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)

To test the hypothesis that c-Myc plays an important role in beta-cell growth and differentiation, we generated transgenic mice overexpressing c-Myc in beta-cells under control of the rat insulin II promoter. F(1) transgenic mice from two founders developed neonatal diabetes (associated with reduced plasma insulin levels) and died of hyperglycemia 3 days after birth. In pancreata of transgenic mice, marked hyperplasia of cells with an altered phenotype and amorphous islet organization was displayed: islet volume was increased threefold versus wild-type littermates. Apoptotic nuclei were increased fourfold in transgenic versus wild-type mice, suggesting an increased turnover of beta-cells. Very few cells immunostained for insulin; pancreatic insulin mRNA and content were markedly reduced. GLUT2 mRNA was decreased, but other beta-cell-associated genes (IAPP [islet amyloid pancreatic polypeptide], PDX-1 [pancreatic and duodenal homeobox-1], and BETA2/NeuroD) were expressed at near-normal levels. Immunostaining for both GLUT2 and Nkx6.1 was mainly cytoplasmic. The defect in beta-cell phenotype in transgenic embryos (embryonic days 17-18) and neonates (days 1-2) was similar and, therefore, was not secondary to overt hyperglycemia. When pancreata were transplanted under the kidney capsules of athymic mice to analyze the long-term effects of c-Myc activation, beta-cell depletion was found, suggesting that, ultimately, apoptosis predominates over proliferation. In conclusion, these studies demonstrate that activation of c-Myc in beta-cells leads to 1) increased proliferation and apoptosis, 2) initial hyperplasia with amorphous islet organization, and 3) selective downregulation of insulin gene expression and the development of overt diabetes.
Diabetes 2002 Jun
PMID:Overexpression of c-Myc in beta-cells of transgenic mice causes proliferation and apoptosis, downregulation of insulin gene expression, and diabetes. 1203 67

Maturity-onset diabetes of the young (MODY) is a subtype of early-onset diabetes mellitus which is characterized by autosomal dominant inheritance. Several genes are known to induce MODY : HNF4A/MODY1, GCK/MODY2, TCF1/MODY3, IPF1/MODY4, TCF2/MODY5 and NEUROD1/MODY6. We studied a Swiss family with 13 diabetic patients over 3 generations. The average age at diagnosis was 35 +/- 15 years (7 subjects before 30). In addition, 2 individuals had an abnormal oral glucose tolerance. The mutation present in this family was located in the DNA binding domain of HNF4A, a strongly conserved region across almost all species, and segregated in all the MODY patients. Identification of this missense mutation allowed for presymptomatic diagnosis in the younger generations and will improve medical follow-up of the predisposed individuals.
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PMID:Large Family With Maturity-Onset Diabetes of the Young and a Novel V121I Mutation in HNF4A. 1220 96

The study of maturity-onset diabetes of the young (MODY), an autosomal dominant form of early-onset diabetes mellitus characterised by defective insulin secretion has been extremely successful in two ways. Firstly it has enabled definitive diagnosis for patients. This allows more accurate prediction of disease and treatment requirements. Secondly it has facilitated an increased understanding of the genes and pathways that are crucial for normal beta-cell function. Five of the six MODY genes, TCF1 (encoding HNF-1alpha), TCF2 (encoding HNF-1beta) HNF4A, insulin promoter factor (IPF)1, and NEUROD1, are transcription factors that operate in a complex network of gene regulation. Several genes have been shown to be regulated by the MODY transcription factors in a beta-cell specific manner. This includes the co-regulation of HNF-1alpha and HNF-4alpha by each other. The exact mechanism of how mutations in these transcription factors result in diabetes in humans remains unknown. However, current opinion favours pleiotropic adverse effects on many genes; extensive in vitro and in vivo studies of these genes has highlighted their importance in both glucose sensing-insulin secretion coupling and maintaining the fully differentiated beta-cell phenotype.
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PMID:The role of transcription factors in maturity-onset diabetes of the young. 1235 28

We have proposed that hyperglycemia-induced dedifferentiation of beta-cells is a critical factor for the loss of insulin secretory function in diabetes. Here we examined the effects of the duration of hyperglycemia on gene expression in islets of partially pancreatectomized (Px) rats. Islets were isolated, and mRNA was extracted from rats 4 and 14 weeks after Px or sham Px surgery. Px rats developed different degrees of hyperglycemia; low hyperglycemia was assigned to Px rats with fed blood glucose levels less than 150 mg/dl, and high hyperglycemia was assigned above 150 mg/dl. beta-Cell hypertrophy was present at both 4 and 14 weeks. At the same time points, high hyperglycemia rats showed a global alteration in gene expression with decreased mRNA for insulin, IAPP, islet-associated transcription factors (pancreatic and duodenal homeobox-1, BETA2/NeuroD, Nkx6.1, and hepatocyte nuclear factor 1 alpha), beta-cell metabolic enzymes (glucose transporter 2, glucokinase, mitochondrial glycerol phosphate dehydrogenase, and pyruvate carboxylase), and ion channels/pumps (Kir6.2, VDCC beta, and sarcoplasmic reticulum Ca(2+)-ATPase 3). Conversely, genes normally suppressed in beta-cells, such as lactate dehydrogenase-A, hexokinase I, glucose-6-phosphatase, stress genes (heme oxygenase-1, A20, and Fas), and the transcription factor c-Myc, were markedly increased. In contrast, gene expression in low hyperglycemia rats was only minimally changed at 4 weeks but significantly changed at 14 weeks, indicating that even low levels of hyperglycemia induce beta-cell dedifferentiation over time. In addition, whereas 2 weeks of correction of hyperglycemia completely reverses the changes in gene expression of Px rats at 4 weeks, the changes at 14 weeks were only partially reversed, indicating that the phenotype becomes resistant to reversal in the long term. In conclusion, chronic hyperglycemia induces a progressive loss of beta-cell phenotype with decreased expression of beta-cell-associated genes and increased expression of normally suppressed genes, these changes being present with even minimal levels of hyperglycemia. Thus, both the severity and duration of hyperglycemia appear to contribute to the deterioration of the beta-cell phenotype found in diabetes.
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PMID:Critical reduction in beta-cell mass results in two distinct outcomes over time. Adaptation with impaired glucose tolerance or decompensated diabetes. 1243 14

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

An alternative approach to the treatment of type I diabetes is the use of genetically altered neoplastic liver cells to synthesize, store and secrete insulin. To try and achieve this goal we modified a human liver cell line, HUH7, by transfecting it with human insulin cDNA under the control of the cytomegalovirus promoter. The HUH7-ins cells created were able to synthesize insulin in a similar manner to that which occurs in pancreatic beta cells. They secreted insulin in a regulated manner in response to glucose, calcium and theophylline, the dose-response curve for glucose being near-physiological. Perifusion studies showed that secretion was rapid and tightly controlled. Removal of calcium resulted in loss of glucose stimulation while addition of brefeldin A resulted in a 30% diminution of effect, indicating that constitutive release of insulin occurred to a small extent. Insulin was stored in granules within the cytoplasm. When transplanted into diabetic immunoincompetent mice, the cells synthesized, processed, stored and secreted diarginyl insulin in a rapid regulated manner in response to glucose. Constitutive release of insulin also occurred and was greater than regulated secretion. Blood glucose levels of the mice were normalized but ultimately became subnormal due to continued proliferation of cells. Examination of the HUH7-ins cells as well as the parent cell line for beta cell transcription factors showed the presence of NeuroD but not PDX-1. PC1 and PC2 were also present in both cell types. Thus, the parent HUH7 cell line possessed a number of endocrine pancreatic features that reflect the common endodermal ancestry of liver and pancreas, perhaps as a result of ontogenetic regression of the neoplastic liver cell from which the line was derived. Introduction of the insulin gene under the control of the CMV promoter induced changes in these cells to make them function to some extent like pancreatic beta cells. Our results support the view that neoplastic liver cells can be induced to become substitute pancreatic beta cells and become a therapy for the treatment of type I diabetes.
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PMID:Function of a genetically modified human liver cell line that stores, processes and secretes insulin. 1262 53

Association of the NEUROD Ala45Thr polymorphism with Type 1 diabetes mellitus (DM) has been found in some but not all populations. We performed a study on the association of two NEUROD exon 2 polymorphisms, the Ala45Thr and the Pro197His, with childhood-onset Type 1 DM in the Czech population. We compared 285 children with Type 1 DM diagnosed under the age of 15 years with 289 non-diabetic control children. The genotypes were determined using novel real-time allele-specific PCR assays in the TaqMan format, and data were analysed using logistic regression. The numbers of subjects with codon 45 genotypes Ala/Ala, Ala/Thr, Thr/Thr were 95, 145, 45 among cases and 117, 130, 42 among controls. Thr45 phenotypic positivity was associated with a significant risk of Type 1 DM (OR=2.01, CI 95% 1.25-3.24) in a multivariate logistic regression model involving also the insulin gene -23HphI genotype and the presence of Type 1 DM-associated HLA-DQB1*0302-DQA1*03 (DQ8) and DQB1*0201-DQA1*05 (DQ2) molecules. No association was observed for the Pro197His mutation which was carried by 5.3% cases and 5.9% controls. Our results confirm that the NEUROD Ala45Thr polymorphism is associated with childhood-onset Type 1 DM.
Diabetes Res Clin Pract 2003 Apr
PMID:NEUROD polymorphism Ala45Thr is associated with Type 1 diabetes mellitus in Czech children. 1263 65

To explore induced islet neogenesis in the liver as a strategy for the treatment of diabetes, we used helper-dependent adenovirus (HDAD) to deliver the pancreatic duodenal homeobox-1 gene (Ipf1; also known as Pdx-1) to streptozotocin (STZ)-treated diabetic mice. HDAD is relatively nontoxic as it is devoid of genes encoding viral protein. Mice treated with HDAD-Ipf1 developed fulminant hepatitis, however, because of the exocrine-differentiating activity of Ipf1. The diabetes of STZ mice was partially reversed by HDAD-mediated transfer of NeuroD (Neurod), a factor downstream of Ipf1, and completely reversed by a combination of Neurod and betacellulin (Btc), without producing hepatitis. Treated mice were healthy and normoglycemic for the duration of the experiment (>120 d). We detected in the liver insulin and other islet-specific transcripts, including proinsulin-processing enzymes, beta-cell-specific glucokinase and sulfonylurea receptor. Immunocytochemistry detected the presence of insulin, glucagon, pancreatic polypeptide and somatostatin-producing cells organized into islet clusters; immuno-electron microscopy showed typical insulin-containing granules. Our data suggest that Neurod-Btc gene therapy is a promising regimen to induce islet neogenesis for the treatment of insulin-dependent diabetes.
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PMID:NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. 1272 55

An elucidation of the key regulatory factors in pancreas development is critical for understanding the pathogenesis of diabetes mellitus. This study examined whether a specific regulatory mechanism that exists in neuronal development also plays a role in the pancreas. In non-neuronal cells, neuron-restrictive silencer factor (NSRF) actively represses gene transcription via a sequence-specific DNA motif known as the neuron-restrictive silencer element (NRSE). This DNA motif has been identified in many genes that are specific markers for cells of neuronal and neuroendocrine lineage. We identified several genes involved in pancreas development that also harbor NRSE-like motifs, including pdx-1, Beta2/NeuroD, and pax4. The paired homeodomain transcription factor Pax4 is implicated in the differentiation of the insulin-producing beta-cell lineage because disruption of the pax4 gene results in a severe deficiency of beta-cells and the manifestation of diabetes mellitus in mice. The NRSE-like motif identified in the upstream pax4 promoter is highly conserved throughout evolution, forms a DNA-protein complex with NRSF, and confers NRSF-dependent transcriptional repression in the context of a surrogate gene promoter. This cis-activating NRSE element also confers NRSF-dependent modulation in the context of the native pax4 gene promoter. Together with earlier reports, these new findings suggest an important functional role for NRSF in the expression of the pax4 gene and infer a role for NRSF in pancreatic islet development.
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PMID:Regulation of Pax4 paired homeodomain gene by neuron-restrictive silencer factor. 1282

The BETA2/NeuroD1 gene product is a transcription factor, a member of a helix-loop-helix (HLH) family that is specifically expressed in the endocrine pancreas. HLH and homeobox proteins are involved in the development and function of pancreatic islets cells. Mice homozygous for a targeted disruption of BETA2/NeuroD1 showed abnormal pancreatic islet morphogenesis and developed overt diabetes. Mutations in the NeuroD/BETA2 gene were linked to the development of type 2 diabetes (T2DM). The aims of the study were to determine the allele and genotype frequency of Ala45Thr polymorphism of BETA2/NeuroD1 in a Polish population and to examine the role of this amino acid variant in the genetic susceptibility to T2DM. We included 394 individuals into this study: 223 T2DM patients with the age at diagnosis above 35 years and 171 controls without a family history of T2DM. The fragment of the gene, corresponding to the Ala45Thr amino acid variant, was amplified by polymerase chain reaction. Alleles and genotypes were determined based on electrophoresis of the specific restriction enzyme EcoI57 DNA digestion products. Differences in distribution between the groups were examined by chi(2) test. The frequencies of the Ala and Thr alleles in T2DM patients (62% and 37.9%) were similar to those in the controls (65.5% and 34.5%; p=0.32). Similarly, there was no difference between the groups when we analyzed the genotype distribution (p=0.24). The stratification analysis based on family history of T2DM, obesity, and age of diagnosis did not show any difference between the groups. In conclusion, the frequency of Ala45Thr polymorphism in this studied Polish population is similar to its frequency in other Caucasians. We did not find evidence that the Ala45Thr polymorphism of BETA2/NeuroD1 played a role in the risk of T2DM in the examined Polish population.
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PMID:The Ala45Thr polymorphism of BETA2/NeuroD1 gene and susceptibility to type 2 diabetes mellitus in a Polish population. 1286 11


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