Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exercise can increase plasma inflammatory cytokine concentrations in humans, but tissue responses are not well studied. We examined plasma concentrations and tissue expression of TNFalpha, IL-1beta, and IL-6 following treadmill running in mice. C57B1/6 mice were randomly assigned to: non-exercise control (CON), sacrifice at 0 or 1.5 h after 60 min running (MOD0, MOD 1.5), sacrifice at 0, 1.5, or 3 h after fatiguing running (approximately 3 h) (EX0, EX1.5, EX3), or lipopolysaccharide (25 microg) with no exercise (LPS). Lung, liver, muscle, and brain mRNA expression was analyzed (n = 4-6/group) using reverse transcriptase-rapid polymerase chain reaction (RT-RPCR). Plasma cytokine concentrations were determined (n =4-10/group) by ELISA. Plasma IL-6 was higher in EX1.5, and lung TNFalpha mRNA was higher in EX1.5 and EX3 compared to CON (P < 0.05). No significant increases in plasma cytokine concentrations or tissue cytokine expression were found in other EX groups. LPS significantly increased these cytokine measures in tissues and plasma, with the exception of plasma IL-1beta which was undetectable. The source of the plasma IL-6 following exercise does not appear to be lung, liver, muscle, or brain tissue, and remains to be determined. These data also suggest that tissue level cytokine expression may not necessarily lead to increased plasma cytokine concentrations.
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PMID:Tissue expression and plasma concentrations of TNFalpha, IL-1beta, and IL-6 following treadmill exercise in mice. 1141 67

Chronic inflammation appears to play a critical role in type 2 diabetes and its complications. Here we tested the hypothesis that this inflammatory dysregulation affects the IL-1beta system and has functional consequences in the brain. Diabetic, db/db, and nondiabetic, db/+, mice were administered i.p. LPS, a potent cytokine inducer, at a dose of 100 microg/kg/mouse. db/db mouse innate immune-associated sickness behavior was 14.8, 33, 44.7, and 34% greater than that of db/+ mice at 2, 4, 8, and 12 h, respectively. When a fixed dose of LPS was used (5 microg/mouse), db/db mouse sickness was again enhanced 18.4, 22.2, and 14.5% at 4, 8, and 12 h as compared with db/+ mice. In diabetic mice, peritoneal macrophages produced more IL-1beta in response to LPS, and peritoneal levels of IL-1beta induced by LPS were increased. Importantly, IL-1R antagonist and type 2 IL-1 receptor (IL-1R2) failed to up-regulate in response to LPS in db/db mice. Finally, both peripheral and central administration of IL-1beta, itself, induced sickness in db/db mice that mimicked the effects of peripheral LPS and was significantly greater than that seen in db/+ mice. Taken together, these results indicate that IL-1beta-mediated innate immunity is augmented in db/db mice both at the periphery and in the brain, and the mechanism is due to diabetes-associated loss of IL-1beta counterregulation.
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PMID:IL-1beta-mediated innate immunity is amplified in the db/db mouse model of type 2 diabetes. 1581 29

Comparing macrophage-derived cytokine and nitric oxide (NO) profiles in type I and type II diabetes mellitus (DM); and determining whether thymoquinone (TQ) has any modulatory effect were the main objectives of the present study. Peritoneal macrophages have been collected from Otsuka Long-Evans Tokushima Fatty (OLETF) as a model for type II DM and its control Long-Evans Tokushima Otsuka (LETO) rats, as well as from streptozotocin (STZ)-injected LETO ones as a model for type I DM. The cells were cultured and incubated with or without TQ (10 microM) in the absence or presence of lipopolysaccharide (LPS; 1 microg/ml). The same parameters have been also assessed in sera of the used animals with or without TQ treatment (3 mg/kg) under both LPS-stimulated (10 mg/kg) and unstimulated conditions. Nitrite, IL-1beta and TNF-alpha were significantly higher in macrophage supernatants and sera of the acutely affected STZ-LETO rats either with or without LPS stimulation compared to corresponding controls. On the other hand, chronically diabetic OLETF rats' macrophage supernatants showed significant decreases of IL-1beta and TNF-alpha levels upon LPS stimulation or even without stimulation (IL-1beta); and insignificant increase in nitrite concentration, which turned significant upon LPS stimulation. Sera of these animals, however, showed significant increase in TNF-alpha level. TQ normalised the elevated nitrite and cytokine profiles both in vitro and in vivo, yet had no significant effect on the already decreased parameters in chronically affected OLETF rats. These data suggest that there is a tendency for macrophage inflammatory products to increase in acute type I and to decrease in chronic type II DM; and that TQ has the potential to normalise the elevated levels of these macrophage-derived inflammatory mediators.
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PMID:Macrophage-derived cytokine and nitric oxide profiles in type I and type II diabetes mellitus: effect of thymoquinone. 1586 10

The plasma lactate concentration in patients with obesity and type 2 diabetes is often higher than that in nondiabetic individuals. Although it is known that increased lactate concentration is an independent risk factor for developing type 2 diabetes, the underlying mechanisms are not well understood. Because inflammation plays an important role in the development of type 2 diabetes, we postulated that increased lactate level might contribute to the pathogenesis of type 2 diabetes by enhancing inflammation. In the present study, we demonstrated that preexposure of U937 macrophage-like cells to sodium lactate increased LPS-stimulated matrix metalloproteinase (MMP)-1, IL-1beta, and IL-6 secretion. Augmentation of LPS-stimulated MMP-1 secretion was diminished when sodium lactate was replaced by lactic acid that reduced pH in the culture medium. Furthermore, quantitative real-time PCR indicated that the increased secretion of MMP-1, IL-1beta, and IL-6 was due to increased mRNA expression. To explore the underlying signaling mechanism, blocking studies using specific inhibitors for NF-kappaB and MAPK cascades were performed. Results showed that blocking of either NF-kappaB or MAPK pathways led to the inhibition of MMP-1, IL-1beta, and IL-6 expression stimulated by sodium lactate, LPS, or both. Finally, electrophoretic mobility shift assays showed a synergy between sodium lactate and LPS on AP-1 and NF-kappaB transcriptional activities. In conclusion, this study has demonstrated for the first time that sodium lactate and LPS exert synergistic effect on MMP and cytokine expression through NF-kappaB and MAPK pathways and revealed a novel mechanism potentially involved in the development of type 2 diabetes and its complications.
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PMID:Sodium lactate increases LPS-stimulated MMP and cytokine expression in U937 histiocytes by enhancing AP-1 and NF-kappaB transcriptional activities. 1594 82

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

TWEAK, a cytokine of the TNF family, has been found to be expressed under different inflammatory conditions but no data is available concerning the expression of this cytokine and its receptor (Fn14) in human obesity. In the present work we have evaluated the expression of many pro-inflammatory TNF system cytokines (TNF-alpha, TWEAK and their respective receptors, TNFR1, TNFR2 and Fn14) in human adipose tissue of 84 subjects some with different degree of obesity and type 2 diabetes, and its relation with inflammation by also measuring the expression of macrophage marker CD68. We detected expression of TWEAK and Fn14 in isolated mature adipocytes and in the stromovascular fraction. Additionally, we found that LPS upregulates the expression of both genes on THP-1 human monocytic cell line. TWEAK was expressed in adipose tissue of all studied subjects with no differences between obesity group, and was associated with Fn14 expression in morbid obese, mainly in women with type 2 diabetes. The data obtained here also showed that TNF-alpha and TNFR2 mRNAs were significantly more expressed in subcutaneous adipose tissue of subjects with morbid obesity compared to obese and non-obese subjects. In contrast, TNFR1 gene expression was negatively associated with BMI. Our results suggest that the expression of TNF-derived pro-inflammatory cytokines are increased in severe obesity, where macrophage infiltrate could modulate the inflammatory environment through activation of its receptors.
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PMID:Expression of TWEAK and its receptor Fn14 in human subcutaneous adipose tissue. Relationship with other inflammatory cytokines in obesity. 1650 47

Chronic inflammation is closely associated with metabolic disorders such as obesity and type 2 diabetes, however, the underlying mechanism is unclear. Toll-like receptors (TLRs) play a key role in innate immune response as well as inflammatory signals. Here, we observed that mRNA level of TLR4 was induced during adipocyte differentiation and remarkably enhanced in fat tissues of obese db/db mice. In addition, activation of TLR4 with either LPS or free fatty acids stimulated NFkappaB signaling and expression of inflammatory cytokine genes, such as TNFalpha and IL-6 in 3T3-L1 adipocytes. Furthermore, we discovered that TLR4 activation in 3T3-L1 adipocytes provoked insulin resistance. Taken together, these results suggest that activation of TLR4 in adipocyte might be implicated in the onset of insulin resistance in obesity and type 2 diabetes.
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PMID:Activation of Toll-like receptor 4 is associated with insulin resistance in adipocytes. 1678 73

Dysregulated inflammation is a complication of type 2 diabetes (T2D). In this study, we show that augmented LPS-induced TNF-alpha production by resident peritoneal macrophages (PerMphi) in type 2 diabetic (db/db) mice is dependent on elevated glucose and requires p38 MAPK. Intraperitoneal LPS administered to db/db and nondiabetic (db/+) mice induced 3- and 4-fold more TNF-alpha in the peritoneum and serum, respectively, of db/db mice as compared with db/+ mice. Examination of the TLR-4/MD2 complex and CD14 expression showed no difference between db/db and db/+ PerMphi. Ex vivo stimulation of PerMphi with LPS produced a similar 3-fold increase in TNF-alpha production in db/db PerMphi when compared with db/+ PerMphi. PerMphi isolated from db/+ mice incubated in high glucose (4 g/L) medium for 12 h produced nearly 2-fold more TNF-alpha in response to LPS than PerMphi incubated in normal glucose medium (1 g/L). LPS-dependent stimulation of PI3K activity, ERK1/2 activation, and p38 kinase activity was greater in PerMphi from db/db mice as compared with db/+ mice. Only inhibition of p38 kinase blocked LPS-induced TNF-alpha production in PerMphi from db/db mice. Taken together, these data indicate that augmented TNF-alpha production induced by LPS in macrophages during diabetes is due to hyperglycemia and increased LPS-dependent activation of p38 kinase.
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PMID:Augmented lipopolysaccharide-induced TNF-alpha production by peritoneal macrophages in type 2 diabetic mice is dependent on elevated glucose and requires p38 MAPK. 1720 26

Increased plasma concentrations of tumor necrosis factor alpha (TNFalpha) system components appear in type 2 diabetes patients with poor glycemic control. We have analyzed the expression of TNFalpha, TNFR1 and TNFR2 when monocytes and lymphocytes isolated from a group of recent onset type 2 diabetic patients, with fasting glucose levels below 7.0mM and glycated haemoglobin (Hb1Ac) in the normal range, were stimulated with high glucose or LPS endotoxin. We report, that cultured monocytes from these type 2 diabetic patients, in comparison to monocytes from non-diabetic individuals, had an enhanced response to LPS but did not respond to an acute glucose challenge (p<0.05). No differences were observed in the cultured lymphocyte fractions. These results indicate the existence of differences, elicited by LPS or high glucose related stimulus, between monocytes isolated from non-diabetic subjects or from type 2 diabetes patients.
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PMID:Different TNFalpha expression elicited by glucose in monocytes from type 2 diabetes mellitus patients. 1724 13

Gut microflora is now considered as a key organ involved in host energy homeostasis. Recent data suggest that the alterations of the gut bacteria ecosystem could contribute to the development of metabolic disorders such as type 2 diabetes and obesity. First, gut microflora may increase energy efficiency of non digested food via the fermentation, thus providing more energy to the host. Secondly, fatty acids flux and storage in the adipose tissue is under the control of the fasting-induced adipocyte factor FIAF, which expression depends on gut microflora. Third, high-fat diet feeding changes gut bacteria profile, leading to a drop in bifidobacteria content, which correlates with a higher LPS plasma levels, thereby participating to the onset of inflammation, insulin resistance and type 2 diabetes associated with obesity. Changing gut microflora composition could be a useful tool to prevent or to treat high-fat/low fibres diet-induced metabolic syndrome. double dagger.
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PMID:[Gut microflora is a key player in host energy homeostasis]. 1846 28


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