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

Recent genome searches suggest a putative linkage of many loci to susceptibility to type I diabetes. The chromosome 2q31-35 region is reported to be linked to susceptibility to type I diabetes and is thought to contain several diabetes susceptibility loci. These candidate genes include the HOXD gene cluster, BETA2, CTLA4, CD28, IGFBP2, and IGFBP5. Association studies in populations and families are required to confirm and/or identify the actual susceptibility loci. We hereby report several previously unknown DNA polymorphisms for HOXD8, BETA2, and IGFBP5, which we have used along with previously known polymorphisms of HOXD8 and CTLA4 to test whether these candidate loci are the susceptibility genes on chromosome 2q31-35. Using a case-control design with a subsequent family-association approach to confirm associations, we find no evidence that these candidate genes are associated with susceptibility to type I diabetes.
Diabetes 1997 Jun
PMID:Analysis of candidate genes for susceptibility to type I diabetes: a case-control and family-association study of genes on chromosome 2q31-35. 916 81

Candidate transcription factors involved in pancreatic endocrine development have been isolated using insulin gene regulation as a paradigm. The cell-type restricted basic helix-loop-helix (bHLH) gene, BETA2/NeuroD, expressed in pancreatic endocrine cells, the intestine, and the brain, activates insulin gene transcription and can induce neurons to differentiate. To understand the importance of BETA2 in pancreatic endocrine cell differentiation, mice lacking a functional BETA2 gene were generated by gene targeting experiments. Mice carrying a targeted disruption of the BETA2 gene developed severe diabetes and died perinatally. Homozygous BETA2 null mice had a striking reduction in the number of insulin-producing beta cells and failed to develop mature islets. Islet morphogenesis appeared to be arrested between E14.5 and E17.5, a period characterized by major expansion of the beta cell population. The presence of severe diabetes in these mice suggests that proper islet structure plays an important role in blood glucose homeostasis. In addition, secretin- and cholecystokinin-producing enteroendocrine cells failed to develop in the absence of BETA2. The absence of these two pancreatic secretagogs may explain the abnormal cellular polarity and inability to secrete zymogen granules in pancreatic acinar exocrine cells. The nervous system appeared to develop normally, despite abundant expression of BETA2 in differentiating neurons. Thus, BETA2 is critical for the normal development of several specialized cell types arising from the gut endoderm.
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PMID:Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. 930 61

NeuroD/BETA2, a transcription factor of the insulin gene, also plays an important role in the development of pancreatic beta-cells. Recently, the NeuroD/BETA2 gene has been mapped to the long arm of human chromosome 2 (2q32) where the IDDM7 gene has previously been mapped, implying its involvement in diabetes. To identify mutations in the NeuroD/BETA2 gene that may predispose patients to develop diabetes, we studied the gene in 50 Japanese subjects with diabetes (4 with type 1 and 46 with type 2) by the polymerase chain reaction (PCR) followed by single-strand conformation polymorphism and sequencing analyses. Further analysis was performed in 392 Japanese subjects (60 with type 1 and 158 with type 2 diabetes and 174 healthy control subjects) by mismatch PCR restriction fragment length polymorphism. We found a DNA polymorphism of the NeuroD/BETA2 gene. A nucleotide G-to-A transition results in the substitution of alanine to threonine at codon 45 (Ala45Thr). The frequencies of heterozygotes for the Ala45Thr variant were 9.8% in the control subjects, 9.5% in the patients with type 2 diabetes, and 25.0% in the patients with type 1 diabetes, a significant difference (P = 0.006). Because the variant of the NeuroD/BETA2 gene (Ala45Thr) is associated with type 1 but not type 2 diabetes, it may be implicated in the loss of pancreatic beta-cells in type 1 diabetes.
Diabetes 1999 Feb
PMID:Association of polymorphism in the NeuroD/BETA2 gene with type 1 diabetes in the Japanese. 1033 23

NeuroD, a bHLH transcription factor, is implicated in differentiation of neurons and pancreatic beta cells. NeuroD-null mice die shortly after birth due to severe neonatal diabetes. To examine if there is postnatal neuronal phenotype in these mice, we rescued them from neonatal lethality by introducing a transgene encoding the mouse neuroD gene under the insulin promoter. These mice survive to adulthood but display severe neurological phenotype due to neuronal deficit in the granule layers of the cerebellum and hippocampus. We show here that NeuroD is required for these postnatally generated microneurons to undergo proper differentiation, the absence of which results in cell death.
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PMID:NeuroD is required for differentiation of the granule cells in the cerebellum and hippocampus. 1039 78

The helix-loop-helix (HLH) protein NEUROD1 (also known as BETA2) functions as a regulatory switch for endocrine pancreatic development. In mice homozygous for a targeted disruption of Neurod, pancreatic islet morphogenesis is abnormal and overt diabetes develops due in part to inadequate expression of the insulin gene (Ins2). NEUROD1, following its heterodimerization with the ubiquitous HLH protein E47, regulates insulin gene (INS) expression by binding to a critical E-box motif on the INS promoter. Here we describe two mutations in NEUROD1, which are associated with the development of type 2 diabetes in the heterozygous state. The first, a missense mutation at Arg 111 in the DNA-binding domain, abolishes E-box binding activity of NEUROD1. The second mutation gives rise to a truncated polypeptide lacking the carboxy-terminal trans-activation domain, a region that associates with the co-activators CBP and p300 (refs 3,4). The clinical profile of patients with the truncated NEUROD1 polypeptide is more severe than that of patients with the Arg 111 mutation. Our findings suggest that deficient binding of NEUROD1 or binding of a transcriptionally inactive NEUROD1 polypeptide to target promoters in pancreatic islets leads to the development of type 2 diabetes in humans.
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PMID:Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. 1054 51

BETA 2/NEUROD1 is a key regulator of pancreatic islet morphogenesis and insulin gene transcription. The BETA 2/NEUROD1 gene-locus lies on human chromosome 2q32, in a region previously linked to Type 1 diabetes (IDDM7). Recently, a significant association has been reported between NEUROD1-A45T polymorphism and Type 1 diabetes in the Japanese population. In an attempt to replicate this observation, we performed a case/control study in the French population. We failed to find any association between the A45T polymorphism and the disease-trait. The study therefore suggests that NEUROD1 is unlikely to play a major role in susceptibility to Type 1 diabetes in the French population.
Diabetes Metab 1999 Dec
PMID:Absence of replication in the French population of the association between beta 2/NEUROD-A45T polymorphism and type 1 diabetes. 1063 78

In the mammalian pancreas, the endocrine cell types of the islets of Langerhans, including the alpha-, beta-, delta-, and pancreatic polypeptide cells as well as the exocrine cells, derive from foregut endodermal progenitors. Recent genetic studies have identified a network of transcription factors, including Pdx1, Isl1, Pax4, Pax6, NeuroD, Nkx2.2, and Hlxb9, regulating the development of islet cells at different stages, but the molecular mechanisms controlling the specification of pancreatic endocrine precursors remain unknown. neurogenin3 (ngn3) is a member of a family of basic helix-loop-helix transcription factors that is involved in the determination of neural precursor cells in the neuroectoderm. ngn3 is expressed in discrete regions of the nervous system and in scattered cells in the embryonic pancreas. We show herein that ngn3-positive cells coexpress neither insulin nor glucagon, suggesting that ngn3 marks early precursors of pancreatic endocrine cells. Mice lacking ngn3 function fail to generate any pancreatic endocrine cells and die postnatally from diabetes. Expression of Isl1, Pax4, Pax6, and NeuroD is lost, and endocrine precursors are lacking in the mutant pancreatic epithelium. Thus, ngn3 is required for the specification of a common precursor for the four pancreatic endocrine cell types.
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PMID:neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. 1067 6

To evaluate the role of the Ala45Thr variant of BETA2/NEUROD1 in the development of type 1 or type 2 diabetes, we studied a Japanese population consisting of 383 control subjects, 234 type 1 diabetes patients and 160 type 2 diabetes patients. Both genotypewise and allelewise, there was no significant association of the variant with type 1 diabetes or type 2 diabetes in Japanese. Also, there were no significant differences in clinical characteristics with and without the variant. Our present results do not support a recent report which described an association of the Ala45Thr variant with type 1 diabetes in Japanese.
Diabetes Res Clin Pract 2000 Jul
PMID:Lack of association of the Ala45Thr variant in the BETA2/NEUROD1 with type 1 diabetes in Japanese. 1080 64

The nature and identity of the pancreatic beta-cell precursor has remained elusive for many years. One model envisions an early multihormonal precursor that gives rise to both alpha- and beta-cells and the other endocrine cell types. Alternatively, beta-cells have been suggested to arise late, directly from the GLUT2- and pancreatic duodenal homeobox factor-1 (PDX1)-expressing epithelium, which gives rise also to the acinar cells during this stage. In this study, we have identified a subset of the PDX1+ epithelial cells that are marked by expression of Neurogenin3 (Ngn3). Ngn3, a member of the basic helix-loop-helix (bHLH) family of transcription factors, is suggested to act upstream of NeuroD in a bHLH cascade. Detailed analysis of Ngn3/paired box factor 6 (PAX6) and NeuroD/PAX6 co-expression shows that the two bHLH factors are expressed in a largely nonoverlapping set of cells, but such analysis also suggests that the NeuroD+ cells arise from cells expressing Ngn3 transiently. NeuroD+ cells do not express Ki-67, a marker of proliferating cells, which shows that these cells are postmitotic. In contrast, Ki-67 is readily detected in Ngn3+ cells. Thus, Ngn3+ cells fulfill the criteria for an endocrine precursor cell. These expression patterns support the notion that both alpha- and beta-cells develop independently from PDX1+/Ngn3+ epithelial cells, rather than from GLU+/INS+ intermediate stages. The earliest sign of alpha-cell development appears to be Brain4 expression, which apparently precedes Islet-1 (ISL1) expression. Based on our expression analysis, we propose a temporal sequence of gene activation and inactivation for developing alpha- and beta-cells beginning with activation of NeuroD expression. Endocrine cells leave the cell cycle before NeuroD activation, but re-enter the cell cycle at perinatal stages. Dynamic expression of Notch1 in PDX+ epithelial cells suggests that Notch signaling could inhibit a Ngn-NeuroD cascade as seen in the nervous system and thus prevent premature differentiation of endocrine cells.
Diabetes 2000 Feb
PMID:Independent development of pancreatic alpha- and beta-cells from neurogenin3-expressing precursors: a role for the notch pathway in repression of premature differentiation. 1086 31

Mutations in the NeuroD/BETA2 gene have been shown to associate with type 2 diabetes. In the present study, we examined mutations in the NeuroD/BETA2 gene for association with either type 1 or 2 diabetes. Three variants were identified in patients with type 2 diabetes: Ala45Thr (allelic frequency 0.36, 95% CI 0.31-0.41), Pro197His (0.01), and Ser259Ser (0.01). Ala45Thr and Pro197His were not associated with type 2 diabetes, but the transmission disequilibrium test showed unequal transmission of the A45 allele to offspring with type 1 diabetes (chi2 = 5.90, P < 0.02, odds ratio 1.55, 95% CI 0.91-2.63). This association could not be explained by linkage disequilibrium between the Ala45 allele and IDDM7 (D2S152), which is also located on chromosome 2q32. When tested in vitro, the biological activity of Thr45 (117+/-36% vs. Ala45) and His197 (90+/-28% vs. Pro197) on the regulation of the human insulin gene promoter appeared normal. In conclusion, mutations in the NeuroD/BETA2 gene are not a common cause of late-onset type 2 diabetes among Danes. However, in the type 1 diabetic Danish population, the Ala45Thr variant of NeuroD/BETA2 may represent a susceptibility marker independent of IDDM7 on chromosome 2q32.
Diabetes 2000 May
PMID:NeuroD/BETA2 gene variability and diabetes: no associations to late-onset type 2 diabetes but an A45 allele may represent a susceptibility marker for type 1 diabetes among Danes. Danish Study Group of Diabetes in Childhood, and the Danish IDDM Epidemiology and Genetics Group. 1090


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