Unprocessed Proinsulin Promotes Cell Survival During Neurulation in the Chick Embryo

Hernández‐Sánchez, Catalina; Rubio, Eva; Serna, J; Rosa, Enrique J. de la; Pablo, Flora de

doi:10.2337/diabetes.51.3.770

Cited by 36 publications

(51 citation statements)

References 58 publications

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“…However, since the majority of C-peptide-positive cells did not stain for mature insulin we speculate that the immunoreactivity was due to unprocessed proinsulin. Our hypothesis is supported by studies showing that in the developing nervous system (or at least in specific areas of it), the majority of proinsulin is not processed to the mature form [44,45,46].…”

Section: Discussionsupporting

confidence: 66%

Insulin expressing cells from differentiated embryonic stem cells are not beta cells

et al. 2004

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Aim/hypothesis. Embryonic stem (ES) cells have been proposed as a potential source of tissue for transplantation for the treatment of Type 1 diabetes. However, studies showing differentiation of beta cells from ES cells are controversial. The aim of this study was to characterise the insulin-expressing cells differentiated in vitro from ES cells and to assess their suitability for the treatment of diabetes. Methods. ES cell-derived insulin-expressing cells were characterised by means of immunocytochemistry, RT-PCR and functional analyses. Activation of the Insulin I promoter during ES-cell differentiation was assessed in ES-cell lines transfected with a reporter gene. ES cell-derived cultures were transplanted into STZ-treated SCID-beige mice and blood glucose concentrations of diabetic mice were monitored for 3 weeks. Results. Insulin-stained cells differentiated from ES cells were devoid of typical beta-cell granules, rarely showed immunoreactivity for C-peptide and were mostly apoptotic. The main producers of proinsulin/insulin in these cultures were neurons and neuronal precursors and a reporter gene under the control of the insulin I promoter was activated in cells with a neuronal phenotype. Insulin was released into the incubation medium but the secretion was not glucose-dependent. When the cultures were transplanted in diabetic mice they formed teratomas and did not reverse the hyperglycaemic state. Conclusions/Interpretation. Our studies show that insulin-positive cells in vitro-differentiated from ES cells are not beta cells and suggest that alternative protocols, based on enrichment of ES cell-derived cultures with cells of the endodermal lineage, should be developed to generate true beta cells for the treatment of diabetes. [Diabetologia (2004) 47:499-508]

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Section: Discussionsupporting

confidence: 66%

Insulin expressing cells from differentiated embryonic stem cells are not beta cells

et al. 2004

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“…A variety of malformations, such as retarded growth, embryonic dysmorphogenesis, exencephaly, an enlarged heart and blood vessels and abnormal somites were observed in the surviving embryos ( Figure 3 and Table 1). Chick embryos cultured for 72 h (approximate HH stages [18][19][20] and treated in a similar manner resulted in 10% and 15% mortality, respectively. Surviving embryos mainly showed retarded growth, abnormal flexures, torsions, macrosomia and abnormal limbs and tail development ( Figure 4 and Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…Shell-less chick embryos at the selected stages of development were treated with either 50 µl glucose of 30 mM, 50 mM [20] or 100 mM concentrations prepared in 0.9% saline. Control embryos were treated with 50 µl of 0.9% saline only.…”

Section: Treatment With Glucosementioning

confidence: 99%

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Shell-Less Chick Embryo Culture as an Alternative in vitro Model to Investigate Glucose-Induced Malformations in Mammalian Embryos

Datar¹,

Bhonde²

2005

Rev Diabetic Stud

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■ AbstractWe have developed a simple shell-less chick embryo culture system to study glucose-induced malformations. This system involves the culturing of chick embryos from the second day to the fifth day of incubation, with associated yolk and thick and thin albumen outside the egg shell. The system allows the observation of embryonic development of chicks in a glass bowl. Developing embryos at 24 h, 48 h and 72 h incubation, corresponding to the Hamberger Hamilton (HH) stages from 7 to 21, were treated with two concentrations of glucose (50 mM and 100 mM) for 24 h. Glucose treatment resulted in a mortality rate of over 70% in younger embryos. Furthermore, a variety of malformations such as retarded growth, abnormal heart development, macrosomia, exencephaly, etc. were observed in older embryos, which were similar to those reported in mammalian embryos as a consequence of diabetic pregnancy. The glucose-induced malformations were found to be concentration-and stage-dependent, thus emphasizing the roles of the degree of hyperglycemia and the stage of embryonic development in diabetic growth anomalies. Here we demonstrate for the first time that the present system can be used (i) for experiments at early stages of chick embryo development and (ii) for assessing the effects of acute glucose toxicity similar to those reported for mammalian embryos in a hyperglycemic environment.

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“…All of the studied insulin promoters contain a TATA box. However, the chicken promoter is distinct from the others in that at least two isoforms can be transcribed from alternative initiation sites (53). In E1.5 chicken embryo pancreas, the single insulin gene is also transcribed from an upstream secondary promoter to yield an mRNA with an additional 32-bp leader sequence.…”

Section: The Proximal Promoter Regionmentioning

confidence: 99%

Comparative Analysis of Insulin Gene Promoters

2006

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DNA sequences that regulate expression of the insulin gene are located within a region spanning ϳ400 bp that flank the transcription start site. This region, the insulin promoter, contains a number of cis-acting elements that bind transcription factors, some of which are expressed only in the ␤-cell and a few other endocrine or neural cell types, while others have a widespread tissue distribution. The sequencing of the genome of a number of species has allowed us to examine the manner in which the insulin promoter has evolved over a 450 million-year period. The major findings are that the A-box sites that bind PDX-1 are among the most highly conserved regulatory sequences, and that the conservation of the C1, E1, and CRE sequences emphasize the importance of MafA, E47/␤2, and cAMP-associated regulation. The review also reveals that of all the insulin gene promoters studied, the rodent insulin promoters are considerably dissimilar to the human, leading to the conclusion that extreme care should be taken when extrapolating rodent-based data on the insulin gene to humans. Diabetes 55:3201-3213, 2006

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Unprocessed Proinsulin Promotes Cell Survival During Neurulation in the Chick Embryo

Cited by 36 publications

References 58 publications

Insulin expressing cells from differentiated embryonic stem cells are not beta cells

Insulin expressing cells from differentiated embryonic stem cells are not beta cells

Shell-Less Chick Embryo Culture as an Alternative in vitro Model to Investigate Glucose-Induced Malformations in Mammalian Embryos

Comparative Analysis of Insulin Gene Promoters

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