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 transcriptional regulatory protein nuclear factor kappa B (NF-kappa B) participates in the control of gene expression of many modulators of inflammatory and immune responses, including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). The heightened expression of these adhesion molecules has been reported to play a critical role in atherosclerosis, inflammation, ischemic vascular disorders, diabetes, and cancer metastasis. In the present study, we investigated the effect of pycnogenol, an antioxidant phytochemical, on the activation of NF-kappa B and the induction of VCAM-1 and ICAM-1 in tumor necrosis factor (TNF)-alpha-treated human umbilical vein endothelial cells (HUVECs). Gel-shift analysis of HUVEC demonstrated that pretreatment with pycnogenol exhibited a concentration-dependent suppression of TNF-alpha-induced activation of NF-kappa B. Induction of VCAM-1 and ICAM-1 surface expression by TNF-alpha was dose-dependently reduced by pycnogenol. TNF-alpha significantly increased the release of superoxide anion and hydrogen peroxide from HUVECs. Pycnogenol dose-dependently inhibited their release. The ability of pycnogenol to inhibit NF-kappa B activation and VCAM-1 and ICAM-1 expression suggests that this phytochemical may play an important role in halting or preventing the atherogenic process.
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PMID:Pycnogenol inhibits tumor necrosis factor-alpha-induced nuclear factor kappa B activation and adhesion molecule expression in human vascular endothelial cells. 1089 47

Mitochondrial glycerol phosphate dehydrogenase (mGPD) is abundant in the normal pancreatic insulin cell, but its level is lowered 50% by diabetes. To evaluate mGPD expression, we cloned and characterized the 5'-flanking region of the human mGPD gene. The gene has two alternative first exons and two promoters. The downstream promoter (B) is 10 times more active than the upstream promoter (A) in insulin-secreting cells (INS-1) and HeLa cells. Promoter B has higher activity in INS-1 than in non-beta cells. Deletion and mutation analysis suggested that a NRF-2 binding site at -94 to -101 and an E2F binding site at -208 to -215 are important regulatory cis elements in promoter B. Gel mobility shift assays indicated that the -94 to -101 region binds the NRF-2 protein. When INS-1 cells were maintained in the presence of high glucose (25 mm) for 7 days, mGPD was the only 1 of 6 enzyme activities lowered (53%). mGPD promoter B activity was reduced by 60% in INS-1 cells by the high glucose, but in HepG2 cells and HeLa cells, promoter B activity was unchanged or slightly increased. Deletion analysis indicated the glucose responsiveness was distributed across the region from -340 to -260 in promoter B. The results indicate that mGPD gene transcription in the beta cell is regulated differently from other cells and that decreased mGPD promoter B transcription is at least in part the cause of the decreased beta cell mGPD levels in diabetes.
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PMID:Functional analysis of two promoters for the human mitochondrial glycerol phosphate dehydrogenase gene. 1095 7

The increased expression of plasminogen activator inhibitor type-1 (PAI-1) is associated with increased concentrations of fatty acids in blood and may accelerate atherogenesis in diabetes. The present study was designed to define mechanisms by which nonesterified (free) fatty acids (FFAs) augment the expression of PAI-1. FFAs increased PAI-1 protein and mRNA expression by HepG2 cells. To identify potential regulatory elements, we constructed chimeric genes by fusing 1313, 853, 610, or 328 bp of human PAI-1 5'-flanking DNA to a luciferase reporter (PAI-LUC). A 2-fold increase in luciferase activity was seen when cells were transfected with PAI-LUC 1313, 863, or 610 and exposed to FFAs. No response to FFAs was seen with PAI-LUC 328 and after deletion of a 72-bp (-599 to -528) fragment from PAI-LUC 1313. This 72-bp fragment conferred FFA responsiveness to a different (simian virus 40) promoter. Two footprinted regions were demonstrated by DNase I analysis. Gel mobility shift assays indicated specific binding of extracted proteins to an FFA response element: 5'-TG(G/C)(1-2)CTG-3'. This sequence is repeated 4 times and is similar to an Sp1-binding site. Sp1 consensus oligonucleotides inhibited binding of extracted proteins to the regulatory elements. Accordingly, FFA-induced increased expression of PAI-1 in HepG2 cells is mediated by the binding of a transcription factor or factors to the repeated fatty acid response element, 5'-TG(G/C)(1-2)CTG-3', that is highly homologous to an Sp1-binding site.
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PMID:Identification and localization of a fatty acid response region in the human plasminogen activator inhibitor-1 gene. 1111 74

The regeneration of pancreatic islet beta cells is important for the prevention and cure of diabetes mellitus. We have demonstrated that the administration of poly(ADP-ribose) synthetase/polymerase (PARP) inhibitors such as nicotinamide to 90% depancreatized rats induces islet regeneration. From the regenerating islet-derived cDNA library, we have isolated Reg (regenerating gene) and demonstrated that Reg protein induces beta-cell replication via the Reg receptor and ameliorates experimental diabetes. However, the mechanism by which Reg gene is activated in beta cells has been elusive. In this study, we found that the combined addition of IL-6 and dexamethasone induced the expression of Reg gene in beta cells and that PARP inhibitors enhanced the expression. Reporter gene assays revealed that the -81 approximately -70 region (TGCCCCTCCCAT) of the Reg gene promoter is a cis-element for the expression of Reg gene. Gel mobility shift assays showed that the active transcriptional DNA/protein complex was formed by the stimulation with IL-6 and dexamethasone. Surprisingly, PARP bound to the cis-element and was involved in the active transcriptional DNA/protein complex. The DNA/protein complex formation was inhibited depending on the autopoly(ADP-ribosyl)ation of PARP in the complex. Thus, PARP inhibitors enhance the DNA/protein complex formation for Reg gene transcription and stabilize the complex by inhibiting the autopoly(ADP-ribosyl)ation of PARP.
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PMID:Activation of Reg gene, a gene for insulin-producing beta -cell regeneration: poly(ADP-ribose) polymerase binds Reg promoter and regulates the transcription by autopoly(ADP-ribosyl)ation. 1113 36

Limitations in understanding the mechanism of transcriptional regulation by insulin are due in part to lack of models in which there is insulin-responsive binding of nuclear factors to critical promoter regions. The insulin-like growth factor I (IGF-I) gene responds to diabetes status via a footprinted sequence, region V, which contains an AT-rich element and a GC-rich site. We tested the hypothesis that insulin regulates nuclear factor binding to the AT-rich site. Gel shift analysis with liver nuclear extracts and a region V probe showed binding of Sp1, Sp3, and B(1), which persisted despite the presence of antibodies against Sp1 and Sp3. B(1) was detected by a probe mutated in the GC-rich site (VmSp1), but not by a probe mutated at the AT-rich site (VmAT). We then asked whether B(1) was responsive to insulin. For both region V and VmSp1 probes, nuclear extracts from normal rat hepatocytes, H4IIE cells, and CHO-IR cells exposed to 10(-6) M insulin exhibited an increase in binding, designated insulin-responsive binding protein (IRBP); IRBP comigrated with B(1) from liver extracts. IRBP binding to region V was competed by VmSp1, but not by VmAT, indicating specific interactions with the AT-rich sequence; insulin response elements from other genes also failed to compete. After addition of insulin, IRBP began to increase by 1 h and rose further at 24 h, suggesting involvement of both posttranslational and transcriptional mechanisms. IRBP responded to as little as 10(-10) M insulin, indicating physiological relevance. Induction of IRBP was blunted by the phosphatidylinositol 3'-kinase inhibitor LY294002, whereas other signal transduction inhibitors had little effect. IRBP interacts with an important sequence in the IGF-I gene and may participate in the metabolic regulation of IGF-I expression. As most insulin-responsive genes do not exhibit insulin-responsive nuclear factor binding, further studies of IRBP may also contribute to understanding of the mechanism of insulin action on gene transcription.
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PMID:Physiological concentrations of insulin promote binding of nuclear proteins to the insulin-like growth factor I gene. 1118 17

Complications at implantation site of implantable insulin pumps may lead to premature removal. To elucidate the origins and the outcomes of these local adverse events. We investigated seromas of the 'pump-pocket' that have been detected for an eight month-period during the follow-up of such-treated forty type 1 diabetic patients. At the start of study period, skin bacterial flora was sampled at umbilicus and groin, and isolated strains of Staphylococcus epidermidis were preserved in specific vials at -20 degrees C. Each time a seroma was detected at transcutaneous 45 days-refill of pump reservoir, it was sampled for bacterial cultures. Isolated strains of S. epidermidis from seroma were genetically compared to preserved strains of corresponding patients using Pulsed-Field Gel Electrophoresis (PFGE) after genomic restriction by SmaI. Among the ten seromas that occurred after a mean time of 9.9 months since implantation, S. epidermidis were isolated in five cases. Genetic comparison of isolated strains could be performed in three cases. Compared strains showed identical (in 2 cases) or closely related (in one case) PFGE profiles. While the five aseptic seromas resolved with rest, four infected cases required explantations after one to nineteen months in spite of antibiotic therapy and the fifth one persisted without impairment under long-term antibiotics. Our results suggest that seeding from the skin flora is a key-factor determining the severity of pump-pocket complications. We recommend that bacterial investigations of pump-pocket seromas should be systematically performed, while prophylactic measures might include antibiotic cover for each puncture of the pump-pocket.
Diabetes Metab 2001 Feb
PMID:Implantable insulin pumps: infections most likely due to seeding from skin flora determine severe outcomes of pump-pocket seromas. 1124 Apr 48

Complications of diabetes have a genetic influence. Since increased inducible nitric oxide synthase (iNOS) gene ( NOS2A) expression can contribute to tissue damage, NOS2A is a worthy candidate for such a role. We therefore tested a 4-bp insertion/deletion (+/-) polymorphism 0.7 kb upstream of NOS2A for association with complications in type 2 diabetes patients, and also performed transient transfection experiments to examine the effect of this variant on promoter activity in kidney cells in culture. We investigated 379 Caucasian type 2 diabetes patients of British/European descent, 93 of whom had microalbuminuria, 26 overt nephropathy, 46 retinopathy, and 73 clinical neuropathy. Genotyping for the variant was carried out by PCR and automated Genescan analysis. Transient transfection studies involved the renal HEK 293 cell line and luciferase reporter gene constructs containing 1.1 kb of 5'-flanking DNA from '+' or '-' allele homozygotes. We found that the '+' allele frequency in patients without microalbuminuria was 12%, but was 23% in those with microalbuminuria ( P=0.0005), and was 26% in those with nephropathy ( P=0.0007), 22% in those with retinopathy ( P=0.037), and 23% in those with neuropathy ( P=0.045). The odds ratios for homozygote +/+ to have microalbuminuria or nephropathy were 2.4 (95% CI 1.4-4.2, P=0.0023) and 5.4 (95% CI 1.8-16, P=0.0009), respectively. Luciferase reporter gene constructs containing 1 kb of NOS2A promoter DNA for each allele were made and sequence analysis confirmed that the +/- variation was the only sequence difference present. Transient transfection of these into HEK 293 cells revealed 25 times higher reporter gene activity for the '+' allele compared with the '-' allele. Gel shift analysis with 30mer oligonucleotides corresponding to each allele showed specific binding to nuclear extracts, being greater for the '+' allele. Thus the '+' allele of the NOS2A promoter variant may confer higher iNOS expression, and could contribute to complications of type 2 diabetes, especially in the approximately 5% of patients homozygous for this variant.
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PMID:Association of a functional inducible nitric oxide synthase promoter variant with complications in type 2 diabetes. 1190 46

Plasminogen activator inhibitor-1 (PAI-1) is an important regulator of fibrinolysis by its inhibition of both tissue-type and urokinase plasminogen activators. PAI-1 levels are elevated in type II diabetes and this elevation correlates with macro- and microvascular complications of diabetes. Insulin increases PAI-1 production in several experimental systems, but the mechanism of insulin-activated PAI-1 transcription remains to be determined. Deletion analysis of the PAI-1 promoter revealed that the insulin response element is between -117 and -7. Mutation of the AT-rich site at -52/-45 abolished the insulin responsiveness of the PAI-1 promoter. This sequence is similar to the inhibitory sequence found in the phosphoenolpyruvate carboxylkinase/insulin-like growth factor-I-binding protein I promoters. Gel-mobility shift assays demonstrated that the forkhead bound to the PAI-1 promoter insulin response element. Expression of the DNA-binding domain of FKHR acted as a dominant negative to block insulin-increased PAI-1-CAT expression. A LexA-FKHR construct was also insulin responsive. These data suggested that a member of the Forkhead/winged helix family of transcription factors mediated the effect of insulin on PAI-1 transcription. Inhibition of phosphatidylinositol 3-kinase reduced the effect of insulin on PAI-1 gene expression, a result consistent with activation through FKHR. However, it was likely that a different member of the FKHR family (not FKHR) mediated this effect since FKHR was present in both insulin-responsive and non-responsive cell lines.
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PMID:A Forkhead/winged helix-related transcription factor mediates insulin-increased plasminogen activator inhibitor-1 gene transcription. 1191 88

Hepatocyte nuclear factor (HNF)1alpha is a homeo-domain-containing transcription factor participating in the regulation of gene expression in liver, kidney, gut and pancreas of vertebrates. In humans mutations in the HNF1 gene are responsible for one form of maturity onset diabetes of the young (MODY3). To define the molecular mechanism underlying MODY3 we investigated the functional properties of seven MODY3-associated mutations representing the spectrum of different kinds of mutations affecting all functional domains of the protein. The mutations introduced into an expression vector encoding human HNF1alpha include in-frame deletion (AN127), nonsense (Q7X, R171X), frameshift (P291fsinsC) and missense (R229Q, P447L, T6201) mutations. Gel retardation and reporter gene assays showed that the functional properties of these mutants differ dramatically, but none of these mutants act in a dominant negative manner. Moreover, the mRNA stability of the mutants AN127, R171X, P291fsinsC and T547E548fsdelTG is impaired compared to the wild-type sequence in transfected cells. This decreased RNA stability is independent of the presence of an intron in the expression vector and thus differs from mechanisms known to be involved in nonsense-mediated decay (NMD). Our results suggest that haploinsufficiency of HNF1alpha is responsible for the pathogenesis of MODY3.
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PMID:Evidence for haploinsufficiency of the human HNF1alpha gene revealed by functional characterization of MODY3-associated mutations. 1253 May 34

Glucokinase (GK) gene transcription initiates in the islet (beta-cell), gut, and brain from promoter sequences residing approximately 35 kbp upstream from those used in liver. Expression of betaGK is controlled in beta-cells by cell-enriched (i.e. pancreatic duodenal homeobox 1 [PDX-1]) and ubiquitously (i.e., Pal) distributed factors that bind to and activate from conserved sequence motifs within the upstream promoter region (termed betaGK). Here, we show that a conserved E-box element also contributes to control in the islet and gut. betaGK promoter-driven reporter gene activity was diminished by mutating the specific sequences involved in E-box-mediated basic helix-loop-helix factor activator binding in islet beta-cells and enteroendocrine cells. Gel shift assays demonstrated that the betaGK and insulin gene E-box elements formed the same cell-enriched (BETA2:E47) and generally distributed (upstream stimulatory factor [USF]) protein-DNA complexes. betaGK E-box-driven activity was stimulated in cotransfection assays performed in baby hamster kidney (BHK) cells with BETA2 and E47, but not USF. Chromatin immunoprecipitation assays performed with BETA2 antisera showed that BETA2 occupies the upstream promoter region of the endogenous betaGK gene in beta-cells. We propose that BETA2 (also termed NeuroD1) regulates betaGK promoter activity.
Diabetes 2003 Feb
PMID:BETA2 activates transcription from the upstream glucokinase gene promoter in islet beta-cells and gut endocrine cells. 1254 Jun 14


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