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)

The G to A single nucleotide polymorphisms (SNPs), at position -376, -308 and -238 in the promoter of the tumor necrosis factor alpha (TNF) gene, have been independently correlated with numerous diseases. Alleles TNF(-376A) and TNF(-238A) are normally found throughout the world with very low frequencies. We investigated the frequency of these SNPs in Sicilian subjects hospitalized after traumatic brain injury and in three groups of subjects from northern Sardinia: healthy subjects and individuals with multiple sclerosis or ischemic stroke. While no significant difference was found between healthy and disease subjects, the frequency of TNF(-376A) and TNF(-238A) was elevated up to 10 times in Sardinia compared to Sicily and other populations throughout the world. These elevated frequencies may be the result of genetic drift or of selective pressure on TNF itself or on neighboring genes, including the HLA. Malaria, endemic to Sardinia until the end of the 1940s, and the bubonic plague, are among the possible causes of selection. These findings indicate that Sardinia is an ideal location to further elucidate the correlation between TNF or HLA polymorphisms and diseases, including multiple sclerosis and type-I diabetes, present with an unusually high frequency and co-morbidity in Sardinia.
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PMID:High frequency of TNF alleles -238A and -376A in individuals from northern Sardinia. 1514 31

Although epidemiologic studies carried out in Taiwan, Bangladesh, and Sweden have demonstrated a diabetogenic effect of arsenic, the mechanisms remain unclear and require further investigation. This paper reviewed the potential biological mechanisms of arsenic-induced diabetes mellitus based on the current knowledge of the biochemical properties of arsenic. Arsenate can substitute phosphate in the formation of adenosine triphosphate (ATP) and other phosphate intermediates involved in glucose metabolism, which could theoretically slow down the normal metabolism of glucose, interrupt the production of energy, and interfere with the ATP-dependent insulin secretion. However, the concentration of arsenate required for such reaction is high and not physiologically relevant, and these effects may only happen in acute intoxication and may not be effective in subjects chronically exposed to low-dose arsenic. On the other hand, arsenite has high affinity for sulfhydryl groups and thus can form covalent bonds with the disulfide bridges in the molecules of insulin, insulin receptors, glucose transporters (GLUTs), and enzymes involved in glucose metabolism (e.g., pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase). As a result, the normal functions of these molecules can be hampered. However, a direct effect on these molecules caused by arsenite at physiologically relevant concentrations seems unlikely. Recent evidence has shown that treatment of arsenite at lower and physiologically relevant concentrations can stimulate glucose transport, in contrary to an inhibitory effect exerted by phenylarsine oxide (PAO) or by higher doses of arsenite. Induction of oxidative stress and interferences in signal transduction or gene expression by arsenic or by its methylated metabolites are the most possible causes to arsenic-induced diabetes mellitus through mechanisms of induction of insulin resistance and beta cell dysfunction. Recent studies have shown that, in subjects with chronic arsenic exposure, oxidative stress is increased and the expression of tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) is upregulated. Both of these two cytokines have been well known for their effect on the induction of insulin resistance. Arsenite at physiologically relevant concentration also shows inhibitory effect on the expression of peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor important for activating insulin action. Oxidative stress has been suggested as a major pathogenic link to both insulin resistance and beta cell dysfunction through mechanisms involving activation of nuclear factor-kappaB (NF-kappaB), which is also activated by low levels of arsenic. Although without supportive data, superoxide production induced by arsenic exposure can theoretically impair insulin secretion by interaction with uncoupling protein 2 (UCP2), and oxidative stress can also cause amyloid formation in the pancreas, which could progressively destroy the insulin-secreting beta cells. Individual susceptibility with respect to genetics, nutritional status, health status, detoxification capability, interactions with other trace elements, and the existence of other well-recognized risk factors of diabetes mellitus can influence the toxicity of arsenic on organs involved in glucose metabolism and determine the progression of insulin resistance and impaired insulin secretion to a status of persistent hyperglycemia or diabetes mellitus. In conclusions, insulin resistance and beta cell dysfunction can be induced by chronic arsenic exposure. These defects may be responsible for arsenic-induced diabetes mellitus, but investigations are required to test this hypothesis.
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PMID:The potential biological mechanisms of arsenic-induced diabetes mellitus. 1516 43

TNF/CD80 mice, a CD8(+) T cell-mediated model for type 1 diabetes, transgenically express tumor necrosis factor alpha (TNF-alpha) and the costimulatory molecule CD80 in their pancreatic islets. Here we show that these molecules bypass the need for CD40-CD154 costimulatory interactions in activation of CD8(+) T cells, allowing us to determine the role of CD40-CD154 signals in regulation of autoaggressive CD8(+) T cells after their in vivo priming. TNF/CD80 CD154-deficient mice rapidly develop diabetes, whereas CD154-sufficient mice do not. This finding correlates with the decreased numbers of CD4(+)CD25(+) T regulatory (T(R)) cells in the islets and pancreatic lymph nodes, in comparison to disease-protected CD154-sufficient mice. Administration of a CD40 agonistic antibody induces a systemic and tissue-specific increase in T(R) cells. However, this increase fails to delay diabetes development in the absence of CD154. Adoptive transfer studies show that CD8(+) T cells from TNF/CD80 CD154-deficient, but not CD154-sufficient, mice are resistant to regulation in vivo. This study provides evidence that CD40-transduced signals initiate T(R) cell increase in vivo and that CD154-transduced signals sensitize autoaggressive CD8(+) T cells to suppression.
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PMID:CD154 is a negative regulator of autoaggressive CD8+ T cells in type 1 diabetes. 1519 49

Tissue factor is critically important for initiating the activation of coagulation zymogens leading to the generation of thrombin. Quiescent endothelial cells do not express tissue factor on their surface, but many stimuli including cytokines and coagulation proteases can elicit tissue factor synthesis. We challenged human endothelial cells simultaneously with tumor necrosis factor alpha (TNFalpha) and thrombin because many pathophysiological conditions, such as sepsis, diabetes, and coronary artery disease, result in the concurrent presence of circulating inflammatory mediators and activated thrombin. We observed a remarkable synergy in the expression of tissue factor by thrombin plus TNFalpha. This was due to altered regulation of the transcription factors c-Jun and c-Fos. The activation of c-Jun was greater and more sustained than that obtained with either thrombin or TNFalpha alone. Thrombin-stimulated expression of c-Fos was both enhanced and prolonged by the concurrent presence of TNFalpha. These changes support the increased availability of c-Jun/c-Fos AP-1 complexes for mediating transcription at the tissue factor promoter. Transcription factors downstream of the extracellular signal-regulated kinases as well as changes in NFkappaB regulation were not involved in the synergistic increase in tissue factor expression by thrombin and TNFalpha. Thus, concurrent exposure of vascular endothelial cells to cytokines and procoagulant proteases such as thrombin can result in greatly enhanced tissue factor expression on the endothelium, thereby perpetuating the prothrombotic phenotype of the endothelium.
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PMID:Thrombin and tumor necrosis factor alpha synergistically stimulate tissue factor expression in human endothelial cells: regulation through c-Fos and c-Jun. 1520 Dec 77

Inappropriate chronic inflammation associated with progressive, chronic kidney disease (CKD) reflects sustained activation of immunocompetent cells, like monocytes/macrophages. Advanced glycation end products (AGE) accumulate in CKD, but it is unclear if they stimulate monocytes by binding with the receptor for AGE (RAGE). Posited was the notion that RAGE plays a contributory role to monocyte-mediated systemic inflammation of progressive CKD. Peripheral blood monocytes were isolated from 102 patients without diabetes with varying severity of CKD. RAGE expression on peripheral blood monocytes increased with worsening CKD (r2 = 0.73) and was strongly correlated with plasma levels of pentosidine, a marker for AGE (r = 0.71). Strongly positive statistical correlations were observed in patients with CKD between monocyte RAGE and plasma levels of tumor necrosis factor alpha (TNF-alpha) (r = 0.61), the monocyte activation marker, neopterin (r = 0.65), and the systemic acute phase reactant, C-reactive protein (r = 0.44). Monocytes obtained from patients with CKD showed a monotonic increase in the number and affinity of specific AGE binding sites and increased production of TNF-alpha under stimulation of AGE. All these upregulatory responses in uremic monocytes could be largely blocked by an anti-RAGE antibody. It was concluded that RAGE expression was upregulated on monocytes from patients with CKD. Enhanced RAGE may amplify AGE-induced monocytes perturbation and contribute to monocyte-mediated systemic inflammation in progressive CKD.
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PMID:Enhanced expression of receptor for advanced glycation end products in chronic kidney disease. 1521 78

Impairment of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear receptor that regulates genes involved in lipid and glucose metabolism, may contribute to the onset of metabolic disorders such as diabetes and the accompanying dyslipidemia. Fat-derived tumor necrosis factor alpha (TNF-alpha) and the acute-phase response protein, C-reactive protein (CRP), may also have a role in the development of obesity-related insulin resistance and type 2 diabetes mellitus. In this study, a group of 14 naturally occurring, insulin-requiring, type 2 diabetic cynomolgus monkeys were used to evaluate the effects of the PPAR-gamma agonist, rosiglitazone, on glycemic and lipid parameters and serum levels of TNF-alpha and CRP. The animals were randomized into 2 groups of 7. One group was treated with 0.5 mg/kg rosiglitazone orally once a day for 7 weeks. Blood was collected for evaluation at baseline, at 2 and 7 weeks during the treatment period, and at 7 and 13 weeks after treatment. Daily insulin requirements were recorded during the entire study. Results showed daily exogenous insulin requirements were significantly reduced (P <.01) in those treated with rosiglitazone, while glycemic control was maintained. Plasma triglyceride concentrations were significantly lower (P <.01) whereas plasma cholesterol levels tended to be lower and high-density lipoprotein (HDL) concentrations tended to be higher after treatment. No significant differences were noted in TNF-alpha and CRP serum levels during the treatment period. Body weights remained steady in both groups during the study. These results suggest overall improvement in insulin regulation and lipid profiles during treatment with rosiglitazone.
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PMID:Rosiglitazone treatment improves insulin regulation and dyslipidemia in type 2 diabetic cynomolgus monkeys. 1533 71

Prevention of autoimmune diabetes and induction of islet transplantation tolerance in nonobese diabetic (NOD) mice can be reached by induction of mixed chimerism via bone marrow transplantation (BMT), but this procedure requires total body irradiation (TBI) conditioning of the recipients. The toxicity of radiation and potential for graft-versus-host disease (GVHD) prevents its clinical application. Donor CD8+ T cells play a critical role in facilitation of engraftment but also contribute to induction of GVHD in TBI-conditioned recipients. Here, we showed that high doses of donor CD8+ T cells in combination with bone marrow (BM) cells induced mixed chimerism without GVHD in NOD recipients conditioned with anti-CD3 monoclonal antibody (mAb). The prevention of GVHD in those recipients was associated with low-level production of inflammatory cytokines (ie, tumor necrosis factor alpha [TNF-alpha]), high-level production of anti-inflammatory cytokines (ie, interleukin 4 [IL-4] and IL-10), and confining of the donor CD8+ T-cell expansion to lymphohematopoietic tissues. The chimeric NOD recipients showed donor-specific tolerance and reversal of insulitis. These results demonstrate that donor CD8+ T-cell-mediated facilitation of engraftment can be separated from GVHD in nonirradiated recipients. This regimen may have potential application in the treatment of autoimmune disorders as well as induction of transplantation tolerance.
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PMID:Donor CD8+ T cells facilitate induction of chimerism and tolerance without GVHD in autoimmune NOD mice conditioned with anti-CD3 mAb. 1537 83

In animal models of lipotoxicity, accumulation of triglycerides within cardiomyocytes is associated with contractile dysfunction. However, whether intramyocardial lipid deposition is a feature of human heart failure remains to be established. We hypothesized that intramyocardial lipid accumulation is a common feature of non-ischemic heart failure and is associated with changes in gene expression similar to those found in an animal model of lipotoxicity. Intramyocardial lipid staining with oil red O and gene expression analysis was performed on heart tissue from 27 patients (9 female) with non-ischemic heart failure. We determined intramyocardial lipid, gene expression, and contractile function in hearts from 6 Zucker diabetic fatty (ZDF) and 6 Zucker lean (ZL) rats. Intramyocardial lipid overload was present in 30% of non-ischemic failing hearts. The highest levels of lipid staining were observed in patients with diabetes and obesity (BMI>30). Intramyocardial lipid deposition was associated with an up-regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) -regulated genes, myosin heavy chain beta (MHC-beta), and tumor necrosis factor alpha (TNF-alpha). Intramyocardial lipid overload in the hearts of ZDF rats was associated with contractile dysfunction and changes in gene expression similar to changes found in failing human hearts with lipid overload. Our findings identify a subgroup of patients with heart failure and severe metabolic dysregulation characterized by intramyocardial triglyceride overload and changes in gene expression that are associated with contractile dysfunction.
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PMID:Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. 1552 14

Although tumor necrosis factor alpha (TNFalpha) decreases the expression of peroxisome proliferator-activated receptor gamma (PPARgamma), its mechanism is not understood. We evaluated the effect of ceramide, the second messenger of TNFalpha, on the expression of PPARgamma in primary cultured adipocytes. PPARgamma mRNA and aP2 mRNA levels were measured with real-time PCR. The PPARgamma protein level was measured with immunoblot. C6- and C2-ceramide, but not dihydroC6-ceramide, reduced the expression of PPARgamma in a time and concentration dependent manner. The application of 1 microM C6-ceramide for 36 h reduced PPARgamma mRNA level, aP2 mRNA level, and PPARgamma protein level to 56.3%, 80.4% and 62.1%, respectively. Since ceramide is known to activate atypical PKC, we also studied the role of atypical PKC on the PPARgamma reducing effect. Overexpression of wild type PKCzeta magnified and accelerated the effect of TNFalpha and C6-ceramide on PPARgamma mRNA levels, whereas overexpression of dominant negative PKCzeta abolished the effect. We also found that the overexpression of constitutive active PKCzeta reduced PPARgamma mRNA level, aP2 mRNA level, and PPARgamma protein level to 61.4%, 70.3% and 81.6%, respectively. Furthermore, TNFalpha activated nuclear factor-kappaB (NF-kappaB), known as a downstream effector of PKCzeta to 256.6%, which was enhanced with overexpression of wild-type PKCzeta. On the other hand, treatment with phorbol 12-myristate 13-acetate, another activator of NF-kappaB, also reduced the expression of PPARgamma to 57.8%. These results indicate that the reducing effect of TNFalpha is mediated through ceramide, atypical PKC and NF-kappaB pathway.
Diabetes Res Clin Pract 2004 Dec
PMID:TNFalpha reduces the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) via the production of ceramide and activation of atypical PKC. 1556 86

Both aging and diabetes are characterized by the formation of advanced glycation end products (AGEs). Both exhibit other similarities including deficits in wound healing that are associated with higher rates of fibroblast apoptosis. In order to investigate a potential mechanism for enhanced fibroblast apoptosis in diabetes and aged individuals, experiments were carried out to determine whether the predominant advanced glycation end product in skin, N-epsilon-(carboxymethyl) lysine (CML)-collagen, could induce fibroblast apoptosis. In vivo experiments established that CML-collagen but not unmodified collagen induced fibroblast apoptosis and that apoptosis was dependent upon caspase-3, -8, and -9 activity. In vitro experiments demonstrated that CML-collagen but not control collagen induced a time- and dose-dependent increase in fibroblast apoptosis. By use of blocking antibodies, apoptosis was shown to be mediated through receptor for AGE signaling. AGE-induced apoptosis was largely dependent on the effector caspase, caspase-3, which was activated through both cytoplasmic (caspase-8-dependent) and mitochondrial (caspase-9) pathways. CML-collagen had a global effect of enhancing mRNA levels of pro-apoptotic genes that included several classes of molecules including ligands, receptors, adaptor molecules, mitochondrial proteins, and others. However, the pattern of expression was not identical to the pattern of apoptotic genes induced by tumor necrosis factor alpha.
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PMID:Advanced glycation end products enhance expression of pro-apoptotic genes and stimulate fibroblast apoptosis through cytoplasmic and mitochondrial pathways. 1559 Jun 48


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