Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vascular endothelium, the electroneutral Na-K-Cl cotransport system is thought to function in the maintenance of a selective permeability barrier in certain vascular beds (e.g., brain), as well as in the preservation of endothelial homeostasis in the face of fluctuating osmotic conditions that may accompany certain pathophysiological conditions (e.g., diabetes mellitus). Here we demonstrate that the gene encoding the bumetanide-sensitive cotransporter BSC2, one of the two major isoforms of Na-K-Cl cotransporters present in mammalian cells, can be differentially regulated by inflammatory cytokines and fluid mechanical forces in cultured endothelium. Interleukin-1beta and tumor necrosis factor-alpha significantly upregulate expression of BSC2 mRNA and protein in human umbilical vein endothelial cells, a response that is inhibited by pretreatment with interferon-gamma. Steady laminar fluid shear stress, at a physiologic magnitude (10 dyn/cm2), is also able to induce and maintain elevated expression of BSC2 in cultured human umbilical vein endothelial cells, while a comparable time-averaged magnitude of turbulent fluid shear stress is not. In vivo, BSC2 mRNA is upregulated after intraperitoneal administration of bacterial endotoxin (LPS) in murine lung and kidney, but not in cardiac tissue. These results provide the first experimental evidence that the BSC2 gene can be selectively regulated by different inflammatory cytokine and fluid mechanical stimuli in endothelium, and support a role for BSC2 in vascular homeostasis and inflammation.
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PMID:Expression of the bumetanide-sensitive Na-K-Cl cotransporter BSC2 is differentially regulated by fluid mechanical and inflammatory cytokine stimuli in vascular endothelium. 918 18

The purpose of this study was to evaluate the effects of resident islet macrophage activation on beta cell function. Treatment of freshly isolated rat islets with TNF-alpha and LPS results in a potent inhibition of glucose-stimulated insulin secretion. The inhibitory actions of TNF + LPS are mediated by the intraislet production and release of IL-1 followed by IL-1-induced inducible nitric oxide synthase (iNOS) expression by beta cells. The IL-1R antagonist protein completely prevents TNF + LPS-induced nitrite production, iNOS expression and the inhibitory effects on glucose-stimulated insulin secretion by rat islets. Resident macrophages appear to be the source of IL-1, as a 7-day culture of rat islets at 24 degrees C (conditions known to deplete islets of lymphoid cells) prevents TNF + LPS-induced iNOS expression, nitrite production, and the inhibitory effects on insulin secretion. In addition, macrophage depletion also inhibits TNF + LPS-induced IL-1alpha and IL-1beta mRNA expression in rat islets. Immunocytochemical colocalization of IL-1beta with the macrophage-specific marker ED1 was used to provide direct support for resident macrophages as the islet cellular source of IL-1. IL-1beta appears to mediate the inhibitory actions of TNF + LPS on beta cell function as TNF + LPS-induced expression of IL-1beta is fourfold higher than IL-1alpha, and Ab neutralization of IL-1beta prevents TNF + LPS-induced nitrite production by rat islets. These findings support a mechanism by which the activation of resident islet macrophages and the intraislet release of IL-1 may mediate the initial dysfunction and destruction of beta cells during the development of autoimmune diabetes.
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PMID:Potential role of resident islet macrophage activation in the initiation of autoimmune diabetes. 951 Jan 67

The fact that insulin-producing islet beta-cells are susceptible to the cytotoxic effects of inflammatory cytokines represents a potential hinderance to the use of such cells for transplantation therapy of insulin-dependent diabetes mellitus (IDDM). In the current study, we show that IL-1beta induces destruction of INS-1 insulinoma cells, while having no effect on a second insulinoma cell line RIN1046-38 and its engineered derivatives, and that this difference is correlated with a higher level of expression of manganese superoxide dismutase (MnSOD) in the latter cells. Stable overexpression of MnSOD in INS-1 cells provides complete protection against IL-1beta-mediated cytotoxicity, and also results in markedly reduced killing when such cells are exposed to conditioned media from activated human or rat PBMC. Further, overexpression of MnSOD in either RIN- or INS-1-derived lines results in a sharp reduction in IL-1beta-induced nitric oxide (NO) production, a finding that correlates with reduced levels of the inducible form of nitric oxide synthase (iNOS). Treatment of INS-1 cells with L-NMMA, an inhibitor of iNOS, provides the same degree of protection against IL-1beta or supernatants from LPS-activated rat PBMC as MnSOD overexpression, supporting the idea that MnSOD protects INS-1 cells by interfering with the normal IL-1beta-mediated increase in iNOS. Because NO and its derivatives have been implicated as critical mediators of beta-cell destruction in IDDM, we conclude that well regulated insulinoma cell lines engineered for MnSOD overexpression may be an attractive alternative to isolated islets as vehicles for insulin replacement in autoimmune diabetes.
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PMID:Stable expression of manganese superoxide dismutase (MnSOD) in insulinoma cells prevents IL-1beta- induced cytotoxicity and reduces nitric oxide production. 957 43

Diabetes mellitus is a systemic disease that affects more than 12 million people in the United States and represents a risk factor for periodontitis with odds ratios of 2.1 to 3.0. New data support the concept that in diabetes-associated periodontitis, the altered host inflammatory response plays a critical role. We have recently examined the gingival crevicular fluid (GCF) mediator level, monocytic secretion, and clinical presentation of 39 insulin-dependent diabetes mellitus (IDDM) patients and 64 non-diabetic patients with various degrees of periodontal health and disease. First, we found that there was an unexpected high level of GCF mediators among the IDDM subjects, even in the gingivitis and mild periodontitis patients. Furthermore, the GCF and monocytic mediator responses were obviously bimodal in distribution with respect to periodontal status. Gingivitis patients and mild periodontitis patients represented one low response group, and the moderate and severe periodontitis subjects the high response group. Accordingly, these 4 periodontal subgroups were pooled to form 2 main groups for analyses--group A (AAP Types I-II) and group B (AAP Types III-IV). Diabetics had significantly higher GCF levels of both PGE2 and IL-1 beta when compared to non-diabetic controls with similar periodontal status. Within the diabetic group, the GCF levels of these inflammatory mediators were almost 2-fold higher in group B subjects when compared to diabetics from group A. Among diabetics, GCF TNF-alpha levels were only marginally detectable and no significant difference was found between group A and group B patients. Insulin-dependent diabetic patients with gingivitis or mild periodontitis (group A) and moderate to severe periodontitis (group B) have abnormal monocytic inflammatory secretion in response to LPS challenge from Porphyromonas gingivalis (P. gingivalis) as compared to non-diabetic periodontal patients. Data suggest that the diabetic state results in a significantly upregulated monocytic secretion of PGE2 (4.2-fold), IL-1 beta (4.4-fold), and TNF-alpha (4.6-fold) when compared to non-diabetic controls. Within diabetics, LPS dose-response curves demonstrated that monocytes from group B patients secreted approximately 3 times more PGE2 and 6.2 times more TNF-alpha than those from group A; however, there was no significant difference in monocytic IL-1 beta secretion between the 2 diabetic groups. This upregulated monocytic trait is thought to exist independently of the presence of severe periodontal disease since, in non-diabetic patients with adult periodontitis, Gram-negative bacterial infections alone are not sufficient to elicit a systemic hyperresponsive monocytic trait. Between group A and group B diabetics, there was no significant difference in metabolic control as expressed by mean level of glycosylated hemoglobin (HbA1c). In conclusion, our data suggest that diabetic patients have exaggerated inflammatory responses when compared to non-diabetic controls. Furthermore, within diabetics, individuals with moderate to severe periodontitis (group B) have significantly elevated monocytic secretion of PGE2 and TNF-alpha upon LPS challenge and significantly higher GCF levels of PGE2 and IL-1 beta when compared to patients with gingivitis or mild periodontal disease (group A). Thus, we suggest that insulin-dependent diabetes mellitus is a significant risk factor for more severe periodontal disease because, as compared to non-diabetics, diabetic subjects react with an abnormally high degree of inflammation to an equivalent bacterial burden.
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PMID:PGE2, IL-1 beta, and TNF-alpha responses in diabetics as modifiers of periodontal disease expression. 972 89

Leukocyte 12-lipoxygenase (12-LO) gene expression in pancreatic beta cells is upregulated by cytotoxic cytokines like IL-1beta. Recent studies have demonstrated that 12-LO inhibitors can prevent glutamate-induced neuronal cell death when intracellular glutathione stores are depleted. Therefore, 12-LO pathway inhibition may prevent beta-cell cytotoxicity. To evaluate the role of 12-LO gene expression in immune-mediated islet destruction, we used 12-LO knockout (12-LO KO) mice. Male homozygous 12-LO KO mice and control C57BL/6 mice received 5 consecutive daily injections of low-dose streptozotocin to induce immune-mediated diabetes. Fasting serum glucose and insulin levels were measured at 7-day intervals, and the mice were followed up for 28 days. 12-LO KO mice were highly resistant to diabetes development compared with control mice and had higher serum insulin levels on day 28. Isolated pancreatic islets were treated with IL-1beta, TNF-alpha, and IFN-gamma for 18 hours. Glucose-stimulated insulin secretion in cytokine-treated islets from C57/BL6 mice decreased 54% from that of untreated islets. In marked contrast, the same cytokine mix led to only a 26% decrease in islets from 12-LO KO mice. Furthermore, cytokine-induced 12-hydroxyeicosatetraenoic acid (12-HETE) production was absent in 12-LO KO islets but present in C57/BL6 islets. Isolated peritoneal macrophages were stimulated for 48 hours with IFN-gamma + LPS and compared for nitrate/nitrite generation. 12-LO KO macrophages generated 50% less nitrate/nitrite when compared with C57BL/6 macrophages. In summary, elimination of leukocyte 12-LO in mice ameliorates low dose streptozotocin-induced diabetes by increasing islet resistance to cytokines and decreasing macrophage production of nitric oxide.
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PMID:Resistance to type 1 diabetes induction in 12-lipoxygenase knockout mice. 1033 Apr 25

Reduced inflammatory responses are frequently associated with diabetes mellitus. In order to investigate the influence of diabetes mellitus on the activation of bronchoalveolar cells, diabetic Wistar rats (alloxan, 40 mg/kg, iv, 30 days) and matched controls were exposed to an aerosol of endotoxin (lipopolysaccharide, LPS) or saline. Bronchoalveolar lavage (BAL) was performed 4 h thereafter. Compared with saline, aerosol administration of LPS significantly increased the number of neutrophils in the BAL fluid of control and diabetic rats. Number of mononuclear cells did not change and eosinophils were absent. A marked increase in luminol-dependent chemiluminescence (LDCL) was observed in control group after stimulation of the cells in vitro with zymosan. In contrast, tests performed with cells from diabetic rats showed a 50% reduction in LDCL generation. Full recovery of cell behaviour to match control values was observed after treatment of diabetic animals with insulin, administered before LPS exposure. Furthermore, relative to controls, level of TNF-alpha in the BAL supernatant of diabetic rats was significantly reduced. Values returned to control levels after treatment of diabetic rats with insulin, prior exposure to LPS. In conclusion, data presented suggest that insulin might regulate superoxide generation and TNF-alpha release by leukocytes upon exposure to LPS in vivo.
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PMID:Endotoxin-induced acute lung injury in rats. Role of insulin. 1054 84

Model systems of human type 1 diabetes have revealed an important role of cellular immune reactions involving macrophages and T cells in the destruction of autologous insulin-producing pancreatic beta cells. Recently, the cholera toxin B chain (CTB) was found to suppress T cell-dependent autoimmune diseases including autoimmune diabetes of nonobese diabetic mice. Therefore, we tested the hypothesis that CTB exerts much of its immunomodulatory activity by targeting macrophages. These studies are reviewed here. Cells of the human monocyte line Mono Mac 6 were exposed to CTB and subsequently tested for proinflammatory immunoreactivity in response to challenge with endotoxin (LPS from Escherichia coli, 10 ng/ml for 5 h). Incubation of monocytes with CTB (10 microgram/ml) suppressed a later proinflammatory response to LPS as demonstrated by suppression of TNFalpha release from 6.7 +/- 0.7 ng/ml in cultures without CTB preexposure to 1.8 +/- 1.1 ng/ml in CTB-pretreated cells (p < 0.001). In contrast, the release of IL-10 remained inducible after CTB pretreatment. RT-PCR analysis showed that the suppression of TNFalpha production occurred at the level of mRNA formation. Control experiments excluded a role of possible contamination of CTB by endotoxin or the intact cholera toxin. Tolerance induction was maximal after 5 h of CTB exposure and persisted for 24 h. The suppressive effect of CTB was dose-dependent and no more recognizable at </=1 microgram/ml. Incubation with IL-10- and TGFbeta-neutralizing antibodies during CTB pretreatment prevented tolerization of macrophages. IFNgamma (1,200 U/ml) was found to antagonize actions of CTB. In contrast to desensitization by low doses of LPS, tolerance induction by CTB occurred 'silently', i.e. in the absence of a measurable proinflammatory response. In view of the potent instructive role of the innate immune system on T cell responses these findings are important in understanding how CTB prevents the development of autoimmune diabetes and improves tolerance to islet autoantigens.
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PMID:Induction of tolerance in macrophages by cholera toxin B chain. 1072 11

In adult rats, bacterial endotoxin (lipopolysaccharide or LPS) is known to diminish the activity of the reproductive axis, mainly by inhibiting luteinizing hormone-releasing hormone (LHRH) secretion; until now, this effect has not been studied in immature rats. The aim of the present study was to evaluate the effect of LPS 1) on LHRH output (and associated changes in the release of inhibitory amino acid neurotransmitters such as gamma-aminobutyric acid (GABA) and taurine) by superfused hypothalamic fragments, and 2) on gonadotropin secretion by incubated hemipituitaries, obtained from young adult (60-day-old) and peripubertal (30-day-old) intact male rats. In adult animals, LPS induced a significant inhibition (50% of basal values) of LHRH release, accompanied by an increase in GABA and taurine output. In juvenile rats the inhibition of LHRH secretion by LPS attained 90% of basal values (p<0.0001 versus adult rats), and the concurrent increase in GABA release was significantly greater (p<0.0001 versus adult rats). LPS did not affect in vitro gonadotropin secretion in adult animals. Conversely, the release of these hormones was significantly (p<0.001 and <0.02 for LH and FSH, respectively) reduced in 30-day-old rats. Our results demonstrate the existence of age-related differences in the effect of LPS on LHRH and gonadotropin secretion. These differences might well be attributed to an increased activity of the hypothalamic GABAergic system. Furthermore, the participation of other factors known to play a role in immune-neuroendocrine relationships (e.g., corticotropin-releasing hormone, testosterone) is discussed.
Exp Clin Endocrinol Diabetes 2000
PMID:Age-related differences in the effects of bacterial endotoxin (LPS) upon the release of LHRH, gonadotropins and hypothalamic inhibitory amino acid neurotransmitters measured in tissues explanted from intact male rats. 1092 20

We compared BM-derived DC from NOD with DC from non-diabetes-prone strains. NOD myeloid progenitors cultured in GM or GM + IL-4 yielded lower numbers of DC than similar cultures from other strains. NOD GM + IL-4 DC produced lower amounts of IL-12 p70 following CD40 ligation or LPS stimulation in the presence of IFN-gamma than DC from other strains, although similar levels of IL-6 and NO were produced by all strains. The low amounts of IL-12 p70 produced by GM + IL-4 DC are despite a more mature DC phenotype observed in NOD mice. The low DC number could diminish the ability of DC to stimulate immunoregulatory T cells. Furthermore, the differentiation/maturation of DC from myeloid progenitors is altered, reflecting disorders in the function of these cells in NOD BM.
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PMID:Phenotypic and functional characteristics of BM-derived DC from NOD and non-diabetes-prone strains. 1114 36

Changes of the tissue factor (TF) pathway of blood coagulation have been described in diabetes and could be involved in its vascular complications. In order to evaluate the influence of the type of diabetes and of the obesity index and age on these changes, factor VII coagulant activity, factor VII antigen, activated factor VII, monocyte TF expression, and plasma Tissue Factor Pathway Inhibitor (TFPI) were examined in 18 Type 1 and 16 Type 2 diabetic patients compared to non-diabetic control subjects matched for age, sex, and obesity index (Types 1 and 2 controls, respectively). Multicomplicated patients were excluded. FVIIc, FVIIAg, and FVIIa were higher in Type 2 diabetic patients and controls than in Type 1 diabetic patients and controls (P< .03). However, FVIIc and FVIIAg were lower in diabetic patients than in their matched controls (P< .03). Monocyte expression of TF was not different between Types 1 and 2 diabetic patients and their matched controls except for LPS-stimulated monocyte TF activity which was lower in Type 2 diabetic patients than in Type 2 controls (P< .05). Plasma TFPI was slightly but significantly higher in Type 1 diabetic patients than in Type 1 controls (P= .01) and was correlated to glycemia. However, both in Type 2 diabetic patients and controls, TFPI was higher than in Type 1 controls and was correlated with BMI (P< .0003). These results indicate that in not multicomplicated patients, the increase of FVII and TFPI was highly dependent on obesity index and age rather than on diabetes by itself.
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PMID:Factor VII, tissue factor pathway inhibitor, and monocyte tissue factor in diabetes mellitus: influence of type of diabetes, obesity index, and age. 1129 53


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