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)

Transforming growth factor (TGF)-beta1-decreased major histocompatibility complex (MHC) class I gene expression in thyrocytes is transcriptional; it involves trans factors and cis elements important for hormone- as well as iodide-regulated thyroid growth and function. Thus, in rat FRTL-5 thyrocytes, TGF-beta1 regulates two elements within -203 bp of the transcription start site of the MHC class I 5'-flanking region: Enhancer A, -180 to -170 bp, and a downstream regulatory element (DRE), -127 to -90 bp, that contains a cAMP response element (CRE)-like sequence. TGF-beta1 reduces the interaction of a NF-kappaB p50/fra-2 heterodimer (MOD-1) with Enhancer A while increasing its interaction with a NF-kappaB p50/p65 heterodimer. Both reduced MOD-1 and increased p50/p65 suppresses class I expression. Decreased MOD-1 and increased p50/p65 have been separately associated with the ability of autoregulatory (high) concentrations of iodide to suppress thyrocyte growth and function, as well as MHC class I expression. TGF-beta1 has two effects on the downstream regulatory element (DRE). It increases DRE binding of a ubiquitously expressed Y-box protein, termed TSEP-1 (TSHR suppressor element binding protein-1) in rat thyroid cells; TSEP-1 has been shown separately to be an important suppressor of the TSH receptor (TSHR) in addition to MHC class I and class II expression. It also decreases the binding of a thyroid-specific trans factor, thyroid transcription factor-1 (TTF-1), to the DRE, reflecting the ability of TGF-beta1 to decrease TTF-1 RNA levels. TGF-beta1-decreased TTF-1 expression accounts in part for TGF-beta1-decreased thyroid growth and function, since decreased TTF-1 has been shown to decrease thyroglobulin, thyroperoxidase, sodium iodide symporter, and TSHR gene expression, coincident with decreased MHC class I. Finally, we show that TGF-beta1 increases c-jun RNA levels and induces the formation of new complexes involving c-jun, fra-2, ATF-1, and c-fos, which react with Enhancer A and the DRE. TGF-beta1 effects on c-jun may be a pivotal fulcrum in the hitherto unrecognized coordinate regulation of Enhancer A and the DRE.
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PMID:Transforming growth factor-beta1 down-regulation of major histocompatibility complex class I in thyrocytes: coordinate regulation of two separate elements by thyroid-specific as well as ubiquitous transcription factors. 1077 Apr 87

Incubation of bovine aortic endothelial cells (BAECs) with erythrocytes from patients with type 2 diabetes induced an increase in endothelin 1 (ET-1) production. The effect of erythrocytes on ET-1 synthesis was dependent on glycemic control. ET-1 levels after incubation with erythrocytes derived from patients with HbA(1c) levels <6% were just half the levels observed after incubation with erythrocytes from patients with HbA(1c) levels >8%. Nepsilon-(carboxymethyl)lysine (CML)-containing protein isolated from patients' erythrocytes induced ET-1, and CML-containing protein-dependent ET-1 induction was blocked by the recombinant decoy peptide soluble receptor for advanced glycation end products (AGEs), which comprises the NH2-terminal Ig domain of the receptor for AGEs. In vitro-generated AGEs induced ET-1 mRNA transcription (nuclear run-on assay and Northern blot) in a time- and dose-dependent manner. Transient transfection of BAECs with a chimeric construct containing the 5' promoter region of the ET-1 gene linked to a reporter gene confirmed that AGE induced ET-1 promoter activity. Electrophoretic mobility shift assay confirmed AGE-inducible binding of members of the nuclear factor-kappab (NF-kappaB) family to a potential binding site at -2,090 bp. Binding was functionally significant because overexpression of the cytoplasmic inhibitor of NF-kappaB or deletion of the NF-kappaB binding site reduced ET-1 induction, whereas overexpression of NF-kappaB p65 induced ET-1 even in the absence of AGEs. Thus, ET-1 transcription is controlled by the AGE-inducible redox-sensitive transcription factor NF-kappaB.
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PMID:Endothelin 1 transcription is controlled by nuclear factor-kappaB in AGE-stimulated cultured endothelial cells. 1096 41

Troglitazone (TGZ), a member of the thiazolidinedione class of anti-diabetic compounds and a peroxisome proliferator activator receptor-gamma (PPAR-gamma) agonist, restores systemic insulin sensitivity and improves the full insulin resistance syndrome in vivo. The mechanisms underlying its in vivo function are not understood. Here we investigated the potential functional interaction between PPAR-gamma and NF-kappaB in adipocytes. We show that TGZ selectively blocked tumor necrosis factor-alpha-induced and NF-kappaB-dependent repression of multiple adipocyte-specific genes and induction of growth phase and other genes. This occurs without interfering with NF-kappaB expression, activation, nuclear translocation, or DNA binding and without suppressing NF-kappaB-dependent survival signals. Notably, the expressions of some tumor necrosis factor-alpha-induced genes in adipocytes were unaffected by PPAR-gamma activation. In reporter gene assays in HeLa cells, ectopic expression of PPAR-gamma abolished induction of a NF-kappaB-responsive reporter gene by the p65 subunit (RelA) of NF-kappaB, and the inhibition was further enhanced in the presence of TGZ. Conversely, overexpression of p65 inhibited induction of a PPAR-gamma-responsive reporter gene by activated PPAR-gamma in a dose-dependent manner. The inhibitory effect was independent of the presence of NF-kappaB-binding sites in the promoter region. Other NF-kappaB family members, p50 and c-Rel as well as the S276A mutant of p65, blocked PPAR-gamma-mediated gene transcription less effectively. Thus, p65 antagonizes the transcriptional regulatory activity of PPAR-gamma in adipocytes, and PPAR-gamma activation can at least partially override the inhibitory effects of p65 on the expression of key adipocyte genes. Our data suggest that inhibition of NF-kappaB activity is a mechanism by which PPAR-gamma agonists improve insulin sensitivity in vivo and that adipocyte NF-kappaB is a potential therapeutic target for obesity-linked type 2 diabetes.
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PMID:Troglitazone antagonizes tumor necrosis factor-alpha-induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF-kappaB. 1273 48

There is much evidence to indicate a role for adipocytokines in insulin resistance and/or type 2 diabetes mellitus. In experimental models, oral salicylates, through their ability to interfere with the nuclear factor-kappa B (NF-kappa B) transcription pathway, have been demonstrated to reverse insulin resistance. The aim of this study was to investigate whether NF-kappa B regulates the release of adipocytokines in human adipose tissue and skeletal muscle. Human sc adipose tissue and skeletal muscle (obtained from normal pregnant women) were incubated in the absence (control) or presence of two NF-kappa B inhibitors sulfasalazine (1.25, 2.5, and 5 mm) and BAY 11-7082 (25, 50, and 100 microm). After an 18-h incubation, the tissues were collected, and NF-kappa B p65 DNA-binding activity and I kappa B kinase (IKK-beta) and insulin receptor-beta protein expression were assessed by ELISA and Western blotting, respectively. The incubation medium was collected, and the release of TNF-alpha, IL-6, IL-8, resistin, adiponectin, and leptin was quantified by ELISA. Treatment of adipose tissue and skeletal muscle with sulfasalazine and BAY 11-7082 significantly inhibited the release of IL-6, IL-8, and TNF-alpha; NF-kappa B p65 DNA-binding activity; and IKK-beta protein expression (P < 0.05, by Newman-Keuls test). There was no effect of sulfasalazine and BAY 11-7082 on resistin, adiponectin, or leptin release. Both sulfasalazine and BAY 11-7082 increased the adipose tissue and skeletal muscle expression of insulin receptor-beta. The data presented in this study demonstrate that the IKK-beta/NF-kappa B transcription pathway is a key regulator of IL-6, IL-8, and TNF-alpha release from adipose tissue and skeletal muscle. Control of the IKK-beta/NF-kappa B pathway may therefore provide an alternative therapeutic strategy for regulating aberrant cytokine release and thereby alleviating insulin resistance in type 2 diabetes mellitus.
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PMID:Sulfasalazine and BAY 11-7082 interfere with the nuclear factor-kappa B and I kappa B kinase pathway to regulate the release of proinflammatory cytokines from human adipose tissue and skeletal muscle in vitro. 1556 33

The mechanisms by which elevated levels of free fatty acids cause insulin resistance are not well understood, but there is a strong correlation between insulin resistance and intramyocellular lipid accumulation in skeletal muscle. In addition, accumulating evidence suggests a link between inflammation and type 2 diabetes. The aim of this work was to study whether the exposure of skeletal muscle cells to palmitate affected peroxisome proliferator-activated receptor (PPAR) beta/delta activity. Here, we report that exposure of C2C12 skeletal muscle cells to 0.75 mM palmitate reduced (74%, P<0.01) the mRNA levels of the PPARbeta/delta-target gene pyruvatedehydrogenase kinase 4 (PDK-4), which is involved in fatty acid utilization. This reduction was not observed in the presence of the PPARbeta/delta agonist L-165041. This drug prevented palmitate-induced nuclear factor (NF)-kappaB activation. Increased NF-kappaB activity after palmitate exposure was associated with enhanced protein-protein interaction between PPARbeta/delta and p65. Interestingly, treatment with the PPARbeta/delta agonist L-165041 completely abolished this interaction. These results indicate that palmitate may reduce fatty acid utilization in skeletal muscle cells by reducing PPARbeta/delta signaling through increased NF-kappaB activity.
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PMID:Agonist-induced activation releases peroxisome proliferator-activated receptor beta/delta from its inhibition by palmitate-induced nuclear factor-kappaB in skeletal muscle cells. 1586 83

Glucagon-like peptide 1 (GLP-1) is an insulinotropic protein. It was reported that the continuous infusion of GLP-1 normalized the blood glucose level in type 2 diabetes animal model. However, the short half-life of GLP-1 has limited its application in clinical settings and prompted us to develop a GLP-1 gene therapy system. Our previous results showed that the delivery of pbeta-GLP-1 using polyethylenimine (PEI) reduced the blood glucose level effectively. However, the glucose level was not completely normalized. In the present study, the more efficient GLP-1 expression system was developed using two-step transcription amplification (TSTA). To evaluate the TSTA system, pbeta-Gal4-p65 and pUAS-Luc were constructed. The pUAS-Luc/pbeta-Gal4-p65 system showed the highest transfection efficiency at a 2:1 pUAS-Luc/pbeta-Gal4-p65 weight ratio. In addition, the transgene expression by the TSTA system was at least 4 times higher than pbeta-Luc. To apply the TSTA system to the GLP-1 expression plasmid, pUAS-GLP-1 was constructed. The pUAS-GLP-1/pbeta-Gal4-p65 system showed higher mRNA level than pbeta-GLP-1. In addition, the level of GLP-1 by the pUAS-GLP-1/pbeta-Gal4-p65 system was more than 4 times higher than pbeta-GLP-1. Therefore, the TSTA GLP-1 expression system may be useful to develop gene therapy system for type 2 diabetes.
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PMID:An efficient GLP-1 expression system using two-step transcription amplification. 1704 57

Oxidative stress may contribute to the pathogenesis of diabetic nephropathy (DN), although the detailed mechanism of reactive oxygen species (ROS) regulation is still unclear. This study examined the effect of high-salt diet on ROS production and expression of antioxidant enzymes in control and experimentally diabetic rats. Wistar fatty rats (WFR) as a type 2 diabetes mellitus model and Wistar lean rats (WLR) as a control were fed a normal-salt diet (NS) and high-salt diet (HS) from the age of 6 to 14 weeks. We then examined the blood pressure, urinary albumin excretion (UAE), and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels. The expression of antioxidant enzymes including alpha-catalase (CAT), Cu-Zn superoxide dismutase (SOD), Mn SOD, and glutathione peroxidase (GPx) were analyzed in the glomeruli of the rats using Western blotting. The expression of NAD(P)H oxidase p47(phox) and NFkappaB p65 was evaluated using immunohistochemical staining. By 14 weeks of age, the WFR-HS group exhibited hypertension and markedly increased UAE. The level of 8-OHdG, a marker of oxidative damage, in the WFR-HS group was also higher than that in the WLR groups or WFR-NS group. The expression of alpha-CAT and Mn SOD proteins was significantly decreased in isolated glomeruli in the WFR-HS group. GPx and Cu-Zn SOD expression did not differ between the WFR and WLR groups. High expression of ROS and decreases in antioxidants were seen in the glomeruli of diabetic rats with hypertension, suggesting that oxidative stress may be involved in the development of DN.
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PMID:Hypertension aggravates glomerular dysfunction with oxidative stress in a rat model of diabetic nephropathy. 1733 48

Adipose tissue secretes a wide range of hormones named adipokines, and these may play a role in obesity-related inflammation. Adiponectin is an exceptional adipokine because low plasma concentrations are associated with obesity, type 2 diabetes, and cardiovascular diseases. It has been observed that plasma adiponectin concentrations are elevated during inflammatory conditions like preeclampsia and arthritis. Nuclear factor-kappaB (NF-kappaB) is an essential transcription factor for expression of inflammation-related proteins. We have used U937 cells stably transfected to express luciferase under the control of NF-kappaB to examine if adiponectin may modulate NF-kappaB activity. Physiological concentrations of native adiponectin induced NF-kappaB activity. This effect was relatively strong compared with proinflammatory adipokines like leptin, resistin, and IL-6. The enhanced NF-kappaB activity was attributed to the high molecular weight adiponectin isoforms. NF-kappaB was not activated by mutated adiponectin that is unable to form high molecular weight complexes. Furthermore, the C-terminal fragment, globular adiponectin, markedly increased NF-kappaB reporter activity, cytokine release, and mRNA expression of inflammation marker genes, at higher levels than stimulation with TNF-alpha and lipopolysaccharide. NF-kappaB activation by globular adiponectin was not affected by antibody inhibition of toll-like receptor 4 or TNF receptors 1 and 2 but was attenuated by inhibitors of p38 MAPK, phosphatidylinositol 3-kinase, and protein kinase C. Analyses of the p65 subunit of NF-kappaB in different leukocyte cell lines showed activation of two monocytic cell lines (U937 and THP-1) by native and globular adiponectin. Our results indicate that adiponectin has proinflammatory properties in monocytic cells.
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PMID:Activation of nuclear factor-kappaB by high molecular weight and globular adiponectin. 1770 46

Insulin resistance of skeletal muscle is a major defect in obesity and type 2 diabetes. Insulin resistance has been associated with a chronic subclinical inflammatory state in epidemiological studies and specifically with activation of the inhibitor kappaB kinase (IkappaBK)-nuclear factor-kappaB (NF-kappaB) pathway. However, it is unclear whether this pathway plays a role in mediating insulin resistance in muscle in vivo. We separately overexpressed the p65 subunit of NF-kappaB and IkappaBKbeta in single muscles of rats using in vivo electrotransfer and compared the effects after 1 wk vs. paired contralateral control muscles. A 64% increase in p65 protein (P < 0.001) was sufficient to cause muscle fiber atrophy but had no effect on glucose disposal or glycogen storage in muscle under hyperinsulinemic-euglycemic clamp conditions. Similarly, a 650% increase in IkappaBKbeta expression (P < 0.001) caused a significant reduction in IkappaB protein but also had no effect on clamp glucose disposal after lipid infusion. In fact, IkappaBKbeta overexpression in particular caused increases in activating tyrosine phosphorylation of insulin receptor substrate-1 (24%; P = 0.02) and serine phosphorylation of Akt (23%; P < 0.001), implying a moderate increase in flux through the insulin signaling cascade. Interestingly, p65 overexpression resulted in a negative feedback reduction of 36% in Toll-like receptor (TLR)-2 (P = 0.03) but not TLR-4 mRNA. In conclusion, activation of the IkappaBKbeta-NF-kappaB pathway in muscle does not seem to be an important local mediator of insulin resistance.
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PMID:Local activation of the IkappaK-NF-kappaB pathway in muscle does not cause insulin resistance. 1802 40

Reduced insulin sensitivity is a key factor in the pathogenesis of type 2 diabetes and hypertension. Skeletal muscle insulin resistance is particularly important for its major role in insulin-mediated glucose disposal. Angiotensin II (ANG II) is integral in regulating blood pressure and plays a role in the pathogenesis of hypertension. In addition, we have documented that ANG II-induced skeletal muscle insulin resistance is associated with generation of reactive oxygen species (ROS). However, the linkage between ROS and insulin resistance in skeletal muscle remains unclear. To explore potential mechanisms, we employed the transgenic TG(mRen2)27 (Ren-2) hypertensive rat, which harbors the mouse renin transgene and exhibits elevated tissue ANG II levels, and skeletal muscle cell culture. Compared with Sprague-Dawley normotensive control rats, Ren-2 skeletal muscle exhibited significantly increased oxidative stress, NF-kappaB activation, and TNF-alpha expression, which were attenuated by in vivo treatment with an angiotensin type 1 receptor blocker (valsartan) or SOD/catalase mimetic (tempol). Moreover, ANG II treatment of L6 myotubes induced NF-kappaB activation and TNF-alpha production and decreased insulin-stimulated Akt activation and GLUT-4 glucose transporter translocation to plasma membranes. These effects were markedly diminished by treatment of myotubes with valsartan, the antioxidant N-acetylcysteine, NADPH oxidase-inhibiting peptide (gp91 ds-tat), or NF-kappaB inhibitor (MG-132). Similarly, NF-kappaB p65 small interfering RNA reduced NF-kappaB p65 subunit expression and nuclear translocation and TNF-alpha production but improved insulin-stimulated phosphorylation (Ser(473)) of Akt and translocation of GLUT-4. These findings suggest that NF-kappaB plays an important role in ANG II/ROS-induced skeletal muscle insulin resistance.
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PMID:Angiotensin II-induced skeletal muscle insulin resistance mediated by NF-kappaB activation via NADPH oxidase. 1807 21


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