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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset (<25 years) and pancreatic beta-cell dysfunction. MODY is genetically heterogeneous with five different genes identified to date: hepatocyte nuclear factor-4 alpha (HNF-4 alpha) [MODY1]; glucokinase [MODY2]; hepatocyte nuclear factor-1 alpha (HNF-1 alpha) [MODY3]; insulin promoter factor-1 (IPF-1) [MODY4]; and hepatocyte nuclear factor-1 beta (HNF-1 beta) [MODY5]. Mutations in the HNF-1 alpha gene represent a common cause of MODY in the majority of populations studied. Sixty-five different mutations have been described in a total of 116 families. The most common mutation is a C-insertion (P291fsinsC) in the polyC tract of exon 4, which has been reported in 22 families. The identification of an HNF-1 alpha gene mutation in a patient with type 2 diabetes confirms the diagnosis of MODY and has important implications for clinical management.
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PMID:Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) mutations in maturity-onset diabetes of the young. 1105 94

PDX-1 is a homeodomain transcription factor whose targeted disruption results in a failure of the pancreas to develop. Mutations in the human pdx-1 gene are linked to an early onset form of non-insulin-dependent diabetes mellitus. PDX-1 binds to and transactivates the promoters of several physiologically relevant genes within the beta-cell, including insulin, glucose transporter 2, glucokinase, and islet amyloid polypeptide. This study focuses on the mechanisms by which PDX-1 activates insulin gene transcription. To evaluate the role of PDX-1 in transcription of the insulin gene, a chloramphenicol acetyltransferase reporter construct was designed with a single yeast GAL4-DNA binding site in place of the A3/PDX-1 binding element in the rat insulin II enhancer. In the presence of GAL4:PDX chimeras containing N-terminal transactivation domain sequences, this GAL4-substituted insulin construct was active in PDX-1-expressing beta-cells and not non-beta-cells. PDX-1 activation was mediated through three highly conserved segments of the transactivation domain. In addition, when cotransfected together with the GAL4-substituted insulin enhancer reporter gene in glucose-responsive MIN-6 beta-cells, glucose-induced activation is observed with GAL4:PDX-1 but not with fusions of the heterologous activation domains from herpes virus VP16 or adenovirus-5 E1A proteins. Using A3 element-substituted GAL4 insulin enhancer reporter constructs containing mutations in two additional key control elements, E1 and C1, we also show that full activation requires cooperative interactions between other enhancer-bound factors, particularly the E1 element activators. In contrast, the activity of the VP16 activation factor was not dependent on the activators of either the E1 or C1 sites. These results suggest that the PDX-1 transactivation domain is specifically required for appropriate regulation of insulin enhancer function in beta-cells.
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PMID:The PDX-1 activation domain provides specific functions necessary for transcriptional stimulation in pancreatic beta-cells. 1111 22

Cell transplantation therapy for diabetes is limited by an inadequate supply of cells exhibiting glucose-responsive insulin secretion. To generate an unlimited supply of human beta-cells, inducibly transformed pancreatic beta-cell lines have been created by expression of dominant oncogenes. The cell lines grow indefinitely but lose differentiated function. Induction of beta-cell differentiation was achieved by stimulating the signaling pathways downstream of the transcription factor PDX-1, cell-cell contact, and the glucagon-like peptide (GLP-1) receptor. Synergistic activation of those pathways resulted in differentiation into functional beta-cells exhibiting glucose-responsive insulin secretion in vitro. Both oncogene-expressing and oncogene-deleted cells were transplanted into nude mice and found to exhibit glucose-responsive insulin secretion in vivo. The ability to grow unlimited quantities of human beta-cells is a major step toward developing a cell transplantation therapy for diabetes.
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PMID:Beta-cell differentiation from a human pancreatic cell line in vitro and in vivo. 1122 48

The endocrine cells of the rat pancreatic islets of Langerhans, including insulin-producing beta-cells, turn over every 40-50 days by processes of apoptosis and the proliferation and differentiation of new islet cells (neogenesis) from progenitor epithelial cells located in the pancreatic ducts. However, the administration to rats of islet trophic factors such as glucose or glucagon-like peptide 1 for 48 h results in a doubling of islet cell mass, suggesting that islet progenitor cells may reside within the islets themselves. Here we show that rat and human pancreatic islets contain a heretofore unrecognized distinct population of cells that express the neural stem cell-specific marker nestin. Nestin-positive cells within pancreatic islets express neither the hormones insulin, glucagon, somatostatin, or pancreatic polypeptide nor the markers of vascular endothelium or neurons, such as collagen IV and galanin. Focal regions of nestin-positive cells are also identified in large, small, and centrolobular ducts of the rat pancreas. Nestin-positive cells in the islets and in pancreatic ducts are distinct from ductal epithelium because they do not express the ductal marker cytokeratin 19 (CK19). After their isolation, these nestin-positive cells have an unusually extended proliferative capacity when cultured in vitro (approximately 8 months), can be cloned repeatedly, and appear to be multipotential. Upon confluence, they are able to differentiate into cells that express liver and exocrine pancreas markers, such as alpha-fetoprotein and pancreatic amylase, and display a ductal/endocrine phenotype with expression of CK19, neural-specific cell adhesion molecule, insulin, glucagon, and the pancreas/duodenum specific homeodomain transcription factor, IDX-1. We propose that these nestin-positive islet-derived progenitor (NIP) cells are a distinct population of cells that reside within pancreatic islets and may participate in the neogenesis of islet endocrine cells. The NIP cells that also reside in the pancreatic ducts may be contributors to the established location of islet progenitor cells. The identification of NIP cells within the pancreatic islets themselves suggest possibilities for treatment of diabetes, whereby NIP cells isolated from pancreas biopsies could be expanded ex vivo and transplanted into the donor/recipient.
Diabetes 2001 Mar
PMID:Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. 1124 71

Deficient insulin secretion and relative hyperproinsulinemia are characteristic features of type 2 diabetes. The gerbil Psammomys obesus appears to be an ideal natural model of the human disease because it shows increased tendency to develop diet-induced diabetes, which is associated with moderate obesity. The disease is characterized by initial hyperinsulinemia, progressing to hypoinsulinemia associated with depleted pancreatic insulin stores and an increased proportion of insulin precursor molecules in the blood and islets. Although the proinsulin translational efficacy was found to be increased in hyperglycemic animals, insulin mRNA levels were not augmented and exhibited a gradual decrease with disease progression. The development of hyperglycemia was associated with a transient increase in beta-cell proliferative activity, as opposed to a prolonged increase in the rate of beta-cell death, culminating in disruption of islet architecture. The hypothesis that glucotoxicity is responsible in part for these in vivo changes was investigated in vitro in primary islet cultures. Islets from diabetes-prone P. obesus cultured at high glucose concentrations displayed changes in beta-cell function that mimic those observed in diabetic animals. These changes include deficient insulin secretion, depleted insulin content, an increased proportion of insulin precursor molecules, a progressive increase of DNA fragmentation, and a transient proliferative response. Furthermore, insulin mRNA was not increased by short-term exposure of P. obesus islets to elevated glucose in vitro. It is proposed that beta-cell glucotoxicity in P. obesus results from the inability of proinsulin biosynthesis to keep pace with chronic insulin hypersecretion. The resulting depletion of the insulin stores may be related to deficient glucose-regulated insulin gene transcription, possibly due to defective PDX-1 (pancreatic duodenal homeobox factor-1) expression in the adult P. obesus. An additional glucotoxic effect involves the loss of beta-cell mass in hyperglycemic P. obesus as a result of progressive beta-cell death without an adequate increase in the rate of beta-cell proliferation.
Diabetes 2001 Feb
PMID:beta-cell glucotoxicity in the Psammomys obesus model of type 2 diabetes. 1127 67

PDX-1 was shown to be expressed early during development in cells of both exocrine and endocrine origin; later it becomes restricted primarily to beta-cells where it regulates the expression of beta-cell-specific genes and mediates the glucose effect on insulin gene transcription. Therefore, it was important to identify the molecular mechanisms that specifically govern the expression of pdx-1 in the mature beta-cell. To address this question, we analyzed 7 kb of the 5' flanking region of the human pdx-1 gene. By transient transfections of beta- and non-beta-cell lines with different 5' and 3' deletions of that region, a strong beta-cell-specific enhancer element located between -3.71 and 3.46 kb was revealed. We also sequenced about 4.5 kb of the human 5' flanking region and compared it with that of the mouse pdx-1 gene. This comparison revealed three short conserved regions, designated PH1, PH2, and PH3. We showed that HNF-3beta can bind and stimulate the activity of the human PH1 and PH2 elements in non-beta-cells. Results reported by Wu et al. (7) and Sharma et al. (6) also indicate that expression of the mouse pdx-1 is controlled by an HNF-3-like element. Thus, it can be stated that at least some aspects of pdx-1 expression rely on the transcription factor HNF-3beta. Because HNF-3beta is not restricted to beta-cells, the selective transcription of pdx-1 is likely to rely on additional factors. Our findings that the PH1 enhancer element binds both HNF-3beta and PDX-1 and that mutations in each individual site dramatically impair its transcriptional activity suggest that these factors cooperate with one another. We therefore propose that a possible feedback mechanism might control the expression of pdx-1 at different stages during development.
Diabetes 2001 Feb
PMID:Regulatory elements involved in human pdx-1 gene expression. 1127 96

beta-Cell transcription factor genes are important in the pathophysiology of the beta-cell, with mutations in hepatocyte nuclear factor (HNF)-1alpha, HNF-4alpha, insulin promoter factor (IPF)-1, HNF-1beta, and NeuroD1/BETA2, all resulting in early-onset type 2 diabetes. We assessed the relative contribution of these genes to early-onset type 2 diabetes using linkage and sequencing analysis in a cohort of 101 families (95% U.K. Caucasian). The relative distribution of the 90 families fitting maturity-onset diabetes of the young (MODY) criteria was 63% HNF-1alpha, 2% HNF-4alpha, 0% IPF-1, 1% HNF-1beta, 0% NeuroD1/ BETA2, and 20% glucokinase. We report the molecular genetic and clinical characteristics of these patients including 29 new families and 8 novel HNF-1alpha gene mutations. Mutations in the transactivation domain are more likely to be protein truncating rather than result in amino acid substitutions, suggesting that a relatively severe disruption of this domain is necessary to result in diabetes. Mutations in the different transcription factors result in clinical heterogeneity. IPF-1 mutations are associated with a higher age at diagnosis (42.7 years) than HNF-1alpha (20.4 years), HNF-1beta (24.2 years), or HNF-4alpha (26.3 years) gene mutations. Subjects with HNF-1beta mutations, in contrast to the other transcription factors, frequently present with renal disease. A comparison of age at diagnosis between subjects with different types and locations of HNF-1alpha mutations did not reveal genotype-phenotype correlations. In conclusion, mutations in transcription factors expressed in the beta-cell are the major cause of MODY, and the phenotype clearly varies with the gene that is mutated. There is little evidence to indicate that different mutations within the same gene have different phenotypes.
Diabetes 2001 Feb
PMID:beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. 1127 11

Type 2 diabetes is a complex disease and genetic as well as environmental factors play a role in its pathogenesis. Six different genes have been identified so far to be responsible for rare forms of autosomal dominant, early onset type 2 diabetes mellitus. All but one are transcription factors which influence expression of the other genes through the regulation of mRNA synthesis. These are hepatocyte nuclear factor (HNF)-4 alpha, HNF-1 alpha, insulin promoter factor (IPF)-1 and HNF-1 beta, which are associated with MODY1, 3, 4, 5 respectively. MODY1 is a relatively rare and usually severe form of diabetes. It is associated with progressive hyperglycemia and frequent chronic complications. The HNF-4 alpha gene is localized on chromosome 20q. Similar clinical characteristics apply to the MODY3 form, however the latter is much more frequent among early onset, autosomal dominant type 2 diabetes (20-40%). HNF-1 alpha gene is localized on chromosome 12q. HNF-1 beta (MODY5 locus on chromosome 17q) is a protein which forms heterodimers with HNF-1 alpha. This rare form of diabetes has a clinical picture similar to MODY1 and MODY3. It is sometimes accompanied by symptoms of early kidney damage which are independent from diabetes. The other two transcription factors responsible for the development of autosomal dominant type 2 diabetes are proteins which bind directly to the insulin promoter. MODY4 (IPF-1, chromosome 13q) is a rare form and of a typical middle and late onset type 2 diabetes. BETA 2/Neurod1 has been recently associated with MODY by Dr Krolewski's group from Joslin Diabetes Center, Boston, MA, USA. BETA 2 is responsible for about 2% of autosomal dominant type 2 diabetes. The clinical characteristics depend on the localization of the mutations in the specific functional domains of the protein. Mutations identified in the glucokinase gene are associated with the MODY2 form. Glucokinase is an enzyme involved in the first level of glucose metabolism in b-cells-enzymatic phosphorylation. MODY2 is a modest form of diabetes. It is characterized by mild hyper-glycemia, mainly fasting, and the chronic complications are very rare. Glucokinase gene is localized on chromosome 7p. It is expected that in the nearest future more type 2 susceptibility genes will be identified.
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PMID:[Molecular background and clinical characteristics of autosomal dominant type 2 diabetes mellitus]. 1129 29

Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. Genetic factors contribute to the development of diabetes. Some forms such as the condition called maturity-onset diabetes of the young(MODY) result from mutations in a single gene. Other forms such as type 1 or type 2 diabetes are multifactorial in origin with different combinations of genes together with non-genetic factors contributing to the development of hyperglycemia. MODY has been a good model for studying the genetics and pathophysiology of diabetes. This form of diabetes can result from mutations in at least seven different genes: hepatocyte nuclear factor(HNF)-4 alpha/MODY1, glucokinase/MODY2, HNF-1 alpha/MODY3, insulin promoter factor(IPF-1)/MODY4, HNF-1 beta/MODY5, NeuroD1/MODY6 and Islet(Isl)-1/MODY7. Mutations in HNF-1 alpha/MODY3 are the most common cause of MODY in Japanese identified to date accounting for about 15% of cases of MODY. Mutations in the HNF-4 alpha/MODY1, glucokinase/MODY2, HNF-1 beta/MODY5 and Isl-1/MODY7 genes have also been found in Japanese; however, they are rare causes of MODY. Clinical studies indicate that patients with MODY are generally not obese and that all forms of MODY are characterized by pancreatic beta-cell dysfunction. Patients who have mutations in the HNF-1 beta/MODY5 gene have non-diabetic kidney dysfunction including renal cysts. Female carriers may also exhibit abnormalities in the upper vagina and uterus. Genetic approach for type 2 diabetes had done by using non-parameteric linkage analysis such as sibpair analysis which worked well and NIDDM1 and NIDDM2 have been identified to date. The responsible gene for NIDDM1 was recently identified to be Calpain 10, and SNP43 in this gene could explain all of the evidence for linkage in Mexican American type 2 diabetes.
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PMID:[Diabetes mellitus]. 1130 9

It is known well that activation of the hexosamine pathway causes insulin resistance, but how this activation influences pancreatic beta-cell function remains unclear. In this study, we found that in isolated rat islets adenovirus-mediated overexpression of glutamine:fructose-6-phosphate amidotransferase (GFAT), the first and rate-limiting enzyme of the hexosamine pathway, leads to deterioration of beta-cell function, which is similar to that found in diabetes. Overexpression of GFAT or treatment with glucosamine results in impaired glucose-stimulated insulin secretion and reduction in the expression levels of several beta-cell specific genes (insulin, GLUT2, and glucokinase). Additionally, the DNA binding activity of PDX-1, an important transcription factor for these three genes, was markedly reduced. These phenomena were not mimicked by the induction of O-linked glycosylation with an inhibitor of O-GlcNAcase, PUGNAc. It was also found that glucosamine increases hydrogen peroxide levels and that several hexosamine pathway-mediated changes were suppressed by treatment with the antioxidant N-acetyl-l-cysteine. In conclusion, activation of the hexosamine pathway leads to deterioration of beta-cell function through the induction of oxidative stress rather than O-linked glycosylation. Thus, the hexosamine pathway may contribute to the deterioration of beta-cell function found in diabetes.
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PMID:Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function through the induction of oxidative stress. 1139 Apr 7


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