Pax-6 Activates Endogenous Proglucagon Gene Expression in the Rodent Gastrointestinal Epithelium

Trinh, Denny K; Zhang, Kai; Hossain, Md. Bellal; Brubaker, Patricia L.; Drucker, Daniel J.

doi:10.2337/diabetes.52.2.425

Cited by 50 publications

(40 citation statements)

References 51 publications

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“…For example, the homeodomain protein Cdx-2 was found to activate glu gene promoter in both pancreatic and intestinal proglucagon-producing cell lines (20,41). Although overexpression of Cdx-2 stimulates endogenous glu mRNA expression in the pancreatic InR1-G9 cells (41) but not in the intestinal GLUTag cells (40), the involvement of Cdx-2 in regulating basal glu mRNA expression in both pancreatic and intestinal cells cannot be excluded. Likewise, the paired homeodomain protein Pax-6 (39,40) and the protein kinase A signaling pathway (21,26,30,35) have been found to regulate glu gene expression in both pancreatic and intestinal proglucagonproducing cell lines, as well as in primary pancreatic islet and intestinal cell cultures.…”

Section: Discussionmentioning

confidence: 99%

“…A challenging question that remains is whether the cultivated cell lines used in these studies are good surrogates of the primary glu producing cells. Our previous studies have demonstrated that the GLUTag cell line responds appropriately to the regulatory factors known to control glu gene expression and GLP-1 synthesis and secretion in primary gut endocrine cells, including cAMP/protein kinase A, glucose-dependent insulinotropic peptide, and bethanechol (26,40,50,51). Likewise, the ␣-TC-1 and InR1-G9 cell lines have been routinely used as ␣ cell models to study glu gene expression and glucagon synthesis and secretion (19,20,30,(52)(53)(54)(55)(56).…”

Section: Discussionmentioning

confidence: 99%

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TCF-4 Mediates Cell Type-specific Regulation of Proglucagon Gene Expression by β-Catenin and Glycogen Synthase Kinase-3β

Brubaker

Jin

2005

Journal of Biological Chemistry

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391

329

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The proglucagon gene (glu) encodes glucagon, expressed in pancreatic islets, and the insulinotropic hormone GLP-1, expressed in the intestines. These two hormones exert critical and opposite effects on blood glucose homeostasis. An intriguing question that remains to be answered is whether and how glu gene expression is regulated in a cell type-specific manner. We reported previously that the glu gene promoter in gut endocrine cell lines was stimulated by ␤-catenin, the major effector of the Wnt signaling pathway, whereas glu mRNA expression and GLP-1 synthesis were activated via inhibition of glycogen synthase kinase-3␤, the major negative modulator of the Wnt pathway (Ni, Z

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TCF-4 Mediates Cell Type-specific Regulation of Proglucagon Gene Expression by β-Catenin and Glycogen Synthase Kinase-3β

Brubaker

Jin

2005

Journal of Biological Chemistry

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391

329

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“…Mice are good experimental models for analyzing the expression of genes concerning diabetes. Mice homozygously null of the Pax6 gene, which died after birth, lacked cells of a-cell-lineage in pancreatic islets [5,27] and had reduced transcription levels of the Gcg gene in endocrine cells during embryogenesis [24]. Conditional inactivation of the Pax6 gene -Original-in the pancreas caused the early onset of diabetes in mice [1].…”

Section: Introductionmentioning

confidence: 99%

Kinetics of Blood Glucose in Mice Carrying Hemizygous Pax6

et al. 2009

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Abstract:The genotype-phenotype relationship was examined experimentally for the Pax6 Sey-4H mutant, which carries deletion of its chromosome 2 middle region hemizygously.The genotyping has indicated that this deleted segment is between 102.6 and 109.2 Mb from the centromere. The glucose-6-phosphatase gene followed by the glucagon and carboxyl ester lipase genes were mapped adjacent to the deleted region. Phenotyping indicates that the Pax6 Sey-4H mutant is more susceptible to diabetes. The glucose tolerance test showed that the mutants were less capable of reducing their level of blood glucose to the standard level than the normal sibs. The insulin-loading test revealed their inability to elevate their blood glucose levels up to normal levels. The time it took for the onset of diabetes induced by streptozotocin was shorter in the mutants than in normal sibs. Both the haploinsufficiency of the genes in the hemizygous segment of chromosome 2 and the quantitative imbalance of the whole genome could contribute the development of this phenotype in the mutant.

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“…It is expressed in intestinal EECs and binds to G1 and G3 elements in the proglucagon promoter to activate its transcription. 158,159 Pax6 might also bind to the promoter and induce production of PC 1/3 pro-hormone convertase, an enzyme essential for the conversion of proinsulin into insulin 160 and of proglucagon into GLP-1. 43 Proglucagon processing is accomplished by PC1 in L-cells and by PC2 in pancreatic alpha cells to produce glucagon.…”

Section: Cell Differentiation and Intestinal Adaptationmentioning

confidence: 99%

Isolated ileal interposition in enteroendocrine L cells differentiation

et al. 2011

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INTRODUCTION:Due to the progressive nature of type 2 diabetes, its complexity and drug treatment perpetuity, there is currently a search for surgical procedures that can promote euglycemia also in non-obese patients. Diabetic patients glycemic control can be achieved by increasing the blood concentration of GLP-1, a hormone produced by L cells that are more densely concentrated in the terminal ileum. Early and extended improvement of diabetes in patients submitted to bariatric surgeries awakened the necessity of investigating the isolated ileal interposition as surgical alternative for the treatment of diabetes. The interposition of this ileal segment to a more anterior region (proximal jejunum) can promote a greater stimulation of the L cells by poorly digested food, increasing the production of GLP-1 and reflecting on glycemic control. However, in order to consolidate the ileal interposition as a surgical treatment of diabetes it is necessary that the interposed ileum keep the same differentiation rate into L cells for a long period to justify the intervention. AIMS:To investigate the isolated ileal interposition influence on the differentiation of intestinal precursor cells into enteroendocrine L cells over time. METHODS:Twelve 12-week-old male Wistar rats (Rattus norvegicus albinus) of the WAB strain (heterogeneous) will be used. All animals will receive a high-calorie, high-fat diet for 16 weeks or more until they develop glucose dysmetabolism confirmed by glycemic test. They will be divided into two groups of 10 animals each: the isolated ileal interposition group (GI) and the control group (GC), comprising animals that will not be submitted to any surgical intervention.Blood samples will be collected under anesthesia at the weeks 12, 26, 36 and 44 for the determination of serum levels of glucose, insulin, GLP-1, glucagon, C-peptide and glycosilated hemoglobin. The insulin tolerance test will be performed and insulin resistance will be calculated. For the comparative analysis of the ileal precursor cells differentiation into enteroendocrine cells among the two groups, the following intestinal fragments will be collected after euthanasia: interposed ileum and remaining ileum from GI, jejunum and ileum from GC. These fragments will be analyzed by imunofluorescence and also by Real Time PCR using PCR Arrays for target genes including the main ones related to stem cell, stem cell singnalling, diabetes, Wnt and Notch signaling pathways and other genes and pathways involved in the differentiation of intestinal precursor cells into enteroendocrine cells, especially GLP-1-producing L cells that play important role in euglycemia.

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Pax-6 Activates Endogenous Proglucagon Gene Expression in the Rodent Gastrointestinal Epithelium

Cited by 50 publications

References 51 publications

TCF-4 Mediates Cell Type-specific Regulation of Proglucagon Gene Expression by β-Catenin and Glycogen Synthase Kinase-3β

TCF-4 Mediates Cell Type-specific Regulation of Proglucagon Gene Expression by β-Catenin and Glycogen Synthase Kinase-3β

Kinetics of Blood Glucose in Mice Carrying Hemizygous Pax6

Isolated ileal interposition in enteroendocrine L cells differentiation

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