Rat Endocrine Pancreatic Development in Relation to Two Homeobox Gene Products (Pdx-1 and Nkx 6.1)

Øster, Anne; Jensen, Jan; Serup, Palle; Galante, Philip; Madsen, Ole; Larsson, Lars

doi:10.1177/002215549804600602

Cited by 112 publications

(95 citation statements)

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“…It is generally believed that the endocrine, exocrine and ductal cell types are derived from endodermal cells [5]. Several studies have shown that the endocrine stem cell require several specific transcription factors to mature into single-hormone-expressing cells [6,7,8,9]. The pancreatic duodenum homeobox 1 (PDX-1) has been shown to be important both for pancreas development [26] and subsequent maturation of the endocrine cells [27], whereas later in the mature islets PDX-1 expression is restricted to the insulin-producing beta cells [8].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that the endocrine stem cell require several specific transcription factors to mature into single-hormone-expressing cells [6,7,8,9]. The pancreatic duodenum homeobox 1 (PDX-1) has been shown to be important both for pancreas development [26] and subsequent maturation of the endocrine cells [27], whereas later in the mature islets PDX-1 expression is restricted to the insulin-producing beta cells [8]. Another transcription factor, Nkx-6.1, is important for maturation of the insulin-producing beta cells [8], whereas Brain-4 is important for maturation of the glucagon-producing α-cells [7].…”

Section: Discussionmentioning

confidence: 99%

“…The pancreatic duodenum homeobox 1 (PDX-1) has been shown to be important both for pancreas development [26] and subsequent maturation of the endocrine cells [27], whereas later in the mature islets PDX-1 expression is restricted to the insulin-producing beta cells [8]. Another transcription factor, Nkx-6.1, is important for maturation of the insulin-producing beta cells [8], whereas Brain-4 is important for maturation of the glucagon-producing α-cells [7]. Previous analysis of mRNA gene expression profiles by semi-quantitative multiplex RT-PCR of the two NHI-phenotypes used in this study, grown under the same conditions, showed that several genes associated with late stages of betacell maturation, such as PDX-1 were expressed in both phenotypes, whereas Nkx-6.1 was restricted to the beta-cell phenotype [20].…”

Section: Discussionmentioning

confidence: 99%

“…During development of the pancreas, all four endocrine cell-types (α, β, δ and pp cells) are believed to arise from the same stem cell [5] and this specialization is dependent upon activation of different transcription factors [6,7,8,9]. Since sensitivity to cytokines, free radicals and toxic chemicals is exquisite for the beta cell, this could reflect an acquired trait during the maturation of stem cells into mature insulin producing beta cells.…”

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Protein expression changes in a cell system of beta-cell maturation reflect an acquired sensitivity to IL-1?

et al. 2004

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Aim/hypothesis. Type 1 diabetes mellitus (T1DM) is caused by specific destruction of the pancreatic beta cells in the islets of Langerhans. Increased sensitivity to cytokines, in particular to interleukin-1β (IL-1β) seems to be an acquired trait during beta-cell maturation. In response to cytokines both protective and deleterious mechanisms are induced in beta cells, and when the deleterious prevail, T1DM develops. The aims of this study were to identify perturbation in protein patterns (PiPP) associated with beta-cell maturation, and compare these changes to previous analyses of IL-1β exposed rat islets. For this purpose, proteome analyses were carried out using a cell-line, which matures from a glucagon-producing pre-beta-cell phenotype (NHI-glu) to an insulin-producing beta-cell phenotype (NHI-ins). We have previously shown that this maturation is accompanied by acquired sensitivity to the toxic effects of IL-1β.Methods. 2D-gel electrophoresis was used to separate the proteins and MALDI-MS and database searches were performed to identify the proteins. Results. During beta-cell maturation 135 protein spots out of 2239 detectable changed expression levels. Of these, 74 were down-regulated, 44 up-regulated, 16 were suppressed and 1 was expressed de novo. Using MALDI-MS, positive identification was obtained for 93 out of the 135 protein-spots revealing 97 different proteins. Of these, 22 proteins were in common with changes identified in previous proteome analysis of perturbation in protein pattern in IL-1β exposed rat islets. Several of the proteins were present in more than one spot suggesting post-translational modification. Conclusion/interpretation. Several proteins and protein modifications were identified that could be critically involved in beta-cell maturation, insulin-gene expression and the acquired IL-1β sensitivity. [Diabetologia (2004) A. E. Karlsen ( ✉ ), Steno Diabetes Center, Niels Steensensvej 2, 2820 Gentofte, Denmark E-mail: aek@novonordisk.com Abbreviations: T1DM, Type 1 diabetes mellitus; PiPP, perturbation in protein pattern; NO, nitric oxide; iNOS, inducible nitric oxide synthase; 2D-GE, 2 dimensional gel electrophoresis; IEF, isoelectric focusing; NEPHGE, non-equilibrium pH-gradient electrophoresis; WF, Wistar Furth; BB, Bio Breeding; PDX-1, pancreatic duodenum homeobox 1; ASS, argininosuccinate synthetase; HSP, heat shock protein; Picot, PKC-interacting cousin of thioredoxin; JNK, Jun N-terminal kinase; VDAC, voltage-dependent anion channel; GST, glutathione-Stransferase; Mw, molecular weight; pI, isoelectric point. Diabetologia (2004) 47:62-74 DOI 10.1007/s00125-003-1277 Protein expression changes in a cell system of beta-cell maturation reflect an acquired sensitivity to IL-1β Autoimmune Type 1 diabetes mellitus (T1DM) is caused by specific destruction of the insulin-producing beta cells in the islets of Langerhans in the pancreas [1]. During this process the islets are infiltrated with macrophages and lymphocytes, and these cells release a mixture of cytokines, such as inte...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Protein expression changes in a cell system of beta-cell maturation reflect an acquired sensitivity to IL-1?

et al. 2004

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“…c-fos, c-jun, junD and nur77 [28,29]. GLP-1 increases the DNA binding activity and expression level of the beta-cell-specific transcription factor pancreatic and duodenal homeobox gene-1 (PDX-1) [30,31], which is implicated in regulating expression of the insulin, GLUT2 and glucokinase genes, and in the regulation of beta cell differentiation [32,33,34]. GLP-1 mobilises intracellular Ca 2+ [35,36] via cyclic AMP guanine nucleotide exchange factor 2 (Epac) [37], an effect that may contribute to the insulinotropic action of the peptide.…”

Section: Introductionmentioning

confidence: 99%

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

et al. 2004

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Aims/hypothesis. We have provided evidence that glucagon-like peptide-1, a potential therapeutic agent in the treatment of diabetes, activates phosphatidylinositol-3 kinase/protein kinase B signalling in the pancreatic beta cell. Since this pathway promotes cell survival in a variety of systems, we tested whether glucagon-like peptide-1 protects beta cells against cell death induced by elevated glucose and/or non-esterified fatty acids. Methods. Human islets and INS832/13 cells were cultured at glucose concentrations of 5 or 25 mmol/l in the presence or absence of palmitate. Apoptosis was evaluated by monitoring DNA fragmentation and chromatin condensation. Wild-type and protein kinase B mutants were overexpressed in INS832/13 cells using adenoviruses. Nuclear factor-κB DNA binding was assayed by electrophoretic mobility shift assay. Results. In human pancreatic beta cells and INS832/13 cells, glucagon-like peptide-1 prevented beta cell apoptosis induced by elevated concentrations of (i) glucose (glucotoxicity), (ii) palmitate (lipotoxicity) and (iii) both glucose and palmitate (glucolipotoxicity). Overexpression of a dominant-negative protein kinase B suppressed the anti-apoptotic action of glucagonlike peptide-1 in INS832/13 cells, whereas a constitutively active protein kinase B prevented beta cell apoptosis induced by elevated glucose and palmitate. Glucagon-like peptide-1 enhanced nuclear factor-κB DNA binding activity and stimulated the expression of inhibitor of apoptosis protein-2 and Bcl-2, two antiapoptotic genes under the control of nuclear factor-κB. Inhibition of nuclear factor-κB by BAY 11-7082 abolished the prevention of glucolipotoxicity by glucagon-like peptide-1. Conclusions/interpretation. The results demonstrate a potent protective effect of glucagon-like peptide-1 on beta cell gluco-, lipo-and glucolipotoxicity. This effect is mediated via protein kinase B activation and possibly its downstream target nuclear factor-κB.

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On the development of the Islets of Langerhans

Larsson¹

1998

Microsc. Res. Tech.

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Rat Endocrine Pancreatic Development in Relation to Two Homeobox Gene Products (Pdx-1 and Nkx 6.1)

Cited by 112 publications

References 41 publications

Protein expression changes in a cell system of beta-cell maturation reflect an acquired sensitivity to IL-1?

Protein expression changes in a cell system of beta-cell maturation reflect an acquired sensitivity to IL-1?

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

On the development of the Islets of Langerhans

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