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)

Starvation and diabetes increase pyruvate dehydrogenase kinase-4 (PDK4) expression, which conserves gluconeogenic substrates by inactivating the pyruvate dehydrogenase complex. Mechanisms that regulate PDK4 gene expression, previously established to be increased by glucocorticoids and decreased by insulin, were studied. Treatment of HepG2 cells with dexamethasone increases the relative abundance of PDK4 mRNA, and insulin blocks this effect. Dexamethasone also increases human PDK4 (hPDK4) promoter activity in HepG2 cells, and insulin partially inhibits this effect. Expression of constitutively active PKB alpha abrogates dexamethasone stimulation of hPDK4 promoter activity, while coexpression of constitutively active FOXO1a or FOXO3a, which are mutated to alanine at the three phosphorylation sites for protein kinase B (PKB), disrupts the ability of PKB alpha to inhibit promoter activity. A glucocorticoid response element for glucocorticoid receptor (GR) binding and three insulin response sequences (IRSs) that bind FOXO1a and FOXO3a are identified in the hPDK4 promoter. Mutation of the IRSs reduces the ability of glucocorticoids to stimulate PDK4 transcription. Transfection studies with E1A, which binds to and inactivates p300/CBP, suggest that interactions between p300/CBP and GR as well as FOXO factors are important for glucocorticoid-stimulated hPDK4 expression. Insulin suppresses the hPDK4 induction by glucocorticoids through inactivation of the FOXO factors.
Diabetes 2004 Apr
PMID:Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors. 1504 4

Insulin gene expression is regulated by pancreatic beta cell-specific factors, PDX-1 and BETA2/E47. Here we have demonstrated that the insulin promoter is a novel target for SREBPs established as lipid-synthetic transcription factors. Promoter analyses of rat insulin I gene in non-beta cells revealed that nuclear SREBP-1c activates the insulin promoter through three novel SREBP-binding sites (SREs), two of which overlap with E-boxes, binding sites for BETA2/E47. SREBP-1c activation of the insulin promoter was markedly enhanced by co-expression of BETA2/E47. This synergistic activation by SREBP-1c/BETA2/E47 was not mediated through SREs but through the E-boxes on which BETA2/E47 physically interacts with SREBP-1c, suggesting a novel function of SREBP as a co-activator. These two cis-DNA regions, E1 and E2, with an appropriate distance separating them, were mandatory for the synergism, which implicates formation of SREBP-1c.BETA2.E47 complex in a DNA looping structure for efficient recruitment of CREB-binding protein/p300. However, in the presence of PDX1, the synergistic action of SREBP-1c with BETA2/E47 was canceled. SREBP-1c-mediated activation of the insulin promoter and expression became overt in beta cell lines and isolated islets when endogenous PDX-1 expression was low. This cryptic SREBP-1c action might play a compensatory role in insulin expression in diabetes with beta cell lipotoxicity.
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PMID:Sterol regulatory element-binding proteins activate insulin gene promoter directly and indirectly through synergy with BETA2/E47. 1605 39

Type 1 diabetes (T1D) is a multifactorial autoimmune disease, with strong genetic component. Several susceptibility loci contribute to genetic predisposition to T1D. One of these loci have been mapped to chromosome 1q42 in UK and US joined affected family data sets but needs to be replicated in other populations. In this study, we evaluated sixteen microsatellites located on 1q42 for linkage with T1D in 97 Russian affected sibling pairs. A 2.7-cm region of suggestive linkage to T1D between markers D1S1644 and D1S225 was found by multipoint linkage analysis. The peak of linkage was shown for D1S2847 (P = 0.0005). Transmission disequilibrium test showed significant undertransmission of the 156-bp allele of D1S2847 from parents to diabetic children (28 transmissions vs. 68 nontransmissions, P = 0.043) in Russian affected families. A preferential transmission from parents to diabetic offspring was also shown for the T(-25) and T1362 alleles of the C/T(-25) and C/T1362 dimorphisms, both located at the TAF5L gene, which is situated 103 kb from D1S2847. Together with the A/C744 TAF5L SNP, these markers share common T(-25)/A744/T1362 and C(-25)/C744/T1362 haplotypes associated with higher and lower risk of diabetes (Odds Ratio = 2.15 and 0.62, respectively). Our results suggest that the TAF5L gene, encoding TAF5L-like RNA polymerase II p300/CBP associated factor (PCAF)-associated factor, could represent the susceptibility gene for T1D on chromosome 1q42 in Russian affected patients.
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PMID:The TAF5L gene on chromosome 1q42 is associated with type 1 diabetes in Russian affected patients. 1620 11

Halofenate has been shown previously to lower triglycerides in dyslipidemic subjects. In addition, significant decreases in fasting plasma glucose were observed but only in type 2 diabetic patients. We hypothesized that halofenate might be an insulin sensitizer, and we present data to suggest that halofenate is a selective peroxisome proliferator-activated receptor (PPAR)-gamma modulator (SPPARgammaM). We demonstrate that the circulating form of halofenate, halofenic acid (HA), binds to and selectively modulates PPAR-gamma. Reporter assays show that HA is a partial PPAR-gamma agonist, which can antagonize the activity of the full agonist rosiglitazone. The data suggest that the partial agonism of HA may be explained in part by effective displacement of corepressors (N-CoR and SMRT) coupled with inefficient recruitment of coactivators (p300, CBP, and TRAP 220). In human preadipocytes, HA displays weak adipogenic activity and antagonizes rosiglitazone-mediated adipogenic differentiation. Moreover, in 3T3-L1 adipocytes, HA selectively modulates the expression of multiple PPAR-gamma-responsive genes. Studies in the diabetic ob/ob mouse demonstrate halofenate's acute antidiabetic properties. Longer-term studies in the obese Zucker (fa/fa) rat demonstrate halofenate's comparable insulin sensitization to rosiglitazone in the absence of body weight increases. Our data establish halofenate as a novel SPPARgammaM with promising therapeutic utility with the potential for less weight gain.
Diabetes 2006 Sep
PMID:Halofenate is a selective peroxisome proliferator-activated receptor gamma modulator with antidiabetic activity. 1693

Increased fibronectin expression is a key feature of diabetic angiopathy. We have previously shown that nuclear factor-kappaB (NF-kappaB) mediates fibronectin expression in endothelial cells and in organs affected by diabetes complications. p300, a transcription coactivator, may regulate NF-kappaB activity via poly(ADP-ribose) polymerase (PARP) activation. Hence, we examined the role of p300 in fibronectin expression in diabetes. High glucose induced fibronectin expression in the endothelial cells, which was associated with increased p300, PARP activity, and NF-kappaB activation. This p300 alteration is mediated by mitogen-activated protein kinase and protein kinase C and B. We then used p300 small interfering RNA (siRNA) and showed decreased fibronectin and PARP expression, as well as NF-kappaB activation, in the endothelial cells. Examination of the heart tissues of streptozotocin-induced diabetic mice revealed increased fibronectin and p300 mRNA. Intravenous injection of p300 siRNA resulted in decreased p300 levels and normalized fibronectin expression in the heart. We further investigated retinal tissues from streptozotocin-induced diabetic rats treated with intravitreal p300 siRNA injection. Similar to the heart, p300 siRNA inhibited fibronectin expression in the retina of the diabetic animals. These results indicate that transcriptional coactivator p300 may regulate fibronectin expression via PARP and NF-kappaB activation in diabetes.
Diabetes 2006 Nov
PMID:Diabetes-induced extracellular matrix protein expression is mediated by transcription coactivator p300. 1706 49

Prolonged elevations of glucose concentration have deleterious effects on beta-cell function. One of the hallmarks of such glucotoxicity is a reduction in insulin gene expression, resulting from decreased insulin promoter activity. Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that inhibits nuclear receptor signaling in diverse metabolic pathways. In this study, we found that sustained culture of INS-1 cells at high glucose concentrations leads to an increase in SHP mRNA expression, followed by a decrease in insulin gene expression. Inhibition of endogenous SHP gene expression by small interfering RNA partially restored high-glucose-induced suppression of the insulin gene. Adenovirus-mediated overexpression of SHP in INS-1 cells impaired glucose-stimulated insulin secretion as well as insulin gene expression. SHP downregulates insulin gene expression via two mechanisms: by downregulating PDX-1 and MafA gene expression and by inhibiting p300-mediated pancreatic duodenal homeobox factor 1-and BETA2-dependent transcriptional activity from the insulin promoter. Finally, the pancreatic islets of diabetic OLETF rats express SHP mRNA at higher levels than the islets from LETO rats. These results collectively suggest that SHP plays an important role in the development of beta-cell dysfunction induced by glucotoxicity.
Diabetes 2007 Feb
PMID:Glucotoxicity in the INS-1 rat insulinoma cell line is mediated by the orphan nuclear receptor small heterodimer partner. 1725 88

The pancreatic and duodenal homeobox factor-1 (Pdx1) is essential for pancreatic development and insulin gene transcription, whereas c-Myc has a deleterious effect on islet function. However, the relationship between c-Myc and Pdx1 is poorly concerned. Here we demonstrated that Pdx1 could suppress c-Myc promoter activity, which relied on T cell factor (Tcf) binding elements harbored in c-Myc promoter. Furthermore, the transcription activity of beta-catenin/Tcf was markedly decreased on Pdx1 expression, but cotransfection of Pdx1 short hairpin RNA abrogated this effect. Pdx1 expression did not induce beta-catenin degradation nor did it alter their subcellular distribution. The mutation analysis showed that the amino acids (1-209) of Pdx1 harboring an inhibitory domain, which might lead to the reduction of beta-catenin/Tcf/p300 complex levels and attenuate their binding activity with c-Myc promoter sequences. Moreover, adenovirus-mediated Pdx1 interference caused cell proliferation and cytokine-induced apoptosis via the dysregulation of c-Myc transcription. These results indicated that the Pdx1 functioned as a key regulator for maintenance of beta-cell function, at least in part, through controlling c-Myc expression and the loss of its regulatory function may be an alternative mechanism for beta-cell neogenesis and apoptosis found in diabetes.
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PMID:Negative regulation of c-Myc transcription by pancreas duodenum homeobox-1. 1731 81

Reversible acetylation of histone and nonhistone proteins plays pivotal role in cellular homeostasis. Dysfunction of histone acetyltransferases (HATs) leads to several diseases including cancer, neurodegenaration, asthma, diabetes, AIDS, and cardiac hypertrophy. We describe the synthesis and characterization of a set of p300-HAT-specific small-molecule inhibitors from a natural nonspecific HAT inhibitor, garcinol, which is highly toxic to cells. We show that the specific inhibitor selectively represses the p300-mediated acetylation of p53 in vivo. Furthermore, inhibition of p300-HAT down regulates several genes but significantly a few important genes are also upregulated. Remarkably, these inhibitors were found to be nontoxic to T cells, inhibit histone acetylation of HIV infected cells, and consequently inhibit the multiplication of HIV.
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PMID:Specific inhibition of p300-HAT alters global gene expression and represses HIV replication. 1758 7

Dysfunction and death of microvascular cells and imbalance between the production and the degradation of extracellular matrix (ECM) proteins are a characteristic feature of diabetic retinopathy (DR). Glucose-induced biochemical alterations in the vascular endothelial cells may activate a cascade of signaling pathways leading to increased production of ECM proteins and cellular dysfunction/death. Chronic diabetes leads to the activation of a number of signaling proteins including protein kinase C, protein kinase B, and mitogen-activated protein kinases. These signaling cascades are activated in response to hyperglycemia-induced oxidative stress, polyol pathway, and advanced glycation end product formation among others. The aberrant signaling pathways ultimately lead to activation of transcription factors such as nuclear factor-kappaB and activating protein-1. The activity of these transcription factors is also regulated by epigenetic mechanisms through transcriptional coactivator p300. These complex signaling pathways may be involved in glucose-induced alterations of endothelial cell phenotype leading to the production of increased ECM proteins and vasoactive effector molecules causing functional and structural changes in the microvasculature. Understanding of such mechanistic pathways will help to develop future adjuvant therapies for diabetic retinopathy.
Exp Diabetes Res 2007
PMID:Cellular signaling and potential new treatment targets in diabetic retinopathy. 1828 48

Diabetic cardiomyopathy, structurally characterized by cardiomyocyte hypertrophy and increased extracellular matrix (ECM) protein deposition, eventually leads to heart failure. We investigated the role of transcriptional coactivator p300 and its interaction with myocyte enhancer factor 2 (MEF2) in diabetes-induced cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes were exposed to variable levels of glucose. Cardiomyocytes were analyzed with respect to their size. mRNA expression of p300, MEF2A, MEF2C, atrial natriuretic polypeptide (ANP), brain natriuretic polypeptide (BNP), angiotensinogen (ANG), cAMP-responsive element binding protein-binding protein (CBP), and protein analysis of MEF2 were done with or without p300 blockade. We investigated the hearts of STZ-induced diabetic rats and compared them with age- and sex-matched controls after 1 and 4 mo of followup with or without treatment with p300 blocker curcumin. The results were that cardiomyocytes, exposed to 25 mM glucose for 48 h, showed cellular hypertrophy and augmented mRNA expression of ANP, BNP, and ANG, molecular markers of cardiac hypertrophy. Glucose caused a duration-dependent increase of mRNA and protein expression in MEF2A and MEF2C and transcriptional coactivator p300. Curcumin, a p300 blocker, and p300 siRNA prevented these abnormalities. Similarly, ANP, BNP, and ANG mRNA expression was significantly higher in the hearts of diabetic rats compared with the controls, in association with increased p300, MEF2A, and MEF2C expression. Treatment with p300 blocker curcumin prevented diabetes-induced upregulation of these transcripts. We concluded that data from these studies demonstrate a novel glucose-induced epigenetic mechanism regulating gene expression and cardiomyocyte hypertrophy in diabetes.
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PMID:Regulation of cardiomyocyte hypertrophy in diabetes at the transcriptional level. 1841 74


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