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)

TNF-alpha is a mediator of insulin resistance in sepsis, obesity, and type 2 diabetes and is known to impair insulin signaling in adipocytes. Akt (protein kinase B) is a crucial signaling mediator for insulin. In the present study we examined the posttranslational mechanisms by which short-term (<6-h) exposure of 3T3-L1 adipocytes to TNF-alpha decreases Akt levels. TNF-alpha treatment both increased the ubiquitination of Akt and decreased its protein level. The decrease in protein was associated with the presence of an (immunoreactive) Akt fragment after TNF-alpha treatment, indicative of Akt cleavage. The broad-spectrum caspase inhibitor t-butoxycarbonyl-Asp(O-Me)-fluoromethyl ketone markedly suppressed these effects of TNF-alpha. The caspase-6 inhibitor Z-Val-Glu(OMe)-Ile-Asp(OMe)-CH(2)F potently suppressed Akt ubiquitination, degradation, and fragment formation, whereas the proteasome inhibitor Z-Leu-Leu-Leu-CHO modestly attenuated the decline in Akt levels. Exposure to TNF-alpha also enhanced the association of Akt with an E3 ligase activity. Adipocytes preexposed to TNF-alpha for 5 h and then stimulated with insulin for 30 min exhibited decreased levels of Akt, phosphorylated Akt, as well as phosphorylated Mdm2, which is a known direct substrate of Akt, and glucose uptake. Caspase inhibition attenuated these inhibitory effects of TNF-alpha. Collectively, our results suggest that TNF-alpha induces the caspase-dependent degradation of Akt via the cleavage and ubiquitination of Akt, which results in its degradation through the 26S proteasome. Furthermore, the caspase- and proteasome-mediated degradation of Akt due to TNF-alpha exposure leads to impaired Akt-dependent insulin signaling in adipocytes. These findings expand the mechanism by which TNF-alpha impairs insulin signaling.
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PMID:Tumor necrosis factor-{alpha} decreases Akt protein levels in 3T3-L1 adipocytes via the caspase-dependent ubiquitination of Akt. 1574 49

Metformin [2-(N,N-dimethylcarbamimidoyl)guanidine] is a drug used in the treatment of type 2 diabetes. Recent studies have suggested that metformin may have effects in addition to lowering serum glucose concentrations (e.g., anti-inflammatory). The aim of the present study was to determine whether metformin prevents the inflammatory reaction and liver damage in a model of postsurgical sepsis. Accordingly, rats underwent 2/3 partial hepatectomy (PH; or sham surgery); 48 h after surgery, animals were administered endotoxin (LPS; 1.5 mg/kg i.v.). Both PH and LPS alone caused some minor liver damage. However, their combined effect (PH/LPS) was synergistic, leading to robust hepatic damage, as indicated by plasma enzymes and histological assessment. Although metformin treatment did not alter changes caused by PH alone, it almost completely blunted the effects of LPS in the PH/LPS group. Increases in biomarkers of inflammation (e.g., interleukin 6, interferon gamma, and neutrophil number) were also blunted by metformin treatment. Furthermore, PH/LPS caused a >200x increase in hepatic plasminogen activator inhibitor 1 (PAI-1) mRNA expression and plasma PAI-1 protein. These increases were associated with inhibition of hepatic urokinase plasminogen activator activity and an increase in fibrin deposition, indicative of local thrombosis. These effects were markedly reduced by metformin treatment. In conclusion, these data demonstrate that metformin prevents liver damage in a model of postsurgical sepsis in rats by decreasing proinflammatory and hemostatic responses.
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PMID:Metformin prevents endotoxin-induced liver injury after partial hepatectomy. 1632 56

Necrotizing fasciitis is a soft-tissue infection characterized by extensive necrosis of subcutaneous fat, neurovascular structures, and fascia. In general, fascial necrosis precedes muscle and skin involvement, hence its namesake. Initially, this uncommon and rapidly progressive disease process can present as a form of cellulitis or superficial abscess. However, the high morbidity and mortality rates associated with necrotizing fasciitis suggest a more serious, ominous condition. A delay in diagnosis can result in progressive advancement highlighted by widespread infection, multiple-organ involvement, and, ultimately, death. We present a case of limb salvage in a 52-year-old patient with type 2 diabetes mellitus and progressive fascial necrosis. A detailed review of the literature is presented, and current treatment modalities are described. Aggressive surgical debridement, comprehensive medical management of the sepsis and comorbidities, and timely closure of the resultant wound or wounds are essential for a successful outcome.
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PMID:Necrotizing fasciitis in a patient with type 2 diabetes mellitus. 1641 86

The impact of multidrug resistance to antimicrobials was assessed in a cohort of 243 patients with microbiologically documented infections by a variety of susceptible and multidrug-resistant (MDR) species. Multidrug resistance was defined as resistance to more than two antimicrobial agents of different chemical structure. Cox regression analysis was performed to define differences and the significance of any predisposing factors. Overall survival of patients infected by susceptible isolates was prolonged compared with patients infected by MDR isolates (P=0.013). Mortality rates of infections caused by susceptible and MDR isolates were 4.87% and 16.15%, respectively (P=0.013); the higher mortality rate for MDR isolates was more pronounced for infections by Klebsiella pneumoniae and Pseudomonas aeruginosa. Mean (+/-standard error (S.E.)) survival of patients infected by susceptible and MDR isolates in patients without signs of severe sepsis was 28 days and 27.29+/-0.35 days, respectively (P=not significant). Mean (+/-S.E.) survival of patients with severe sepsis caused by susceptible and MDR isolates was 7.70+/-4.62 days and 10.45+/-2.18 days, respectively (P=0.048). Diabetes mellitus type 2, the presence of severe sepsis and any underlying malignancy were the most important risk factors affecting survival. It is concluded that infections by MDR isolates were accompanied by higher mortality rates and decreased survival compared with infections by susceptible isolates. Diabetes mellitus type 2 and underlying malignancies were significant co-morbid conditions, whereas survival after infection by susceptible isolates was particularly decreased in the event of severe sepsis.
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PMID:Multidrug resistance to antimicrobials as a predominant factor influencing patient survival. 1670 52

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

We have investigated predictive value of HbA1c for hospital mortality and length of stay (LOS) in patients with type 2 diabetes admitted because of sepsis. A prospective observational study was implemented in a university hospital, 286 patients with type 2 diabetes admitted with sepsis were included. Leukocyte count, CRP, admission plasma glucose, APACHE II and SOFA score were noted at admission, HbA1c was measured on the first day following admission. Hospital mortality and hospital length of stay (LOS) were the outcome measures. Admission HbA1c was significantly lower in surviving patients than in non-survivors (median 8.2% versus 9.75%, respectively; P<0.001). There was a significant correlation between admission HbA1c and hospital LOS of surviving patients (r=0.29; P<0.001). Logistic regression showed that HbA1c is an independent predictor of hospital mortality (odds ratio 1.36), together with female sex (OR 2.24), APACHE II score (OR 1.08) and SOFA score (OR 1.28). Multiple regression showed that HbA1c and APACHE II score are independently related to hospital LOS. According to our results, HbA1c is an independent predictive factor for hospital mortality and hospital LOS of diabetic patients with sepsis.
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PMID:HbA1c is outcome predictor in diabetic patients with sepsis. 1714 50

The recent insight that inflammation contributes to the development of atherosclerosis and type 2 diabetes mellitus constitutes a major breakthrough in understanding the mechanisms underlying these conditions. In addition, it opens the way for new therapeutic approaches that might eventually decrease the prevalence of these public health problems. Tumor necrosis factor-alpha (TNF-alpha) has been shown to play a key role in these processes and thus might be a potential therapeutic target. Increased concentrations of TNF-alpha are found in acute and chronic inflammatory conditions (e.g., trauma, sepsis, infection, rheumatoid arthritis), in which a shift toward a proatherogenic lipid profile and impaired glucose tolerance occurs. Although therapeutic blockade of TNF-alpha worsens the prognosis in patients with abscesses and granulomatous infections, this strategy is highly beneficial in the case of chronic inflammatory conditions, including rheumatoid arthritis. Current investigations assessing the impact of anti-TNF agents on intermediary metabolism suggest that TNF-alpha blockade may improve insulin resistance and lipid profiles in patients with chronic inflammatory diseases.
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PMID:The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. 1720 30

The object of this review is to provide the definitions and criteria for diabetic ketoacidosis (DKA) and the hyperglycemic hyperosmolar state (HHS), and convey current knowledge of the causes of permanent disability or mortality from complications of these conditions, of the risk factors for DKA and HHS, and of early indicators and contemporary treatment of suspected cerebral edema. The frequency of DKA at onset of type 1 diabetes mellitus (DM1) varies from 10-70%, depending on availability of health care and frequency of diabetes. At the onset of type 2 diabetes (DM2), DKA occurs in 5-52%. One study reported HHS in approximately 4% of new patients with DM2. Recurrent DKA rates are equally dependent on variability in medical services and socio-economic circumstances, and are estimated to be eight episodes per 100 patient years, with 20% of patients accounting for 80% of the episodes. Mortality for each episode of DKA internationally varies from 0.15-0.31%, with idiopathic cerebral edema accounting for two-thirds or more of this mortality. Other causes of death or disability include untreated DKA or HHS, hypokalemia, hypophosphatemia, hypoglycemia, other intracerebral complications, peripheral venous thrombosis, mucormycosis, rhabdomyolysis, acute pancreatitis, acute renal failure, sepsis, aspiration pneumonia, and other pulmonary complications. Population-based studies from the UK, Australia, the USA, and Canada report cerebral edema incidence in DKA of 0.5-2.0%. Published information does not support the notion that treatment factors are causal in cerebral edema. Younger age, greater severity of acidosis, degree of hypocapnia, and severity of dehydration have been suggested as risk factors in several studies. Bimodal distribution of the time of onset of cerebral edema and wide variation in brain imaging findings suggest the variability and likely multiple causation of the clinical picture. Functional brain scanning has indicated that DKA is accompanied by increased cerebral blood flow suggesting that the predominant mechanism of edema formation is a vasogenic process. A method of monitoring for diagnostic and major and minor signs of cerebral edema has been proposed and tested which indicates that intervention will be required in five individuals to provide early intervention for a single case of cerebral edema. The preferred intervention of mannitol infusion has typically been accompanied by intubation and hyperventilation, but recent evidence indicates outcome is adversely affected by aggressive hyperventilation. The prevention of DKA and HHS at the onset of diabetes mellitus requires a high degree of awareness and suspicion by primary care providers; prevention of recurrent DKA necessitates a diligent team effort.
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PMID:Hyperglycemic crises and their complications in children. 1731 23

We report a case of fatal necrotizing pneumonia and sepsis caused by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) in an otherwise well, 48-year-old Canadian man with type 2 diabetes mellitus who had travelled to Texas. Despite therapy that included intravenous antibiotics, intravenous immune globulin and other supportive measures, the patient succumbed to his illness. Recently, CA-MRSA pneumonia has been reported in several countries. The virulence of this organism may in part be related to its ability to produce toxins, such as Panton-Valentine leukocidin. As rates of CA-MRSA increase worldwide, physicians should be aware of the potential for MRSA to cause life-threatening infections in patients presenting to Canadian emergency departments (EDs). Necrotizing pneumonia caused by MRSA must be considered in the differential diagnosis of acute, severe respiratory illness. Early recognition of this syndrome in the ED may help physicians initiate appropriate antibiotic therapy in a timely manner.
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PMID:Necrotizing pneumonia and septic shock: suspecting CA-MRSA in patients presenting to Canadian emergency departments. 1762 97

Dyslipidemia and insulin resistance are commonly associated with catabolic or lipodystrophic conditions (such as cancer and sepsis) and with pathological states of nutritional overload (such as obesity-related type 2 diabetes). Two common features of these metabolic disorders are adipose tissue dysfunction and elevated levels of tumour necrosis factor-alpha (TNF-alpha). Herein, we review the multiple actions of this pro-inflammatory adipokine on adipose tissue biology. These include inhibition of carbohydrate metabolism, lipogenesis, adipogenesis and thermogenesis and stimulation of lipolysis. TNF-alpha can also impact the endocrine functions of adipose tissue. Taken together, TNF-alpha contributes to metabolic dysregulation by impairing both adipose tissue function and its ability to store excess fuel. The molecular mechanisms that underlie these actions are discussed.
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PMID:TNF-alpha and adipocyte biology. 1803 76


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