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

More than 120 published reports have described associations between single nucleotide polymorphisms (SNPs) and type 2 diabetes. However, multiple studies of the same variant have often been discordant. From a literature search, we identified previously reported type 2 diabetes-associated SNPs. We initially genotyped 134 SNPs on 786 index case subjects from type 2 diabetes families and 617 control subjects with normal glucose tolerance from Finland and excluded from analysis 20 SNPs in strong linkage disequilibrium (r(2) > 0.8) with another typed SNP. Of the 114 SNPs examined, we followed up the 20 most significant SNPs (P < 0.10) on an additional 384 case subjects and 366 control subjects from a population-based study in Finland. In the combined data, we replicated association (P < 0.05) for 12 SNPs: PPARG Pro12Ala and His447, KCNJ11 Glu23Lys and rs5210, TNF -857, SLC2A2 Ile110Thr, HNF1A/TCF1 rs2701175 and GE117881_360, PCK1 -232, NEUROD1 Thr45Ala, IL6 -598, and ENPP1 Lys121Gln. The replication of 12 SNPs of 114 tested was significantly greater than expected by chance under the null hypothesis of no association (P = 0.012). We observed that SNPs from genes that had three or more previous reports of association were significantly more likely to be replicated in our sample (P = 0.03), although we also replicated 4 of 58 SNPs from genes that had only one previous report of association.
Diabetes 2007 Jan
PMID:Screening of 134 single nucleotide polymorphisms (SNPs) previously associated with type 2 diabetes replicates association with 12 SNPs in nine genes. 1719 90

The regeneration of insulin-producing cells in vivo has emerged as a promising method for treating type I diabetes. Pancreatic duodenal homeobox-1 (Pdx-1), NeuroD, and Neurogenin-3 (Ngn3) are pancreatic transcription factors important for the development of insulin-producing cells in the liver. Other groups have demonstrated that adenoviral-mediated transgene expression of these transcription factors in the liver can reverse hyperglycemia in diabetic mice. We delivered Pdx-1 and Ngn3 to the livers of diabetic mice using adeno-associated virus (AAV) serotype 8, a vector that has been shown to result in non-toxic, persistent, high level expression of the transgene. We were unable to correct hyperglycemia in mice with streptozotocin-induced diabetes using AAV vectors expressing Pdx-1 and Ngn3. However, when we co-delivered these transcription factor expression cassettes in non-viral vectors with an irrelevant adenoviral vector, we were able to correct hyperglycemia in diabetic animals. Further studies demonstrated that an antigen-dependent immune response elicited by the adenoviral capsid together with the expression of a pancreatic transcription factor was required for restoration of serum insulin levels by the liver. Our results suggest that a host response to adenovirus in combination with expression of a pro-endocrine pancreas transcription factor is sufficient to induce insulin production in the livers of diabetic mice.
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PMID:Adenovirus transduction is required for the correction of diabetes using Pdx-1 or Neurogenin-3 in the liver. 1723 2

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

Pancreatic and duodenal homeobox factor-1 (PDX-1) plays a crucial role in pancreas development, beta-cell differentiation, and maintaining mature beta-cell function. During pancreas development, PDX-1 expression is maintained in precursor cells, and later it becomes restricted to beta-cells. In mature beta-cells, PDX-1 regulates gene expression of various beta-cell-related factors including insulin. Also, PDX-1 has potency to induce insulin-producing cells from non-beta-cells in various tissues, and PDX-1-VP16 fusion protein more efficiently induces insulin-producing cells, especially in the presence of NeuroD or Ngn3. MafA is a recently isolated beta-cell-specific transcription factor which functions as a potent activator of insulin gene transcription. During pancreas development, MafA expression is first detected at the beginning of the principal phase of insulin-producing cell production. Furthermore, MafA markedly enhances insulin gene promoter activity and ameliorates glucose tolerance in diabetic mice, especially in the presence of PDX-1 and NeuroD. Taken together, PDX-1 and MafA play a crucial role in inducing surrogate beta-cells and could be a therapeutic target for diabetes.
Diabetes Res Clin Pract 2007 Sep
PMID:Role of PDX-1 and MafA as a potential therapeutic target for diabetes. 1744 32

Forkhead transcription factors of the FoxO family have important roles in cellular proliferation, apoptosis, differentiation and stress resistance. FoxO proteins also play important roles in metabolism of complex organisms. FoxO1 regulates glucose and lipid metabolism in liver, as well as preadipocyte, myoblast and vascular endothelial cell differentiation. In the hypothalamus, FoxO controls food intake. In this chapter, we review the role of FoxO in pancreatic beta cells. Pancreatic beta cells secrete insulin to maintain the plasma glucose levels in a strict physiological range. Defects of beta cell function cause diabetes. The expression pattern of FoxO1 during pancreatic organogenesis is similar to that of Pdx1, Nkx2.2 and Pax4, transcription factors known to be critical for beta cell development. FoxO1 is expressed in a subset of pancreatic duct cells, in which insulin and/or Pdx1 are occasionally expressed. FoxO1 inhibits beta cell proliferation through suppression of Pdx1 by competing with FoxA2 and protects against beta cell failure induced by oxidative stress through NeuroD and MafA induction. Thus, a series of FoxO1 studies in pancreas suggested that FoxO1 plays important roles in pancreatic beta cell differentiation, neogenesis, proliferation and stress resistance. Genetic or pharmacological manipulation of FoxO can be used to prevent beta cell failure or aid in the differentiation of uncommitted endocrine progenitors into beta cells for transplantation.
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PMID:Role of FoxO Proteins in Pancreatic beta Cells. 1751 Apr 98

Forkhead transcription factors of the FoxO family play a critical role in cellular differentiation, proliferation, apoptosis and stress resistance. FoxO1 regulates glucose and lipid production in liver; food intake in the hypothalamus and cell differentiation in preadipocytes, myoblasts and vascular endothelium. In this review, we summarize recent literature on the role of FoxO1 in pancreatic beta cells. FoxO1 regulates beta-cell proliferation and protects against beta-cell failure induced by oxidative stress through NeuroD and MafA induction. In addition, FoxO1 nuclear exclusion is required for the proliferative effects of glucoincretin glucagon-like peptide-1 in islets. The data begin to outline an overarching role of FoxO1 in beta-cell function.
Diabetes Obes Metab 2007 Nov
PMID:Regulation of pancreatic beta-cell function by the forkhead protein FoxO1. 1791 88

The related basic helix-loop-helix transcription factors neurogenin3 (Neurog3) and neurogenic differentiation 1 (NeuroD1) regulate pancreatic islet cell formation. The transient expression of Neurog3 initiates endocrine differentiation and activates its target, NeuroD1, which continues the endocrine differentiation process. Despite their distinct developmental roles, the expression of either factor can drive islet differentiation in progenitor cells. To determine whether Neurog3 and NeuroD1 function by targeting a common set of genes, we compared gene expression patterns in cells ectopically expressing these two factors using cDNA microarrays. The array data demonstrated that both factors regulated largely overlapping sets of genes, providing the molecular basis for their functional equivalence in gain-of-functions approaches. Distinct differences in the timing and level of expression of a subset of target genes, however, show that the functions of these two factors are not completely redundant. Interestingly, in addition to NeuroD1, Neurog3 also induced both NeuroD2 and NeuroD4 gene expression. NeuroD2 mRNA peaked in the embryonic pancreas during endocrine differentiation and induced endocrine differentiation in vitro. These data suggest possible redundant roles for the NeuroD1 paralogs NeuroD2 and NeuroD4 in pancreatic endocrine differentiation and their potential utility in cell-based therapies for diabetes mellitus.
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PMID:Induction of pancreatic islet cell differentiation by the neurogenin-neuroD cascade. 1792 61

The conversion of expandable liver progenitor cells into pancreatic beta cells would provide a renewable cell source for diabetes cell therapy. Previously, we reported the establishment of liver epithelial progenitor cells (LEPCs). In this work, LEPCs were modified into EGFP/Pdx-1 LEPCs, cells with stable expression of both Pdx-1 and EGFP. Unlike previous work, with persistent expression of Pdx-1, EGFP/Pdx-1 LEPCs acquired the phenotype of pancreatic endocrine progenitor cells rather than giving rise to insulin-producing cells directly. EGFP/Pdx-1 LEPCs proliferated vigorously and expressed the crucial transcription factors involved in beta cell development, including Ngn3, NeuroD, Nkx2.2, Nkx6.1, Pax4, Pax6, Isl1, MafA and endogenous Pdx-1, but did not secrete insulin. When cultured in high glucose/low serum medium supplemented with cytokines, EGFP/Pdx-1 LEPCs stopped proliferating and gave rise to functional beta cells without any evidence of exocrine or other islet cell lineage differentiation. When transplanted into diabetic SCID mice, EGFP/Pdx-1 LEPCs ameliorated hyperglycemia by secreting insulin in a glucose regulated manner. Considering the limited availability of beta cells, we propose that our experiments will provide a framework for utilizing the immortal liver progenitor cells as a renewable cell source for the generation of functional pancreatic beta cells.
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PMID:Conversion of immortal liver progenitor cells into pancreatic endocrine progenitor cells by persistent expression of Pdx-1. 1797 80

To determine the role of cholesterol synthesis in pancreatic beta-cells, a transgenic model of in vivo activation of sterol-regulatory element binding protein 2 (SREBP-2) specifically in beta-cells (TgRIP-SREBP-2) was developed and analyzed. Expression of nuclear human SREBP-2 in beta-cells resulted in severe diabetes as evidenced by greater than 5-fold elevations in glycohemoglobin compared with C57BL/6 controls. Diabetes in TgRIP-SREBP-2 mice was primarily due to defects in glucose- and potassium-stimulated insulin secretion as determined by glucose tolerance test. Isolated islets of TgSREBP-2 mice were fewer in number, smaller, deformed, and had decreased insulin content. SREBP-2-expressing islets also contained increased esterified cholesterol and unchanged triglycerides with reduced ATP levels. Consistently, these islets exhibited elevated expression of HMG-CoA synthase and reductase and LDL receptor, with suppression of endogenous SREBPs. Genes involved in beta-cell differentiation, such as PDX1 and BETA2, were suppressed, explaining loss of beta-cell mass, whereas IRS2 expression was not affected. These phenotypes were dependent on the transgene expression. Taken together, these results indicate that activation of SREBP-2 in beta-cells caused severe diabetes by loss of beta-cell mass with accumulation of cholesterol, providing a new lipotoxic model and a potential link of disturbed cholesterol metabolism to impairment of beta-cell function.
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PMID:Cholesterol accumulation and diabetes in pancreatic beta-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity. 1868 8

Transdifferentiation of cells from a patient's own liver into pancreatic beta-cells could be useful for beta-cell replacement. We hypothesized that intrahepatic biliary epithelial cells (IHBECs) could become a new source of insulin-producing cells. IHBECs isolated from adult mice were expanded using our novel culture method termed, collagen-embedded floating culture method (CEFCM). With CEFCM, IHBECs formed three-dimensional ductal cysts and rapidly expanded their number by about 15-fold within 2 weeks. Over 90% of cells were positive for cytokeratin 7 and 19. At day 14, IHBECs were transfected with adenoviral (Ad)- pancreas duodenum homeobox 1 (Pdx-1), NeuroD or Pdx-1/VP16. After 7 additional days in serum- and insulin-free differentiation medium (DM), cell phenotypes were determined by RT-PCR, immunostaining and ELISA for insulin. In DM control IHBECs started to express some endocrine progenitor genes (Neurog3, NeuroD, Nkx6.1, and Pdx-1) but lacked insulin gene (Ins) mRNA. Transduced expression of PDX-1, NEUROD or PDX-1/VP16 led to expression of not only INS but also GLUT2 and prohormone convertase 1 and 2. About 3% of 4000 cells counted in PDX-1/VP16 transduced cultures stained strongly for C-peptide suggesting that a subpopulation may have the capacity for differentiation. Transduced cells released insulin (Ad-PDX-1 0.08+/-0.05, Ad-NEUROD 0.33+/-0.09, Ad-PDX-1/VP16 0.37+/-0.14 ng/1x10(5) cells after 48 h in culture). IHBECs can be markedly expanded, and then with molecular manipulation a subpopulation of these cells can differentiate towards a beta-cell phenotype. This approach may lead to a new source of beta-cells that can be used for transplantation in diabetes.
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PMID:Adult mouse intrahepatic biliary epithelial cells induced in vitro to become insulin-producing cells. 1916 5


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