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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To assess the mechanism of insulin resistance in sepsis, we investigated insulin receptor binding and glucose uptake in isolated rat epididymal adipocytes. Male Sprague-Dawley (SD) rats weighing 200-220 g were submitted to cecal ligation under chloral hydrate anesthesia, followed by double punctures with 18-G needle into the ligated portion to produce peritonitis. Age-matched SD rats without operation were used as the controls. After starvation for 16 h, blood samples were taken from the inferior vena cava for bacterial culture and assayed for plasma glucose and IRI levels, and then adipocytes were isolated from the dissected epididymal fat tissues. Plasma levels of both glucose and IRI in septic rats were higher than those in the controls. The [125I]-insulin binding rate of the adipocytes in septic rats was similar to that of the controls. However, [3H]-2-deoxy-D-glucose uptake by adipocytes was markedly decreased in the septic group (approximately 45% of the control group at the plateau). In conclusion, this study suggests that insulin resistance in the septic state results, at least partly, from impairment in the post-binding level of the insulin receptor.
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PMID:Sepsis inhibits insulin-stimulated glucose transport in isolated rat adipocytes. 157 21

This study was undertaken to investigate possible factors contributing to altered glucose homeostasis in a patient with a history of total pancreatectomy and intermittent sepsis. Blood was drawn when the patient had received no exogenous insulin for the previous 24 hours, had a serum insulin level of 0.3 microU/mL, and gave an inappropriately low glucose response to large amounts of infused glucose. The IgG fraction prepared from this serum stimulated glucose oxidation in vitro and inhibited binding of insulin labeled with I 125 to isolated rat adipocytes, thus fulfilling some of the criteria for autoantibodies to the insulin receptor. The results are compatible with the hypothesis that insulin-receptor autoantibodies may have developed as a result of perturbation of this patient's immune status promoted by intermittent septic episodes and that, preterminally, as these antibodies converted in vivo to their in vitro-type behavior, they may have been partially responsible for the severe disturbances of glucose homeostasis.
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PMID:Insulin receptor autoantibodies in sepsis. 638 97

Carbohydrate dyshomeostasis is a characteristic feature of sepsis. Sepsis elevates glucose uptake and cellular lactate levels in muscle. The mechanisms responsible for these alterations are unknown. We examined the effects of a chronic, intra-abdominal septic abscess upon glucose uptake, the expression of the insulin receptor, glucose transporter proteins (Glut-1 and Glut-4) and mRNA, and the content of glycolytic intermediates in muscle from the hindlimb. Sepsis caused a 67% increase in glucose uptake compared with control. A differential expression of the Glut-1 and Glut-4 transporter proteins in skeletal muscle of septic rats was observed. Sepsis increased the expression of Glut-1 protein 1.7-fold. The increased Glut-1 protein correlated with a similar increase in the relative abundance of Glut-1 mRNA. In contrast, sepsis did not alter the amount of Glut-4 protein and mRNA or insulin receptor protein. The tissue content of glucose-6-phosphate was increased approximately twofold compared with control. The increase in the glucose-6-phosphate content was not associated with increased glycogen deposition in skeletal muscle of septic animals. Analysis of the glycolytic intermediates showed that only the lactate content of muscles from septic rats was significantly elevated in sepsis. The results are consistent with the hypothesis that sepsis enhances glucose uptake secondary to increased Glut-1 expression. Furthermore, once transported, glucose may be preferentially metabolized to lactate.
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PMID:Mechanisms regulating skeletal muscle glucose metabolism in sepsis. 765 63

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

Sepsis and endotoxin (LPS) have been demonstrated to impair insulin-mediated glucose uptake in skeletal muscle. However, the intracellular mechanism responsible for this defect is not fully defined. The purpose of the present study was to determine whether specific elements of the insulin receptor (IR) signaling pathway in skeletal muscle are altered by LPS. In vivo injection of Escherichia coli LPS resulted in a 44% reduction in whole body glucose disposal under euglycemic hyperinsulinemic conditions, which was largely accounted for by a decreased rate of glycogen synthesis. Scatchard analysis indicated that the number and affinity of the high-affinity insulin binding sites in muscle were similar between control and LPS-treated rats. Western blot analysis indicated that under basal conditions, the levels of total and phosphorylated IR, insulin receptor substrate (IRS)-1, and mitogen-activated protein (MAP) kinase were not significantly different between control and endotoxic rats. In control animals, muscle obtained 2 min after intravenous injection of a maximally stimulating dose of insulin demonstrated a marked increase in the amount of phosphorylated IR (approximately 5-fold), IRS-1 (approximately 10-fold), and MAP kinase (approximately 10-fold). Insulin-stimulated phosphorylation of IR, IRS-1, and MAP kinase was markedly diminished (approximately 75%, 90%, and 78%, respectively) in LPS-treated rats. However, there was no concomitant reduction in the total abundance of these proteins under hyperinsulinemic conditions. These data demonstrate that LPS alters multiple steps in the insulin signal transduction pathway, but not insulin binding, in skeletal muscle that may mediate the observed impairment in glucose uptake.
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PMID:Endotoxin-induced alterations in insulin-stimulated phosphorylation of insulin receptor, IRS-1, and MAP kinase in skeletal muscle. 888 80

Sepsis is known to induce insulin resistance, but the exact molecular mechanism involved is unknown. In the present study we have examined the levels and phosphorylation state of the insulin receptor and of insulin receptor substrate 1 (IRS-1), as well as the association between IRS-1 and phosphatidylinositol 3-kinase (PI 3-kinase) in the liver and muscle of septic rats by immunoprecipitation and immunoblotting with anti-insulin receptor, anti-IRS-1, anti-PI 3-kinase and anti-phosphotyrosine antibodies. There were no changes in the insulin receptor concentration and phosphorylation levels in the liver and muscle of septic rats. IRS-1 protein levels were decreased by 40+/-3% (p < 0.01) in muscle but not in liver of septic rats. In samples previously immunoprecipitated with anti-IRS-1 antibody and blotted with antiphosphotyrosine antibody, the insulin-stimulated IRS-1 phosphorylation levels in the muscle of septic rats decreased by 38+/-5% (p < 0.01) and insulin-stimulated IRS-1 association with PI 3-kinase decreased by 44+/-7% in muscle (p < 0.01) but no changes were seen in liver. These data suggest that there is a tissue-specific regulation of early steps of insulin signal transduction in septic rats, and the changes observed in muscle may have a role in the insulin resistance of these animals.
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PMID:Tissue-specific regulation of early steps in insulin action in septic rats. 1166 54

Hemorrhage, sepsis, burn injury, surgical trauma and critical illness all induce insulin resistance. Recently we found that trauma and hemorrhage acutely induced hepatic insulin resistance in the rat. However, the mechanisms of this hemorrhage-induced acute hepatic insulin resistance are unknown. Here we report on the mechanisms of this hepatic insulin resistance. Protein levels and phosphorylation of the insulin receptor and insulin receptor substrate-1/2 (IRS-1/2) were measured, as was the association between IRS-1/2 and phosphatidylinositol 3-kinase (PI3K). Also examined were the hepatic expression of TNFalpha and TNFalpha-induced serine phosphorylation of IRS-1. Insulin receptor and IRS-1/2 protein levels and insulin-induced tyrosine phosphorylation of the insulin receptor were unaltered. In contrast, insulin-induced tyrosine phosphorylation of IRS-1/2 and association between IRS-1/2 and PI3K were dramatically reduced after hemorrhage. Hepatic levels of TNFalpha mRNA and protein were increased as was phosphorylation of IRS-1 serine 307 after hemorrhage. Our data provide the first evidence that compromised IRS-1/2 tyrosine phosphorylation and their association with PI3K contribute to hemorrhage-induced acute hepatic insulin resistance. Increased local TNFalpha may play a role in inducing this hepatic insulin resistance after trauma and hemorrhage.
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PMID:Mechanisms of hemorrhage-induced hepatic insulin resistance: role of tumor necrosis factor-alpha. 1529 37

Hyperglycemia in critical illness is a common complication and a strong independent risk factor for morbidity and death. Intensive insulin therapy decreases this risk by up to 50%. It is unclear to what extent this benefit is due to reversal of glucotoxicity or to a direct effect of insulin, because antiinflammatory effects of insulin have already been described, but the underlying mechanisms are still poorly understood. The insulin receptor is expressed on resting neutrophils, monocytes, and B cells, but is not detectable on T cells. However, significant up-regulation of insulin receptor expression is observed on activated T cells, which suggests an important role during T cell activation. Exogenous insulin in vitro induced a shift in T cell differentiation toward a T helper type 2 (Th2)-type response, decreasing the T helper type 1 to Th2 ratio by 36%. This result correlated with a corresponding change in cytokine secretion, with the interferon-gamma to IL-4 ratio being decreased by 33%. These changes were associated with increased Th2-promoting ERK phosphorylation in the presence of insulin. Thus, we demonstrate for the first time that insulin treatment influences T cell differentiation promoting a shift toward a Th2-type response. This effect of insulin in changing T cell polarization may contribute to its antiinflammatory role not only in sepsis, but also in chronic inflammation associated with obesity and type 2 diabetes.
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PMID:Potential antiinflammatory role of insulin via the preferential polarization of effector T cells toward a T helper 2 phenotype. 1700 95

Pre-B-cell colony-enhancing factor (PBEF) was recently found in high levels in visceral fat, and was therefore renamed visfatin. This new adipocytokine exerts insulin-mimetic effects in mice and in cultured cells by binding to and activating the insulin receptor. Despite some recent studies on this topic, the proposed role of visfatin in metabolism remains largely unknown. Initially, PBEF/visfatin was discovered as a cytokine for the differentiation of B-cells. Pre-B-cell colony-enhancing factor was also shown to inhibit apoptosis of neutrophils in sepsis and was discussed as a novel biomarker for acute lung injury (ALI). Although PBEF is missing a signal sequence, its secretion and function as a molecule involved in the regulation of inflammatory processes was reported in several studies. Investigations of PBEF/visfatin in gestational membranes suggest a function in the physiologic and pathologic pathways leading to labor. Furthermore, it was found upregulated in colorectal cancer and was brought into connection with the regulation of the cell cycle. Intra-cellular, PBEF/visfatin acts as a cytosolic enzyme involved in nicotinamide adenine dinucleotide (NAD) synthesis. This activity was shown to be important for vascular smooth muscle cell (SMC) maturation, indicating a possible involvement in vascular pathology. The important physiologic role of PBEF/visfatin is also underlined by its evolutionary highly conserved gene in different species. This review summarizes the current knowledge of the various functions of PBEF/visfatin towards involvements in pathophysiology of several diseases.
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PMID:Visfatin/pre-B-cell colony-enhancing factor: a protein with various suggested functions. 1739 4

Inflammation provokes significant abnormalities in host metabolism that result from the systemic release of cytokines. An early response of the host is hyperglycemia and resistance to the action of insulin, which progresses over time to increased glucose uptake in peripheral tissue. Although the cytokine TNF-alpha has been shown to exert certain catabolic effects, recent studies suggest that the metabolic actions of TNF-alpha occur by the downstream regulation of additional mediators, such as macrophage migration inhibitory factor (MIF). We investigated the glycemic responses of endotoxemic mice genetically deficient in MIF (MIF(-/-)). In contrast to wild-type mice, MIF(-/-) mice exhibit normal blood glucose and lactate responses following the administration of endotoxin, or TNF-alpha. MIF(-/-) mice also show markedly increased glucose uptake into white adipose tissue in vivo in the endotoxemic state. Treatment of adipocytes with MIF, or anti-MIF mAb, modulates insulin-mediated glucose transport and insulin receptor signal transduction; these effects include the phosphorylation of insulin receptor substrate-1, its association with the p85 regulatory subunit of PI3K, and the downstream phosphorylation of Akt. Genetic MIF deficiency also promotes adipogenesis, which is in accord with a downstream role for MIF in the action of TNF-alpha. These studies support an important role for MIF in host glucose metabolism during sepsis.
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PMID:The proinflammatory cytokine macrophage migration inhibitory factor regulates glucose metabolism during systemic inflammation. 1791 26


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