Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sepsis, surgery and critical illness are associated with an increased catabolic rate, which if prolonged delays recovery and increases morbidity and mortality. There is evidence that changes in the GH/IGF-I axis are permissive to protein catabolism. Critically ill, septic patients have high basal levels of GH, low levels of IGF-I and its carrier binding protein IGFBP-3, high levels of an inhibitory binding protein, IGFBP-I, and increased serum protease activity which reduces the affinity of IGFBP-3 for IGF-I. Overall there is a reduction in the indirect IGF-I-mediated anabolic actions of GH and an increase in the direct catabolic actions of GH. These physiological changes may be adaptive when a sick patient is fasting; however, the availability of modern intensive care means that these changes are no longer an advantage. GH and IGF-I, in pharmacological doses, promote positive nitrogen balance, in both animal models and man. Preliminary studies with IGF-I in postsurgical patients suggest that it may provide a practical therapy. Future studies need to focus on outcome measures in relation to the use of GH and IGF-I as anabolic therapies.
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PMID:Acquired growth hormone resistance in patients with hypercatabolism. 750 79

Endotoxemia and sepsis cause severe shifts in metabolism towards catabolic events. The objective of the research was to determine whether endotoxin administration changes plasma concentrations of IGF-I and IGF-binding protein-2 (IGFBP-2) in Angus x Hereford steers. In Experiment 1, mean feed intake in endotoxin-treated steers (n = 6) decreased 60% within the first 24 h after endotoxin and averaged, for the duration of the 96 h test period, an intake 35.5% lower than the mean ad libitum intake recorded prior to endotoxin. Plasma concentrations of IGF-I averaged 182 ng/ml in steers before endotoxin (E. coli, 055:B5, 0.2 micrograms/kg, i.v. bolus) and decreased an average of 24.2% at 24 to 96 h after endotoxin. In Experiment 2, a paired feeding strategy was used to determine whether the reduced feed intake was a significant factor in changing plasma concentrations of IGF-I and IGFBP-2 after endotoxin challenge. Steers were divided into endotoxin (0.2 micrograms/kg, i.v., n = 6) or control (saline, i.v., n = 3) treatments. Each of three endotoxin-treated steers was paired to a specific control. In this fashion, the adjusted feed intake of each endotoxin-treated steer was fed to it's paired control every 24 h through 96 h after endotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endotoxin administration decreases plasma insulin-like growth factor (IGF)-I and IGF-binding protein-2 in Angus x Hereford steers independent of changes in nutritional intake. 753 26

Hypoglycaemia is a relatively common cause for referral of patients to the accident and emergency departments of hospitals but most of it is iatrogenic. Occasionally, however, hypoglycaemia is due to any one of up to a hundred different disorders. In some, hypoglycaemia is the cause of intermittent neuroglycopenic symptoms that lead to their referral to medical outpatients for investigation. Only the most important are discussed here. Hyperinsulinism due to abnormal beta-cell function is an uncommon but important cause of spontaneous hypoglycaemia. The diagnosis is suspected from the history of episodes of altered consciousness confirmed by demonstrating raised plasma insulin, C-peptide and proinsulin levels in peripheral blood in the presence of hypoglycaemia. Differentiation of the various causes of endogenous hyperinsulinism before surgery is difficult if not impossible and the low predictive value of most of the localizing techniques that are available makes them an additional and unnecessary cost, producing little clinical benefit. Hypoglycaemia caused by non-islet cell tumours (NICTH) is seemingly rarer than hyperinsulinism from insulinoma and tends to occur in older patients. The clinical features are similar to those of hyperinsulinism but laboratory investigation reveals appropriately depressed plasma insulin, C-peptide and proinsulin levels in the presence of hypoglycaemia. The plasma IGF-II:IGF-I ratio is characteristically high and the concentration of the E-domain of proIGF-II is raised. Autoimmune hypoglycaemia is more common in some countries than others and is most often due to autoantibodies to insulin (AIS). It may also be caused by autoantibodies to the insulin receptor and possibly to autoantibodies that are stimulatory to pancreatic beta-cells. Contrary to popular belief, idiopathic reactive hypoglycaemia is rare and only one of the possible causes of the postprandial syndrome. It is characterized by a low blood glucose concentration in blood collected during a spontaneous symptomatic episode but not at other times. Its cause is unknown. Other causes of hypoglycaemia include endocrinopathies of various kinds; sepsis including malaria; congestive cardiac failure; hepatic and renal insufficiencies; diverse inborn errors of metabolism; and exogenous toxins, of which alcohol is probably the commonest.
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PMID:Hypoglycaemia in the adult. 837 12

Normal human ageing is associated with changes in body composition which include a decrease in muscle mass and strength, bone mass loss and increase in adipose mass. A physiological decrease in growth hormone (GH) and IGF-I secretion accompanies these changes. Many of the physiological changes that accompany normal human ageing are very similar to those found in GH deficient patients. Nevertheless, responsiveness to exogenous administered GH persists with advancing age. GH administration to elderly individuals has produced an decrease in fat mass and an increase in lean body mass, being this finding consistent with the hypothesis that GH deficiency could be a contributing cause to senescent changes in some elderly individuals. GH treatment has also been used with encouraging results in adult subjects with isolated or combined GH deficiency. On the other hand, several clinical studies have recently shown the efficiently of GH treatment on diverse pathological processes such as severe catabolic states (surgery, sepsis, trauma, buns), osteoporosis, diabetic ulcers and obesity. The most frequent side effects are sodium and water retention, impairment in glucose tolerance and carpal tunnel syndrome, although in general the treatment has been well tolerated. The clear definition of the therapeutical applications of GH in the adult warrants further clinical investigation.
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PMID:[New physiological and pharmacological aspects of the growth hormone (II). Therapeutic applications in adults]. 849 41

The purpose of the present investigation was to determine whether endogenously produced interleukin (IL)-1 mediates the changes in insulin-like growth factor (IGF) I and IGF binding proteins (IGFBP) induced by chronic abdominal sepsis in rats and to correlate the changes in the IGF system with the alternations in protein synthesis. A constant infusion of IL-1 receptor antagonist (IL-1ra) was begun after the induction of sepsis and was continued for 5 days. Sepsis decreased IGF-I levels in the blood, liver, and gastrocnemius muscle, increased the content in the kidney, and did not alter IGF-I levels in heart, jejunum, and spleen. IL-1ra attenuated the sepsis-induced decrease in plasma IGF-I and completely prevented the changes in IGF-I observed in liver, kidney, and the gastrocnemius. IGFBP-1 was increased in the blood, liver, and muscle of septic rats. IL-1ra prevented this increase in IGFBP-1 in blood and liver but not in muscle. The rate of in vivo protein synthesis was decreased in the gastrocnemius and kidney and unaltered in the heart, liver, jejunum, and spleen. A strong linear correlation existed between levels of IGF-I and the rate of protein synthesis determined simultaneously in the gastrocnemius. These results provide evidence for the role of IL-1 as an endogenous mediator of the sepsis-induced changes in IGF-I and IGFBP-1 and suggest that the accompanying changes in muscle protein synthesis are partially mediated via changes in IGF-I.
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PMID:IL-1 receptor antagonist attenuates sepsis-induced alterations in the IGF system and protein synthesis. 863 89

The purpose of the present study was to determine whether insulin-like growth factor (IGF)-I would increase whole body and muscle glucose uptake in septic rats that are known to be insulin resistant. Animals were infused with either saline, low-dose IGF-I, high-dose IGF-I, or a maximally stimulating dose of insulin for 2 h, and the glucose metabolic response was assessed using a euglycemic clamp in combination with [3-3H]glucose. Under basal conditions, sepsis increased the rates of whole body glucose uptake, glycolysis, and hepatic glucose production. Under euglycemic hyperinsulinemic conditions, septic rats demonstrated a marked insulin resistance as evidenced by the impaired rate of insulin-stimulated glucose uptake and muscle glycogen synthesis. In contrast, the infusion of either dose of IGF-I increased total glucose uptake, glycolysis, and glycogen synthesis in both control and septic rats to the same extent. Furthermore, there was no difference in the IGF-I stimulation of glucose uptake (as determined by [14C]-2-deoxyglucose) in the gastrocnemius, soleus, and heart between control and septic rats. These results indicate that the glucose metabolic response to IGF-I is intact in insulin-resistant septic rats.
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PMID:IGF-I stimulates muscle glucose uptake during sepsis. 882 Oct 99

Acquired growth hormone (GH) resistance is an increasingly recognized feature of catabolic states. Low circulating levels of the insulin-like growth factors (IGF-I and II) have been shown to be associated with changes in the IGF binding proteins (IGFBP-1 to -6) that may significantly impact on IGF bioactivity. IGFBP-3 binds IGF and a third glycoprotein, the acid labile subunit (ALS), to form a stable 150 kDa ternary complex that serves as an intravascular store for IGFs and prolongs IGF half-life. IGFBP-1 is present at much lower concentration in serum but levels fluctuate acutely, suggesting regulation of IGF bioactivity in response to short-term metabolic changes. The function of IGFBP-2 remains unclear, but studies suggest that this protein may act as an alternative carrier for IGF when IGFBP-3 levels are low. Multiple regulatory influences on circulating IGFBP levels have been identified but three appear prominent. Nutritional influences, in particular substrate availability, appear to be a central regulatory influence on IGFBP levels in catabolic states. Low substrate availability increases IGFBP-1 levels acutely and decreases IGFBP-3 and IGFBP-2 levels in the intermediate term, with each of these changes likely to further limit IGF bioactivity. End organ failure, particularly of liver and kidney significantly affects production and clearance rates of the circulating IGFBPs and may contribute to the catabolism frequently seen in these states. Severe protein catabolism often accompanies malignancy and chronic sepsis and it is likely that additional ill-defined factors influence IGF bioactivity in this setting. Recent studies have identified post-translational modifications to the IGFBPs such as proteolysis and phosphorylation, which appear to further impact on IGF bioactivity. The relative contributions of these changes to the overall impairment of IGF bioactivity in GH-resistant states remains to be fully elucidated.
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PMID:Insulin-like growth factor bioactivity and its modification in growth hormone resistant states. 885 49

Malnutrition is a critical predictor of mortality and morbidity in children with biliary atresia who undergo orthotopic liver transplantation. Growth hormone (GH) enhances nitrogen retention in patients with chronic obstructive lung disease, sepsis, and in fasted adult volunteers. The goal of this study was to assess the acute response to recombinant human GH (rhGH) treatment in children with biliary atresia to determine whether GH therapy was likely to improve pretransplant nutritional status. Five children, aged 10-32 months, with biliary atresia and persistent cholestasis despite surgical attempts to reestablish bile flow, were studied. All five children had portal hypertension, conjugated hyperbilirubinemia, and decreased serum albumin concentrations. Length, weight, and growth velocity were decreased in all five children. Despite adequate energy and protein intake, fat stores were depleted in all five subjects, and somatic protein stores were diminished in all except one child. Baseline serum concentrations of insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) were low (8.4 +/- 2 ng/ml and 0.2 +/- 0.1 mg/l respectively). In the four children who completed the study, serum IGF-I and IGFBP-3 levels did not change after treatment with rhGH (0.1 mg/kg/day) for 4 days. Our findings indicate that children with biliary atresia awaiting liver transplantation are insensitive to GH and that treatment with GH is unlikely to promote anabolism. A rationale exists for examining the effect of treatment with IGF-I, which mediates the anabolic effects of GH.
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PMID:Growth hormone insensitivity in children with biliary atresia. 885 79

Sepsis is characterized by a severe shift in metabolism, characterized by low IGF-I levels. We have studied the influence of caecal ligation and puncture (CLP) on the levels of circulating IGF-I and hepatic IGF-I and IGF-binding protein (IGFBP)-1, -2 and -3 mRNA in adult male Wistar rats (n = 12) and compared it with sham-operated rats (n = 6). In order to exclude anorexia-induced changes we also studied animals pair-fed to both groups. IGF-I levels were measured by RIA. Steady-state hepatic IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3 mRNA levels were measured by Northern blot analysis using specific rat cDNA probes. Food intake averaged 13.0 +/- 2.0 g/day in the sham-operated rats fed ad libitum during the study period, with a sharp decline in food intake in the CLP animals (2.3 +/- 1.3 g/day). After CLP, there was a significant reduction in circulating IGF-I levels (467.2 +/- 50.9 micrograms/l) compared with sham-operated animals (924.0 +/- 75.3 micrograms/l; P = 0.04) or those pair-fed to the CLP rats (612.5 +/- 52.9 micrograms/l; P = 0.04). Total hepatic IGF-I mRNA levels were significantly reduced (2.57 +/- 0.05 densitometric units (DU) after CLP compared with the sham-operated group (2.71 +/- 0.04); P = 0.04), or their pair-fed controls (2.75 +/- 0.08 DU; P < 0.05). Hepatic IGFBP-3 mRNA levels were lower after CLP (0.37 +/- 0.04 DU) than in the sham-operated animals (0.66 +/- 0.09 DU; P = 0.04) or their pair-fed controls (0.61 +/- 0.05 DU; P = 0.04). On the other hand, hepatic IGFBP-2 mRNA levels were increased after CLP (0.91 +/- 0.11 DU) compared with sham-operated animals (0.28 +/- 0.06 DU; P = 0.01) or with their pair-fed controls (0.22 +/- 0.02; P = 0.01), as were hepatic IGFBP-1 mRNA levels (CLP animals 0.95 +/- 0.11 DU; sham-operated 0.30 +/- 0.04 DU, P = 0.01; pair-fed 0.30 +/- 0.02 DU, P = 0.01). No significant difference between sham-operated animals and their pair-fed controls was observed in circulating IGF-I levels (888.0 +/- 109.3 micrograms/l; P = not significant (N.S.)), hepatic mRNA levels for IGF-I (2.72 +/- 0.06 DU; P = N.S), IGFBP-3 (0.71 +/- 0.07 DU; P = N.S.), IGFBP-2 (0.25 +/- 0.07 DU; P = N.S.) or IGFBP-1 (0.27 +/- 0.06 DU; P = N.S.). In summary, after CLP there was a reduction in both circulating and hepatic IGF-I mRNA levels associated with a specific and differential regulation of hepatic IGFBP-1, -2 and -3 mRNA levels. Although we cannot eliminate a possible effect of surgical stress combined with malnutrition, our results suggest that these changes are a specific effect of sepsis rather than simply a result of surgical stress or poor nutrition alone.
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PMID:Reduction in circulating IGF-I and hepatic IGF-I mRNA levels after caecal ligation and puncture are associated with differential regulation of hepatic IGF-binding protein-1, -2 and -3 mRNA levels. 895 89

Hyperlactatemia is a frequent complication of sepsis. We investigated the effect of pentoxifylline on plasma lactate concentrations and lactate release by epitrochlearis incubated in vitro following intravenous injection of Escherichia coli. Plasma lactate concentrations were elevated on day 2 postinfection and remained elevated for at least another 4 days. Lactate production by incubated epitrochlearis was not increased in septic rats on day 2 postinfection, and lactate production from muscles incubated with insulin (2 nM) or insulin-like growth factor-I, (10 nM) was similar in control and septic rats. On day 6 postinfection, lactate production was augmented 1.8-fold in muscles from septic rats and both insulin and IGF-I caused an exaggerated stimulation of lactate production compared with control. Pentoxifylline decreased plasma TNF concentrations 100-fold following injection of bacteria and prevented the sepsis-induced hyperlactatemia and increase in lactate production by incubated muscles in presence or absence of insulin or IGF-I. Thus, pentoxifylline prevented the sepsis-induced abnormalities in skeletal muscle lactate production and plasma lactate concentrations.
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PMID:Modulation of skeletal muscle lactate metabolism following bacteremia by insulin or insulin-like growth factor-I: effects of pentoxifylline. 918 44


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