1987

Exogenous ATP and carbohydrate metabolism in the rat liver.

The present study analyzed the actions of exogenous ATP on liver carbohydrate metabolism by using both isolated perfused rat livers and hepatocytes as model systems. The metabolic parameters measured in the perfused livers were glucose production, lactate production, oxygen consumption, and K+ movement. All parameters were monitored continuously during the perfusions in order to assess transient effects. ATP increased both glucose and lactate production in the isolated rat liver when perfused with either constant pressure or constant flow. ATP increased oxygen consumption in the perfused liver at a low concentration (10 microM) but was inhibitory at high concentrations (40 and 160 microM). ATP also increased K+ efflux in the isolated perfused liver. ATP did not alter basal glucose production in isolated hepatocytes; however, it did inhibit glucagon-stimulated glucose output by hepatocytes. ATP inhibited lactate production in the isolated hepatocytes. Extracellular ATP has the potential to modify basal as well as hormonal modulation of hepatic carbohydrate metabolism during shock.

Adenine Nucleotides↗
PubMed1985

Glucose dyshomeostasis and cardiovascular failure in endotoxic dogs.

Fasted mongrel dogs were anesthetized with pentobarbital sodium and instrumented for the on-line measurement of blood glucose (BG), a lead II electrocardiogram, and pressures in the left ventricle and pulmonary and systemic artery concomitant with on-line monitoring of BG. Serum insulin was measured by radioimmunoassay, and cardiac output (CO) was determined by thermodilution. Stroke work (SW) and pulmonary and systemic resistances were calculated. After a 30-min control period dogs were treated with Escherichia coli endotoxin (E) or normal saline (S) and then observed for 10 h or until death. Preinjection control BG was maintained in S dogs, and early hyperglycemia (H) was observed in six dogs; in contrast 10 E dogs showed no hyperglycemia (NH). During the late stages all E dogs were markedly hypoglycemic. In both groups of E dogs an early hyperinsulinemia occurred. CO and SW were depressed in both groups of E dogs. These variables were significantly lower in NH than in H dogs. Pulmonary and systemic resistance progressively increased in NH dogs after endotoxin administration. The results suggest that the ability to increase blood glucose levels after endotoxin injection is important for the maintenance of cardiovascular function. Glucose dyshomeostasis leading to hypoglycemia, however, may be a factor in the development of endotoxic cardiovascular failure.

Animals↗
PubMed1985

Glucose clamping and cardiovascular function in endotoxic dogs.

Fasted mongrel dogs were anesthetized with pentobarbital sodium and instrumented for the continuous measurement of blood glucose (BG), a lead II electrocardiogram, and pressures in the left ventricle (LV), pulmonary artery, and aorta. Cardiac output was measured every 15 min using thermodilution and LV stroke work, and pulmonary and systemic resistances were calculated. After a 30-min pretreatment period, glucose clamping was initiated. The desired glucose levels were reached within 45 min (hypoglycemic 20 +/- 1 mg/dl, n = 11; normoglycemic 85 +/- 1, n = 7; hyperglycemic 156 +/- 3, n = 7). At this point dogs were treated with either endotoxin (8 mg/kg to 6 hypoglycemic, 4 normoglycemic, and 4 hyperglycemic) or saline (5 hypoglycemic, 3 normoglycemic, and 3 hyperglycemic). All infusions were terminated after 2 h glucose clamping, and all dogs were monitored either until death or for a maximum of 10 h. Hypoglycemic clamping curtailed survival in endotoxic dogs. Hyperglycemic clamping markedly prolonged survival. Normoglycemic clamping left survival time unchanged compared with untreated dogs. The effects of glucose clamping on cardiovascular function during endotoxic shock paralleled the effects on survival. Cardiovascular function was also depressed in hypoglycemic-clamped saline dogs. It is concluded that glucose dyshomeostasis may be a crucial factor in the development of fatal cardiovascular dysfunction and shock after endotoxin administration.

Animals↗
PubMed1985

Monokines and the metabolic pathophysiology of septic shock.

The role of the macrophage system in shock pathogenesis now embraces both classic endocytic functions as well as the more recently discovered function of the macrophages as a multifaceted secretory apparatus. Among the major macrophage secretory products are the monokines, regulatory proteins that mediate via both local or paracrine and systemic or endocrine mechanisms, the nonspecific host defense and metabolic responses to inflammation and sepsis. Evidence is reviewed for a monokine involvement in the alterations of protein, fat, and carbohydrate metabolism in sepsis and/or endotoxicosis, viz., enhanced muscle proteolysis, enhanced hepatic acute phase protein synthesis, depressed lipogenesis and lipoprotein lipase function, enhanced peripheral glucose oxidation, and depression of hepatic gluconeogenesis. Monokines are also related to the disturbed endocrine mechanisms of sepsis, viz., enhanced insulin secretion and depressed adrenal steroidogenesis. It is suggested that the macrophage system mediates via secretion of monokines an integrated fuel substrate and hormonal adjustment to sepsis, which on the one hand may provide optimal metabolic homeostasis for systemic host defense, but on the other hand, if allowed to act unchecked, may contribute to the metabolic dyshomeostasis of septic shock.

Animals↗
PubMed1984

Reticuloendothelial system function and glucose-insulin dyshomeostasis in sepsis.

Circulating glucose levels, peripheral glucose utilization, and hepatic gluconeogenesis were compared in late endotoxicosis and severe septic shock in rats. Endotoxin was administered intravenously as 5 mg of Salmonella enteritidis lipopolysaccharide B. Sepsis was induced in the peritoneal cavity by use of the cecal ligation and puncture technique. Late endotoxicosis and severe sepsis were comparable in hypoglycemia, increased peripheral glucose use, and depression of gluconeogenesis. Immunoreactive insulin was lower in endotoxicosis than in sepsis; both models demonstrated elevations in serum nonsuppressible insulin-like activity. Endotoxic pancreata secreted excessive insulin, as did pancreata obtained after blockade of the reticuloendothelial system (RES). Macrophage-conditioned media induced a hypersecretory state of the beta cells in donor pancreata. The RES serves as a source of secretory products, i.e., gluco-regulatory monokines, which affects insulinization of tissues in sepsis and thus underwrites the hypoglycemia of late endotoxicosis and severe sepsis.

Animals↗
PubMed1984

Role for calcium in the insulin hypersecretory state of the endotoxic rat pancreas.

Previous studies have demonstrated that the endotoxic rat pancreas hypersecretes insulin in response to a glucose stimulus. However, the mechanism for this phenomenon is unknown. Since increases in pancreatic beta (B)-cell cytosolic ionic calcium are required for insulin secretion, this study evaluated the role of extracellular calcium on insulin secretion from the isolated, perfused endotoxic pancreas in the presence of and in the absence of extracellular calcium. Isolated pancreas preparations were obtained from control and endotoxin-treated rats and were perfused with either glucose (which primarily utilizes extracellular calcium to trigger insulin secretion) or 3-isobutyl-1-methylxanthine (IBMX, which primarily utilizes intracellular calcium to trigger secretion). In the presence of extracellular calcium, endotoxic pancreases hypersecreted insulin in response to either glucose or IBMX in comparison to control pancreases. In the absence of extracellular calcium, no insulin secretion occurred from control pancreases perfused with either glucose or IBMX. For endotoxic pancreases perfused with calcium-free conditions, insulin secretion was substantially less than that which occurred in the presence of calcium, but a significant amount of insulin secretion occurred from endotoxic pancreases in response to either IBMX or glucose. Insulin secretion from endotoxic pancreases was nearly three times greater with IBMX than with glucose under calcium-free conditions. Owing to the manner in which IBMX triggers insulin release, these data suggest that calcium handling within the endotoxic B-cell differs from that of the normal B-cell. In addition, endotoxic hypersecretion of insulin did not occur in response to endotoxin in vitro. Therefore this study indicates that endotoxin alters the regulation of calcium movements within the pancreatic B-cell via a mediated pathway.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Cardiac and splenic norepinephrine turnovers in endotoxic rats.

Although sympathetic hyperactivity has been implicated in the pathogenesis of endotoxin shock, methodologies employed to assess the activity have been indirect in nature and results have been equivocal. The present experiments quantitated postganglionic sympathetic activity by measuring norepinephrine (NE) turnovers in hearts and spleens of fasted male Holtzman rats injected intravenously with Salmonella enteritidis lipopolysaccharide (2 mg/300 g rat; 5.7-6.7 mg/kg). NE turnovers were measured over 12 h by the [3H]NE decay method. Cardiac NE turnovers were increased in endotoxic rats (0.075 micrograms X g-1 X h-1) compared with controls (0.009). Similarly, NE turnovers in spleens of endotoxic rats (0.099 micrograms X g-1 X h-1) were increased compared with control rats (0.033). Because NE reuptake is depressed in spleens of severely shocked endotoxic rats, the singular effect of reduced reuptake (desmethylimipramine treatment, 20 mg/kg) on NE turnovers was evaluated in spleens of a separate group of control rats. Desmethylimipramine had no effect on the slopes of the NE decay lines compared with untreated rats (-0.015 +/- 0.008 vs. -0.015 +/- 0.029, respectively). Thus these experiments support the concept of heightened sympathetic activation during endotoxicosis as assessed quantitatively in a noninvasive, unanesthetized rat model.

Animals↗
PubMed1983

Nonsuppressible insulinlike activity (NSILA) and the glucose dyshomeostasis of agonal sepsis.

Peritonitis was induced through the ligation and puncture of rat ceca. The rats were divided into three groups: 1) rats whose ceca were ligated and punctured (CLP); 2) rats whose ceca were isolated and replaced without being tied or perforated (SHAM); and 3) rats which were fasted but not subjected to surgery (FC). Plasma glucose levels, serum insulin content, basal and stimulated glucose oxidation rates of adipose tissue, and nonsuppressible insulinlike activity were measured at the time of death or sacrifice. CLP rats were hypoglycemic (35.9 +/- 2.7 mg/dl) at death whereas both FC and SHAM groups were normoglycemic at 101 +/- 1.6 mg/dl and 94.3 +/- 3.9 mg/dl, respectively. Terminal serum immunoreactive insulin content for the three groups did not vary from each other. The oxidation of 14C-glucose to 14CO2 by the septic rats' epididymal fat pads was significantly greater than either SHAM or FC (56.3 +/- 6.4 vs 35.0 +/- 3.3 or 24.5 +/- 2.4 X 10(3) 14CO2 dpm/g/h). When a suprastimulatory concentration of insulin (1 mU/ml) was added in vitro, the septic rats' fat pads were further stimulated to a greater glucose oxidation rate than either SHAM or FC group. Finally, nonsuppressible insulinlike activity (NSILA) was assessed by the addition of guinea pig antiinsulin serum (GPAIS) and rat sera to the in vitro preparations. CLP sera demonstrated a significantly greater NSILA level than either control group. The gathered data suggest that enhanced peripheral tissue glucose oxidation in late sepsis is associated with elevated NSILA.

Animals↗
PubMed1983

Relation of endotoxin structure to hypoglycemic and insulinlike actions.

Various endotoxin preparations were used to determine which portion of endotoxin, lipid A, polysaccharide, or lipid-associated protein (LAP), mediates the hypoglycemic and insulinlike action in rats. Salmonella enteriditis Boivin (SEB), complete endotoxin, and S enteriditis Westphal (SEW), lacking LAP, were equally lethal to endotoxin-sensitized rats; however, S minnesota (SM) glycolipid (lipid A plus 16% polysaccharide) was comparatively more toxic. Toxic effects were prevented by alteration of lipid A through alkaline hydrolysis or polymixin B treatment. SM-lipid A (0.02% polysaccharide) was less toxic than SM-glycolipid. Similar hypoglycemic effects were produced by SEB and SEW; however, SM-glycolipid produced a significantly greater hypoglycemia. Although SEB, SEW, and SM-glycolipid all produced significant increases in adipose tissue glucose oxidation a decreasing trend in effectiveness was observed, while the SM-lipid A was without effect. However, adding detoxified hydrolysates of endotoxin to SM-lipid A produced a significant increase in glucose oxidation. In conclusion, lipid A is the primary endotoxin moiety mediating both the lethal effects of endotoxin and its hypoglycemic action. However, maximal expression of insulinlike action requires the presence of all three portions of endotoxin.

Adrenalectomy↗
PubMed1982

Mechanism of hyperinsulinemia after reticuloendothelial system phagocytosis.

Endocytic loading of the reticuloendothelial system (RES) results in acute hyperinsulinemia and functional hyperinsulinism. Colloidal carbon blockade of the RES in rats resulted in elevations of both portal vein and systemic serum immunoreactive insulin and increases in the hepatic portal vein insulin glucose ratios. Two mechanisms for the hyperinsulinemia were evaluated: 1) decreased removal of insulin by the postendocytic liver and 2) increased secretion of insulin by the isolated perfused pancreas. Colloidal carbon blockade did not alter removal of 125I-insulin as evaluated in the isolated perfused rat liver. Pancreases from postendocytic donor rats when perfused according to the technique of Grodsky manifested enhanced insulin secretion. Macrophage culture-conditioned media enhanced glucose-mediated insulin secretion both as assayed in vivo and in the isolated perfused rat pancreas. The data suggest that postendocytic activated macrophages secrete a monokine that alters insulin release and thus produces the hyperinsulinemia of RES blockade. The acronym MIRA for macrophage insulin-releasing activity is proposed for the monokine.

Animals↗
PubMed1982

Insulin hypersecretion and potentiation of endotoxin shock in the rat.

Endotoxin has been shown to disrupt the metabolic regulation of blood glucose and insulin levels. This study determined the effect of arginine on plasma glucose and insulin regulation during endotoxicosis in order to assess its contribution to glucose dyshomeostasis in the pathogenesis of endotoxin shock. In addition, the ability of arginine to stimulate insulin secretion from the endotoxic pancreas was assessed directly by using the in vitro perfused rat pancreas model. Arginine significantly increased the lethal effects of endotoxin in rats and shortened the time course to death. Rats treated with both arginine and endotoxin demonstrated 1) a rapidly ensuing hypoglycemia, 2) an absence of the characteristic endotoxin-induced hyperglycemia, and 3) a rapidly progressive and profound hypoglycemia. In contrast alanine (which does not stimulate insulin secretion) did not profoundly exacerbate the glucose dyshomeostases of endotoxin shock. Lastly, arginine induced a hypersecretion of insulin as directly determined from the in vitro perfused pancreas of the endotoxic rat. These results demonstrated that arginine, through its direct insulinotropic effect on the hypersecretory endotoxic pancreas, contributed to the endotoxic hyperinsulinemia and thereby accelerated the development of glucose dyshomeostasis and lethal hypoglycemia in the endotoxic rat. This study has emphasized the important role for insulin in the pathogenesis of endotoxin-induced hypoglycemia. Furthermore, the potential role of insulin secretagogues other than glucose has been identified with regard to the insulin hypersecretory state of the endotoxic pancreas.

Alanine↗
PubMed1982

Role of the RES in the pathogenesis of endotoxic hypoglycemia.

The role of the RES in the alteration of glucose homeostasis was evaluated in male rats treated with S enteritidis endotoxin. Depression of hepatic gluconeogenesis coupled to enhanced peripheral glucose use was substantiated in vivo using the primed-constant infusion technique with 2-3H-D glucose. Immuno-reactive insulin was elevated in the early hyperglycemic phase but declined in endotoxic hypoglycemia. NSILA was elevated in late endotoxin shock. Two monokines--macrophage insulin-like activity (MILA) and macrophage insulin releasing activity (MIRA)--are related to the pathogenesis of endotoxic hypoglycemia.

Adipose Tissue↗
PubMed1982

Contribution of depressed reuptake to the depletion of norepinephrine from rat heart and spleen during endotoxin shock.

Norepinephrine content (microgram/g) was depressed in hearts and spleens of fasted male Holtzman rats treated intravenously with Salmonella enteritidis lipopolysaccharide (14-17 mg/kg). To investigate the mechanism of norepinephrine depletion during endotoxicosis, in vivo norepinephrine reuptake was evaluated in control and severely shocked rats using the incorporation of 3H-norepinephrine into hearts and spleens. Incorporation of 3H-norepinephrine into spleens of endotoxic rats was reduced 88%, i.e., from a control of 2309 +/- 224 dpm/gm to 270 +/- 69 dpm/gm after endotoxin. In contrast, cardiac tissue incorporation of 3H-norepinephrine was not significantly impaired, i.e., control of 11838 +/- 845 dpm/gm versus severe shock of 17783 +/- 2904 dpm/gm. In vitro analysis of total norepinephrine retained in cardiac and splenic tissue slices incubated with 3H-norepinephrine yielded results consistent with in vivo experiments: Splenic norepinephrine reuptake was significantly decreased on the order of 50% in preparations from endotoxic rats, while myocardial norepinephrine reuptake was the same in both groups. The results indicate that depression of norepinephrine reuptake is a mechanism of norepinephrine depletion in spleens but not hearts of endotoxic rats.

Animals↗
PubMed1981

Insulin-like action of endotoxin: antagonism by steroidal and nonsteroidal anti-inflammatory agents.

Studies were undertaken to evaluate the direct insulin-like action of S enteritidis endotoxin on glucose oxidation in the rat epididymal fat pad and to assess antagonism by steroidal and nonsteroidal anti-inflammatory agents. In vitro administration of endotoxin at concentrations of 500, 100, 50, and 10 micrograms/ml significantly increased adipose tissue glucose oxidation by 115, 92, 55, and 32%, respectively. Exposure of the fat pads to endotoxin (100 microgram/ml) for timed incubations of 120 to 5 min, all produced significant increments in glucose oxidation. The insulin-like action of endotoxin was significantly less in Ca2+ free-KRB plus EGTA. Cotreatment of the fat pads with endotoxin and the steroidal anti-inflammatory agents, dexamethasone and methylprednisolone, as well as the nonsteroidal anti-inflammatory agent, indomethacin, significantly antagonized endotoxin-stimulated glucose oxidation. Dexamethasone antagonism was not significant if it was added after endotoxin treatment. Testosterone, a steroid with no anti-inflammatory activity, did not antagonize endotoxin's insulin-like action. The data provide further evidence of the direct insulin-like action of endotoxin and suggest that the protective effect of dexamethasone, methylprednisolone, and indomethacin may be due, in part, to a direct antagonism of endotoxin at the tissue level.

Adipose Tissue↗
PubMed1981

Hypoglycemic depression of hepatic phagocytosis in vivo and in the in situ perfused rat liver.

Depression of the phagocytic function of the reticuloendothelial system (RES) during endotoxic hypoglycemia has been implicated in the pathogenesis of endotoxin shock. The present study evaluated the in vivo effects of hypoglycemia on RES function and assessed the effects of an vivo bout of hypoglycemia on phagocytosis in the in situ perfused rat liver. Hypoglycemia was produced in male Holtzman rats using either 1 U of regular insulin (RI) (ILETIN, Lilly) or 0.75 U of long-acting insulin (LAI) (85% LENTE/15% ULTRALENTE, Lilly). RES function was quantitated by intravascular clearance of 8 mg/100 gm body weight colloidal carbon (CC). Two hr after RI and 2.5 hr after LAI, the intravascular halftimes of CC clearance were 19 +/- 2 min (N = 22) and 18 +/- 1 min (N = 19), respectively, as compared to control, 11.3 +/- 0.4 min (N = 53, P less than 0.001). The corresponding plasma glucose (PG) levels were 95 +/- 2 mg/dl in control, 14.4 +/- 0.9 for the RI group, and 17 +/- 1 for LAI. Two hr after RI, livers were perfused for 10 min in situ with 50 mg/liter CC in saline 5% rat serum. PG for control liver donors were 90 +/- 3 mg/dl, while those for hypoglycemic liver donors were 15 +/- 2. CC uptake was decreased from 22 micrograms/min/gm liver in the control (+ serum, n = 19) to 11 +/- 2 in hypoglycemia livers (N = 6); no effect of serum on hypoglycemic depression of the RES was seen. There were no differences in flow rates in the 2 groups. These results indicate that hypoglycemia directly impairs RES function and that the in vivo depression of intravascular clearance is not related to either the presence or absence of serum factors or total hepatic blood flow. Thus, the characteristic hypoglycemia of endotoxin shock may contribute to RES depression and the lethal shock syndrome.

Animals↗
PubMed1980

Mechanism of hyperinsulinemia in endotoxicosis.

Hyperinsulinemia subsequent to endotoxemia is a key factor leading to the disturbance of glucose homeostasis in endotoxin shock. This study investigated the mechanism(s) of hyperinsulinemia during endotoxicosis in the rat. Two primary mechanisms for the hyperinsulinemia were evaluted: 1) decreased removal of insulin by the endotoxic liver, and 2) increased secretion of insulin by the endotoxic pancreas. Endotoxin treatment of donor rats did not impair the removal of TCA-precipitable 125I-labeled insulin by the isolated perfused liver. Perfused pancreases from endotoxic donors secreted more insulin tha control pancreases in response to a provocative stimulus of glucose. In vivo measurements of plasma immunoreactive insulin and glucose indicated an elevated hepatic portal vein insulin:glucose ratio associated with endotoxicosis. Therefore, the hyperinsulinemia of endotoxicosis is due primarily to hypersecretion of insulin by the endotoxic pancreas.

Animals↗