Biomedical subjects

C H Lang

Publications and source records attributed to C H Lang.

At least 91 records · Page 5Linked to original sources

PubMed1995

Regulation of insulin-like growth factor-I (IGF-I) and IGF-binding proteins by tumor necrosis factor.

The purpose of the present study was to determine 1) whether exogenous administration of tumor necrosis factor-alpha (TNF-alpha) alters insulin-like growth factor-I (IGF-I) and IGF-binding proteins (BPs) and 2) whether the enhanced endogenous production of TNF mediates the lipopolysaccharide (LPS)-induced changes in the IGF system. The overnight infusion of murine TNF-alpha reduced circulating concentrations of both growth hormone (GH) and IGF-I in fasted rats. Furthermore, TNF-alpha decreased IGF-I content in liver, gastrocnemius muscle, and pituitary. In contrast, TNF-alpha increased IGF-I content in kidney and brain. IGFBP-1 was increased in plasma, liver, and muscle in response to TNF-alpha. In a second study, rats were injected with LPS after treatment with a neutralizing anti-TNF antibody (Ab), and blood and tissues were collected 4 h later. In LPS-treated rats, plasma concentrations of GH and IGF-I were reduced. LPS also decreased the IGF-I content in liver and skeletal muscle and increased plasma, liver, and muscle concentrations of IGFBP-1. Pretreatment with anti-TNF Ab attenuated the LPS-induced reduction in IGF-I and the increased IGFBP-1 in plasma and liver and completely prevented the decrease in IGF-I observed in muscle. In contrast, the LPS-induced decrease in plasma GH and the increased IGFBP-1 observed in muscle were unaltered by the anti-TNF Ab.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Insulin-like growth factor-binding protein-2 and insulin: studies in children with type 1 diabetes mellitus and maturity-onset diabetes of the young.

The regulation of circulating insulin-like growth factor-binding protein-2 (IGFBP-2) in humans is not well understood. In vitro and animal data have identified the role of insulin in the regulation of IGFBP-2, but such a relationship has not been established clearly in humans. In the present study, serum IGFBP-2 concentrations were assessed by Western ligand blot and immunoblot analysis in children with newly diagnosed and untreated insulin-dependent diabetes mellitus (IDDM) and maturity-onset diabetes of the young before and at various times after insulin therapy. For comparison, IGFBP-2 levels were also determined in lean and obese age-matched controls. Children with IDDM were grouped according to their serum bicarbonate levels at the time of presentation (group A, > 20; group B, 13-20; group C, < 13 milliequivalents/L). Densitometric analysis demonstrated that before insulin therapy, group A patients had serum IGFBP-2 levels comparable to those in lean controls, and no significant change in IGFBP-2 was observed during insulin therapy. However, group B patients had a 2-fold elevation in IGFBP-2 levels before insulin therapy compared to lean controls. In these patients, IGFBP-2 tended to decrease at 1 week, but was not significantly reduced until 1 month after the initiation of insulin therapy. Group C patients had a 2.5-fold elevation of IGFBP-2 before treatment, which normalized by 1 month after treatment. Children with maturity-onset diabetes of the young, who had insulin levels and body mass indexes greater than IDDM patients and lean controls, had significantly lower IGFBP-2 levels than both lean and obese controls. IGFBP-2 levels tended to decrease further during insulin therapy. These results indicate that long standing alterations in serum insulin concentrations beyond the physiological range have significant influence on serum IGFBP-2 levels in children and confirm earlier findings that serum IGFBP-2 levels are not acutely regulated by insulin.

Blood Glucose↗

PubMed1995

Effect of insulin on the insulin-like growth factor system in children with new-onset insulin-dependent diabetes mellitus.

To further characterize the mechanism of impaired growth in children with insulin-dependent diabetes mellitus, we examined the serum components of the insulin-like growth factor (IGF) system in 11 children with new-onset insulin-dependent diabetes mellitus and followed the effect of insulinization on the IGF system longitudinally 1 day, 1 week, and 1 month after starting insulin treatment. Before insulin therapy, serum IGF-I, IGF-II, IGF-binding protein-3 (IGFBP-3), and GH-binding protein (GHBP) levels were significantly decreased, whereas IGFBP-1 and cortisol were significantly increased in diabetic children compared to those in an age-, sex-, and stage of puberty-matched control group. Random serum GH concentrations did not differ significantly. The alterations in the IGF system reversed with insulin therapy in a sequential manner. IGFBP-1 fell rapidly and was comparable to control values within 24 h after insulin treatment. IGF-I rose 1 week after treatment, reaching levels comparable to those in controls and continued to rise through 1 month of treatment. IGF-II, IGFBP-3, and GHBP showed a slower pattern of change, with their levels reaching control values only 1 month after the start of insulin treatment. Improvement in glycemic control, as determined by a change in hemoglobin-A1c, correlated positively with improvement in IGF-I, IGF-II, IGFBP-3, GHBP, and weight gain after 1 month of insulin therapy. These data are consistent with the hypothesis that changes in the IGF system in the insulinopenic state are similar to those during nutritional deprivation and may serve to minimize IGF's anabolic actions. The decreases in IGF-I, IGF-II, and IGFBP-3 may in part be due to a decrease in the GHBP/receptor. However, the observation that an increase in serum IGF-I was observed earlier than an increase in GHBP and without a significant change in serum GH suggests a direct stimulatory effect of insulin on liver IGF-I production or reversal by insulin of some postreceptor defect in GH action independent of GHBP.

Adolescent↗

PubMed1995

Insulin-like growth factor binding protein-3 proteolysis in children with insulin-dependent diabetes mellitus: a possible role for insulin in the regulation of IGFBP-3 protease activity.

Limited proteolysis of serum insulin-like growth factor (IGF) binding protein (IGFBP)-3 has been described in various conditions and may increase the bioavailability of IGFs. The physiological regulators of serum IGFBP-3 protease activity are unknown. To characterize the relationship between insulin and IGFBP-3 protease activity, we have examined serum IGFBP-3 proteolysis in children with untreated insulin-dependent diabetes mellitus (IDDM) and have followed the effect of insulin therapy on serum IGFBP-3 proteolysis at 1 day, 1 week, and 1 month after the initiation of insulin therapy. Ligand blot analysis of sera from untreated children with IDDM showed that intact IGFBP-3 was 50 +/- 9% of the age-matched control pool. After the initiation of insulin treatment, IGFBP-3 did not change significantly at 1 day after treatment but increased dramatically at 1 week (90 +/- 13%) and 1 month after treatment (102 +/- 13%). In contrast, when measured by immunoradiometric assay (which detects both intact and fragments of IGFBP-3), IGFBP-3 levels were 70% of the control pool before insulin therapy and did not increase significantly until 1 month after treatment. Immunoblot analysis demonstrated that intact IGFBP-3 doublet was diminished to 41 +/- 7% of controls, whereas the major IGFBP-3 fragment (30 kDa) was increased in IDDM sera before insulin therapy. After insulin, intact IGFBP-3 increased and the 30-kDa fragment decreased to values comparable to those observed in controls. In vivo IGFBP-3 proteolysis, which implies preassay exposure of serum IGFBP-3 to proteases, was estimated by immunoblot analysis. IGFBP-3 proteolysis was increased before insulin therapy (160 +/- 9%) and decreased to 81 +/- 9% at 1 week and to 71 +/- 11% at 1 month after insulin treatment. Residual serum IGFBP-3 protease activity was estimated by a 125I-IGFBP-3 degradation assay. Serum IGFBP-3 protease activity increased significantly in untreated diabetics, compared with activity in controls (128 +/- 5% vs. 99 +/- 11%). During insulin therapy, serum IGFBP-3 protease activity decreased gradually to 91 +/- 5% of control values at 1 month. Molecular sizes of the IGFBP-3 proteolytic fragments (30 kDa, 24 kDa, and 19 kDa) and inhibition profile of IGFBP-3 protease were similar in IDDM and pregnancy sera, indicating that similar proteases (cation-dependent serine proteases) were active in both conditions. These results suggest an important role of insulin in the regulation of IGFBP-3 protease activity. Increased IGFBP-3 proteolysis in the sera of children with IDDM may serve to counteract the catabolic state induced by insulin deficiency.

Adolescent↗

PubMed1995

Nutritional support of the septic patient.

Nutrition and metabolic support is just one of many weapons at the clinician's disposal in the battle against infection. Much has been learned in the past several decades concerning the host's response to infection and the competition among substrates during health and disease. Despite these advances, we still are remarkably ineffective at preventing the muscle wasting that accompanies sepsis and other chronic catabolic conditions. This likely is the result of our lack of understanding concerning the molecular mechanisms responsible for changes in protein metabolism. It is anticipated that the optimal or preferred mixture of glucose, fat, and protein will be better defined in the future, and that new supplements (e.g., MCTs, amino acids, growth factors, antioxidants) will prove beneficial, so the protein-catabolic response to sepsis can be ameliorated and patient outcome improved. Until that time, nutritional interventions should be initiated early in the septic episode and be assessed and altered frequently. Specific guidelines for nutritional support are presented in Table 3.

Carbohydrate Metabolism↗

PubMed1995

Endogenous opiates do not modulate LPS-induced alterations in carbohydrate metabolism.

This study aimed to determine the contribution of endogenous opiates to the hormonal and glucose metabolic response to lipopolysaccharide (LPS). Rats were infused with naloxone (NAL) (32 micrograms/h) for 2 h prior to the injection of LPS (100 micrograms/100 g body weight) and hemodynamic, hormonal, and metabolic parameters were determined. NAL produced no detectable alterations in any of the parameters assessed. LPS transiently decreases (26%) mean arterial blood pressure (MABP) and increased plasma glucose concentration (100-130%), glucose rate of appearance (50-100%), and glucose rate of disappearance (50-100%). NAL did not alter the LPS-induced drop in mean arterial blood pressure or the glucose response to LPS. LPS reduced plasma insulin (54%), and increased glucagon (270%), corticosterone (180%), and tumor necrosis factor concentrations in plasma (peak 3200-4600 pg/mL at 90 min), with no modification by NAL pretreatment. These results suggest a lack of involvement of endogenous opiate pathways in the glucose metabolic and hormonal responses to LPS.

Animals↗

PubMed1994

Central NMDA enhances hepatic glucose output and non-insulin-mediated glucose uptake by a nonadrenergic mechanism.

One of the hallmarks of the stress response is an increased rate of hepatic glucose production (HGP) which, in conjunction with the presence of insulin resistance, leads to hyperglycemia. Excitatory amino acids (EAA) within the brain mediate some of the cardiovascular responses to stress, but their role in the hormonal and metabolic alterations is poorly defined. The aim of the present study was to determine whether the intracerebroventricular (i.c.v.) injection of either N-methyl-D-aspartate (NMDA) or kainate would produce metabolic alterations comparable to those observed under stress conditions. An i.c.v. cannula and vascular catheters were placed in rats prior to the experiment. After an overnight fast, HGP and peripheral glucose utilization (GU) were assessed in conscious unrestrained rats using [3-3H]glucose. Arterial glucose levels were increased 34% by 15 min after the i.c.v. injection of NMDA (1 microgram) and remained elevated throughout the 3-h protocol. The hyperglycemia resulted from an early increase in HGP (84%) that exceeded a smaller elevation (66%) in GU. The increased glucose flux was associated with sustained insulinopenia (-30%), and elevated levels of corticosterone (40-100%) and epinephrine (75-216%). The hormonal and glucose metabolic responses were quantitatively similar, although of shorter duration, in rats injected with kainate (10 ng). Intravenous adrenergic blockade completely prevented the NMDA-induced hyperglycemia. Adrenergic blockade blunted the early rise in HGP, so that in this group the NMDA-induced increase in HGP was offset by a comparable elevation in GU.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Differential control of glucoregulatory hormone response and glucose metabolism by NMDA and kainate.

The aim of the present study was to elucidate the effect of kainate and N-methyl-D-aspartate (NMDA), two different excitatory amino acid (EAA) agonists, on glucoregulatory hormone production and whole body glucose metabolism. Rates of hepatic glucose production (HGP) and peripheral glucose utilization (GU) were assessed in overnight fasted, catheterized, conscious rats using [3-3H]glucose. At the highest dose of kainate examined (16 mg/kg), glucose levels increased 97% after 1 h; thereafter, glucose fell towards basal values but was still elevated 25% at the end of the 3 h experiment. This hyperglycemia resulted from a rapid increase in HGP that exceeded an increased rate of GU. Both HGP and GU were elevated 86% throughout the final 2 h of the experiment. NMDA induced changes in glucose flux that were qualitatively similar, yet of smaller magnitude and of shorter duration, than those produced by kainate. Kainate-induced increases in glucose metabolism were associated with an early transient hyperinsulinemia followed by a period of insulinopenia, and sustained increases in the plasma concentrations of glucagon, corticosterone, epinephrine and norepinephrine. In contrast, sustained increases in glucagon and catecholamines, as well as the late hypoinsulinemia were not detected in NMDA-treated rats. Adrenergic blockade attenuated the kainate- but not the NMDA-induced increase in glucose metabolism. These results indicate that EAA agonists that bind preferentially to different receptor subtypes produce qualitatively similar changes in glucose metabolism. Whereas the increased HGP in kainate-injected rats was associated with sustained elevations in glucagon, catecholamines and corticosterone, NMDA only transiently elevated circulating glucocorticoid levels, suggesting a different mechanism of action. These data, support the involvement of EAA in various aspects of glucoregulation.

Adrenergic Antagonists↗

PubMed1994

Thiamin deficiency impairs endotoxin-induced increases in hepatic glucose output.

We addressed the role of thiamin, a cofactor for several enzymes involved in glucose metabolism, in the glucose metabolic response to endotoxin. Characterized by hyperglycemia, increased hepatic glucose production exceeding elevated rates of whole-body glucose utilization, this response is mediated by hormones and cytokines and is dependent on the immune and nutritional status of the host. We hypothesized that a thiamin-deficient state would impair the metabolic response to endotoxin. Rats were fed a thiamin-deficient or control diet for 6 wk before in vivo assessment of glucose kinetics. In control rats, Escherichia coli endotoxin increased the rate of glucose appearance (+76%), disappearance (+70%), and metabolic clearance (+50%). Thiamin deficiency resulted in increased plasma glucose (18%) and lactate (3- to 4-fold) as well as in a 30% decrease in insulin and an increase in glucagon (2.6-fold) and corticosterone (3.6-fold). Thiamin deficiency inhibited the endotoxin-induced hyperglycemia and the rise in hepatic glucose production, glucose utilization, and metabolic clearance rate.

Animals↗

PubMed1994

Stress induced by central cholinergic stimulation alters regional distribution of glucose uptake.

The purpose of the present study was to determine whether the intracerebroventricular (ICV) injection of carbachol enhances whole body glucose utilization and, if so, how this cholinergic agonist influences in vivo regional glucose uptake. An ICV cannula and vascular catheters were placed in rats prior to the experiment. Whole body glucose flux was assessed in overnight-fasted conscious unrestrained rats using [3-3H]glucose. Hyperglycemia was elicited 30 min after carbachol (50 nmol), and resulted from an increased rate of hepatic glucose production (135%) that exceeded an elevated rate of peripheral glucose uptake (105%). The glucose metabolic clearance rate was not altered by carbachol. Despite the hyperglycemia, no compensatory increase in plasma insulin levels were observed. Carbachol, however, did increase glucagon (64-164%), catecholamines (3.5- to 15-fold), and corticosterone (62-160%). Complete alpha- and beta-adrenergic blockade prevented the carbachol-induced changes in glucose flux. In vivo glucose uptake (Rg) by individual tissues was determined at the peak of the carbachol-induced hyperglycemia, using [2-14C]deoxyglucose. In addition, a separate group of control rats received an intravenous hormone infusion that increased plasma glucose, glucagon, and catecholamine levels to the same extent seen in carbachol-treated rats. The Rg in liver, spleen, and lung was elevated to a similar extent in carbachol-treated (60, 47, and 48%, respectively) and hormone-infused (60, 53, and 70%, respectively) rats. In contrast, whereas the hormone infusion increased Rg by ileum, skin, and kidney (80, 67, and 110%, respectively), no change was observed in these tissues from rats injected with carbachol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Modulation of endotoxin-induced changes in hemodynamics and glucose metabolism by an N-methyl-D-aspartate receptor antagonist.

Excitatory amino acids (EAAs) are the principal mediators of fast excitatory neurotransmission in the mammalian central nervous system. Previous studies have demonstrated that N-methyl-D-aspartate (NMDA), an EAA agonist, produces a stress response that mimics that observed in animals receiving lipopolysaccharide (LPS). The present investigation determined the role that NMDA receptors play in the hemodynamic, metabolic, and hormonal changes induced by LPS. Chronically catheterized fasted rats received LPS with or without prior injection of MK 801, an NMDA receptor antagonist. LPS produced a classical stress response characterized by hypotension, tachycardia, increased glucose flux, and elevated plasma levels of glucagon, corticosterone, and catecholamines. MK 801 (intravenously) prevented the tachycardia in response to LPS, but did not consistently alter the fall in arterial blood pressure. The NMDA receptor antagonist also blunted the early elevation in plasma epinephrine and norepinephrine levels seen in LPS-injected rats, and this was associated with a smaller increment in plasma glucose and lactate concentrations and glucose flux. To confirm that MK 801 was functioning by antagonizing NMDA receptors within the brain, a second group of rats received an intracerebroventricular injection of MK 801 prior to LPS. The central administration of MK 801 also attenuated the increase in heart rate. These results indicate that central NMDA receptor stimulation mediates the LPS-induced tachycardia and suggest that the partial inhibition of the glucose metabolic response to LPS by MK 801 resulted from the smaller increment in plasma catecholamines.

Animals↗

PubMed1994

Epinephrine-induced changes in hepatic glucose production after ethanol.

Previous studies indicate that catecholamines play an important role in mediating the glucose metabolic response to endotoxin. Because acute ethanol (EtOH) intoxication impairs this response, the present study was initiated to ascertain whether EtOH attenuates the lipopolysaccharide response by decreasing the increment in plasma catecholamines after endotoxin or by decreasing the responsiveness of rats to epinephrine. All studies were performed on chronically catheterized fasted rats infused intravenously with either EtOH or an equal volume of saline. In the first series of experiments, intravenous administration of Escherichia coli endotoxin increased, to the same extent, the plasma concentrations of epinephrine and norepinephrine in both saline- and EtOH-infused rats. In the second study, rats were infused with [3-3H]glucose to assess whole body glucose metabolism and the ability of EtOH to alter the glucose metabolic response to epinephrine. The exogenous infusion of a maximally stimulating dose of epinephrine (1 microgram.min-1.kg-1) into saline-infused control animals for 3 h produced a marked hyperglycemia that resulted from a sustained increase in the rate of hepatic glucose production and a reduction in the metabolic clearance rate for glucose. EtOH infusion did not prevent the epinephrine-induced hyperglycemia but blunted the stimulatory effect of epinephrine on glucose production. The differences in glucose metabolism between saline- and EtOH-treated rats could not be explained by changes in plasma insulin or glucagon concentrations. Furthermore, the ability of EtOH to impair the epinephrine-induced increase in glucose production was still evident in rats treated with 4-methylpyrazole, an inhibitor of alcohol dehydrogenase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Contribution of central and peripheral adrenergic stimulation to IL-1 alpha-mediated glucoregulation.

The present study determined the contribution of central adrenoceptors and the peripheral sympathetic nervous system in regulating the hormonal and glucose metabolic response to intracerebroventricular injection of interleukin (IL)-1 alpha. After an overnight fast, hepatic glucose production (HGP) and peripheral glucose uptake (GU) were assessed in catheterized conscious unrestrained rats using [3-3H]glucose. Intracerebroventricular injection of IL-1 alpha (100 ng) produced a hyperglycemia that resulted from an early increase in HGP (108%) that exceeded a smaller elevation (82%) in GU. Intracerebroventricular injection of the alpha- and beta-adrenergic antagonists phentolamine and propranolol before IL-1 alpha blunted the glucose metabolic response 30-50%. This attenuated response was associated with normalization of the IL-1 alpha-induced hyperglucagonemia and hyperinsulinemia and a 50-60% reduction in the incremental increase in plasma catecholamines. In contrast to central administration, systemic infusion of adrenergic blockers completely prevented the IL-1 alpha-induced increases in plasma glucose, as well as HGP and GU. In these rats, the elevated plasma levels of insulin, glucagon, and corticosterone produced by intracerebroventricular injection of IL-1 alpha were still present. The results indicate that 1) the enhanced whole body glucose metabolism seen after central administration of IL-1 alpha is mediated by increased sympathoadrenal activity and 2) the IL-1 alpha-induced increase in pancreatic insulin and glucagon secretion as well as part of the peripheral catecholamine release is mediated by central adrenoreceptors.

Adrenalectomy↗

PubMed1994

Differential tissue regulation of insulin-like growth factor-I content and binding proteins after endotoxin.

The purpose of the present study was to investigate the regulation of plasma and tissue levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-1, -2, and -3 (IGFBP-1, -2, and -3) in rats injected with Escherichia coli lipopolysaccharide (LPS), a component of the outer cell wall of gram-negative bacteria. When injected iv into conscious overnight fasted rats, plasma IGF-I levels were initially decreased within 1 h, maximally depressed at 4 h, and still only 35-45% of control values at 24 h. GH levels were reduced as early as 30 min after LPS, averaged 80-90% of control values between 1-4 h, but had returned to basal levels by 24 h. The magnitude and duration of these changes were similar regardless of whether 100 or 10 micrograms/100 g BW (LD20 and LD0, respectively) LPS were injected. Plasma levels of IGFBP-1 and a 28K mol wt BP (BP-28K) were elevated 2- to 3-fold 4 h after LPS treatment, whereas IGFBP-3 and -2 levels were unchanged. The elevation in plasma IGFBP-1 and IGFBP-28K was observed as early as 1 h and was sustained for up to 24 h after LPS treatment. IGF-I levels were decreased 30-50% in liver, pituitary, and skeletal muscle, unchanged in brain, and elevated 5-fold in kidney in response to LPS. Of the tissues sampled, IGFBP-3 and -2 were selectively elevated in liver after LPS treatment. IGFBP-1 was increased in liver, muscle, and kidney in response to LPS. The level of the 28,000 mol wt BP was increased in liver (83%) and not changed in muscle or brain. These data indicate that LPS produces both rapid and sustained alterations in circulating levels of GH, IGF-I, and IGFBPs. Furthermore, there were marked tissue-specific changes in levels of IGF-I and IGFBPs. LPS-induced changes in plasma and tissue IGFBP-3 were not regulated by changes in GH, and changes in insulin could not explain the alterations in IGFBP-1 and -2. These results suggest that after the injection of LPS, changes in IGF-I and IGFBP levels are regulated by a mechanism(s) different from those previously described.

Animals↗

PubMed1994

Phosphorylation of insulin-like growth factor binding protein-1 in patients with insulin-dependent diabetes mellitus and severe trauma.

We have determined the level of phosphorylated insulin-like growth factor binding protein-1 (pIGFBP-1) in serum during two catabolic states: diabetes mellitus and trauma. Human sera were incubated with [125I]IGF-I for 2 h followed by non-denaturing PAGE. [125I]IGF-I/IGFBP-1 complexes from serum co-migrated with a pure p4IGFBP-1 standard. Complex formation was specifically inhibited by unlabeled IGF-I. The migration of IGF-I/pIGFBP-1 complexes was retarded by IGFBP-1 antibodies, but not by antibodies against IGFBP-2 or IGFBP-3. Sera from three severely traumatized patients had up to 12-fold more pIGFBP-1 than sera from age-matched controls. The level of pIGFBP-1 was reduced in all three patients upon hospital discharge. Sera from three patients with insulin dependent diabetes mellitus (IDDM) and severe ketoacidosis (DKA) had more pIGFBP-1 than controls. Administration of insulin to DKA patients lowered the level of pIGFBP-1. The present study shows that IGFBP-1 exists as a free, high affinity, phosphorylated form in vivo during two catabolic states.

Accidents, Traffic↗

PubMed1993

Role of IL-1 alpha in central nervous system immunomodulation of glucoregulation.

Hyperglycemia is a hallmark of the stress response, and has been largely attributed to elevated plasma levels of catabolic hormones. Recently, various cytokines have been shown to be endogenously produced within the brain and may represent an important component of the central regulation of this metabolic response. Therefore, the aim of the present study was to determine whether the intracerebroventricular (i.c.v.) injection of one such peptide, interleukin (IL)-1, can produce hormonal and metabolic alterations comparable to those observed under stress conditions. An i.c.v. cannula and vascular catheters were placed in rats prior to the experiment. Whole body glucose flux was assessed in overnight fasted conscious unrestrained rats using [3-3H]glucose. A mild hyperglycemia was elicited 20 min after the i.c.v. injection of IL-1 alpha (human recombinant, 100 ng) that was not detected in control rats. Glucose levels gradually increased and were 26% higher than control values during the last hour of the 3 h experimental period. The hyperglycemia resulted from a 44% increase in the rate of hepatic glucose output (HGO), which preceded a proportional rise in peripheral glucose utilization. No increase in metabolic clearance rate was observed, suggesting that the increased glucose uptake was the result of mass action. The increased glucose flux was associated with a transient hyperinsulinemia (+95%), and sustained elevations in the arterial concentrations of glucagon (56%) and corticosterone (175%). In contrast, glucose flux was not altered by intravenous administration of the same dose of IL-1 alpha, or i.c.v. injection of IL-1 beta, or heat-inactivated IL-1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗

PubMed1993

Effect of high-dose endotoxin on glucose production and utilization.

The purpose of the present study was to determine how a high dose of endotoxin (lipopolysaccharide [LPS]), which produces hypoglycemia, alters in vivo glucose uptake by individual tissues. Catheterized conscious fasted rats were injected intravenously (i.v.) with either saline, LPS (1 mg/100 g body weight [BW], lethal dose [LD] 100), or 3-mercaptopicolinic acid (3-MP), an inhibitor of gluconeogenesis. In the latter two groups, blood glucose levels were clamped at either 6 mmol/L (euglycemia) or 3 mmol/L (hypoglycemia). In the first series of experiments, whole-body glucose flux was determined using [3-3H]glucose, and in the second study in vivo glucose uptake (Rg) by individual tissues was estimated by the tracer [U-14C]-2-deoxyglucose technique. The relative contribution of hypoglycemia per se to the LPS effect was determined by comparing the values from LPS- versus 3-MP-treated animals. There was no difference in the rate of whole-body glucose utilization (Rd) between saline-infused control rats and LPS-treated animals that were hypoglycemic. However, Rg by diaphragm, spleen, liver, and lung was increased in hypoglycemic LPS-treated rats. The increased Rg in these tissues was not observed in 3-MP-treated rats with a comparable hypoglycemia. Only the gastrocnemius muscle showed a reduction in Rg under hypoglycemic conditions, and the decrease was similar in both LPS- and 3-MP-treated animals. When sufficient glucose was infused into LPS-injected rats to maintain euglycemia, whole-body glucose Rd was increased compared with that in hypoglycemic LPS-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Ethanol alters the metabolic response of isolated perfused rat liver to a phagocytic stimulus.

Intercellular communication in the liver is a potentially important mechanism for the regulation of hepatic metabolism. Since alcohol (ethanol, ETOH) can interact with both parenchymal and nonparenchymal cells, the present study was performed to assess the possible effects of ETOH on the nonparenchymal cell-to-hepatocyte signal traffic by studying the glycogenolytic and glycolytic response of the perfused rat liver to colloidal carbon, a phagocytic stimulus for Kupffer and sinusoidal endothelial cells. Livers from fed rats were perfused with hemoglobin-free Krebs Ringer bicarbonate buffer containing ETOH (20 mM) or acetaldehyde (1 mM). Twenty minutes after initiating the infusion of ETOH or acetaldehyde, colloidal carbon was infused and the rate of carbon uptake, glucose, lactate and pyruvate output, and oxygen consumption were determined. In control livers, carbon stimulated the output of glucose (60%), lactate (25%), and pyruvate (53%), without affecting the lactate/pyruvate ratio. ETOH, but not acetaldehyde, enhanced the carbon effect on glucose output (38%), but suppressed the increased lactate and pyruvate output (48% and 91% respectively) resulting in a dramatic 10-fold increase in the lactate/pyruvate ratio. By using inhibitors of cyclooxygenase or alcohol dehydrogenase (indomethacin and 4-methylpyrazole, respectively) in the presence of carbon and/or ETOH, we determined that: (1) following carbon stimulation prostaglandins are the likely mediators secreted by nonparenchymal cells that increase carbohydrate output; and (2) the ETOH-induced enhancement of carbon-stimulated glycogenolysis is also mediated by prostaglandins and is not dependent on the oxidative metabolism of ETOH.

Acetaldehyde↗