Transcription Factors Contributing to the Pancreatic β-Cell Phenotype

Madsen, Ole; Jensen, Jan; Petersen, Helle V.; Pedersen, Elisa; Øster, Anne; Andersen, Frank G.; Jørgensen, Mette C.; Jensen, Per Bo; Larsson, Lars; Serup, Palle

doi:10.1055/s-2007-979035

Cited by 73 publications

(33 citation statements)

References 21 publications

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“…Using this characteristic of DTZ, we identified insulin-producing cells in EB outgrowths derived from mouse ES cells as well as cellular clusters. We then analyzed the characteristic features of these DTZ-stained clusters by immunohistochemistry for insulin production and by reverse transcriptase-polymerase chain reaction (RT-PCR) for gene expression of the pancreatic β-cell markers, including proinsulin 1, proinsulin 2, pancreatic transcription factor pancreatic-duodenal homeobox 1 (PDX1) [32,33], glucose transporter-2 (GLUT2) [34,35], and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) [36,37]. We also examined insulin secretion using an enzyme-linked immunoassay (ELISA).…”

Section: ® Original Articlementioning

confidence: 99%

Identification of Insulin‐Producing Cells Derived from Embryonic Stem Cells by Zinc‐Chelating Dithizone

et al. 2002

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Background and Aims. Embryonic stem (ES) cellshave a pluripotent ability to differentiate into a variety of cell lineages in vitro. We have recently identified the emergence of cellular clusters within differentiated ES cell cultures by staining with dithizone (DTZ). DTZ is a zinc-chelating agent known to selectively stain pancreatic beta cells because of their high zinc content. The aim of the present study was to investigate the characteristics of DTZ-stained cellular clusters originating from ES cells.Methods. Embryoid bodies (EBs), formed by a 5-day hanging drop culture of ES cells, were allowed to form outgrowths in the culture. The outgrowths were incubated in DTZ solution (final concentration, 100 µg/ml ) for 15 minutes before being examined microscopically. The gene expression of endocrine pancreatic markers was also analyzed by reverse transcriptase-polymerase chain reaction. In addition, insulin production was

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Section: ® Original Articlementioning

confidence: 99%

Identification of Insulin‐Producing Cells Derived from Embryonic Stem Cells by Zinc‐Chelating Dithizone

et al. 2002

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“…Induction of these nonspecific proteins has been previously described (7,12,14,15); it is now shown that they occur independently of cytotoxic effects. Suppression of transcription factor PDX-1 is expected to result in lower expression of -c e l l -s p e c i fic genes, such as insulin, I A P P, GLUT2, and glucokinase (31)(32)(33)(34). These data are consistent with the concept that IL-1 can shift the functional state of -cells to that of a glucose-unresponsive population, which explains the loss of their characteristic property, namely the production of insulin in response to glucose (6).…”

Section: Interleukin-1 -Induced Protection Of -Cellsmentioning

confidence: 99%

Interleukin-1beta-induced alteration in a beta-cell phenotype can reduce cellular sensitivity to conditions that cause necrosis but not to cytokine-induced apoptosis.

et al. 2000

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Previous work has shown that interleukin-1 ( I L-1 ) alters protein expression in -cells. This alteration is associated with cell death in isolated rat islets but not in isolated rat -cells. We examined whether IL-1 p r etreatment of isolated -cells influences their sensitivity to toxic agents. After a 24-h culture with IL-1 ( 3 0 U/ml), -cells exhibited a lower expression of the -cell-specific protein transcription factor pancreatic and duodenal homeobox gene (PDX)-1, glucose transporter GLUT2, and proinsulin convertase PC2, with a marked reduction (60-70%) in glucose-induced insulin production and selective sensitivity to the toxins alloxan (ALX) and streptozotocin (STZ). On the other hand, the cells presented an increased expression of Mn-superoxide dismutase, heat shock protein 70, inducible heme oxygenase, and inducible nitrite oxide synthase. This IL-1 -induced alteration in -cell phenotype resulted in a reduced cellular sensitivity to the -cell-specific toxins ALX and STZ; the production of nontoxic conditions of nitric oxide (NO) also rendered the cells less susceptible to radical-induced damage. Exposure to IL-1 can thus protect -cells against conditions that cause necrosis; however, it did not protect against apoptosis induced by the additional presence of i n t e r f e r o n-or tumor necrosis factor-. Release of I L-1 in the endocrine pancreas is thus not necessarily the cause of massive NO-dependent -cell destruction. On the contrary, IL-1 may protect these cells against necrosis, though with a loss of their characteristic phenotype and homeostatic functions.

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“…Recently, the study of the transcriptional regulation of the insulin gene has led to the identification of several ␤ cell/islet transcription factors that are important for the development of the endocrine pancreas, the tissue-specific expression of key ␤ cell genes and maintenance of ␤ cell differentiation (9,10). In islets of diabetic animals and in long term culture of immortalized insulin-secreting cells, chronic exposure to high glucose can result in loss of insulin gene expression (11,12).…”

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confidence: 99%

Chronic Hyperglycemia Triggers Loss of Pancreatic β Cell Differentiation in an Animal Model of Diabetes

Jonas¹,

Sharma²,

Hasenkamp

et al. 1999

Journal of Biological Chemistry

531

474

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Differentiated pancreatic ␤ cells are unique in their ability to secrete insulin in response to a rise in plasma glucose. We have proposed that the unique constellation of genes they express may be lost in diabetes due to the deleterious effect of chronic hyperglycemia. To test this hypothesis, Sprague-Dawley rats were submitted to a 85-95% pancreatectomy or sham pancreatectomy. One week later, the animals developed mild to severe chronic hyperglycemia that was stable for the next 3 weeks, without significant alteration of plasma nonesterified fatty acid levels. Expression of many genes important for glucose-induced insulin release decreased progressively with increasing hyperglycemia, in parallel with a reduction of several islet transcription factors involved in ␤ cell development and differentiation. In contrast, genes barely expressed in sham islets (lactate dehydrogenase A and hexokinase I) were markedly increased, in parallel with an increase in the transcription factor c-Myc, a potent stimulator of cell growth. These abnormalities were accompanied by ␤ cell hypertrophy. Changes in gene expression were fully developed 2 weeks after pancreatectomy. Correction of blood glucose by phlorizin for the next 2 weeks normalized islet gene expression and ␤ cell volume without affecting plasma nonesterified fatty acid levels, strongly suggesting that hyperglycemia triggers these abnormalities. In conclusion, chronic hyperglycemia leads to ␤ cell hypertrophy and loss of ␤ cell differentiation that is correlated with changes in c-Myc and other key transcription factors. A similar change in ␤ cell differentiation could contribute to the profound derangement of insulin secretion in human diabetes.Pancreatic ␤ cells are highly specialized cells that secrete insulin in response to a variety of stimuli, the most important being glucose (1, 2). Their correct function is dependent on the expression of a unique set of genes that allow ␤ cells to respond to even small increases in plasma glucose levels by releasing appropriate amounts of insulin into the circulation (3). Type 2 diabetes is characterized by the combination of insulin resistance and profound alteration in glucose-stimulated insulin secretion (4). The latter can be ascribed, at least in part, to the deleterious effect of even mild chronic hyperglycemia and elevated plasma nonesterified fatty acids (NEFA) 1 on pancreatic ␤ cell function, a process often referred to as "gluco-lipotoxicity" (5, 6). In islets isolated from animal models of diabetes, several defects have been identified at the level of gene expression and/or enzymatic activity, but none by itself can entirely account for the ␤ cell defect characteristic of type 2 diabetes (5,7,8).Recently, the study of the transcriptional regulation of the insulin gene has led to the identification of several ␤ cell/islet transcription factors that are important for the development of the endocrine pancreas, the tissue-specific expression of key ␤ cell genes and maintenance of ␤ cell differentiation (9, 10). In islets ...

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Transcription Factors Contributing to the Pancreatic β-Cell Phenotype

Cited by 73 publications

References 21 publications

Identification of Insulin‐Producing Cells Derived from Embryonic Stem Cells by Zinc‐Chelating Dithizone

Identification of Insulin‐Producing Cells Derived from Embryonic Stem Cells by Zinc‐Chelating Dithizone

Interleukin-1beta-induced alteration in a beta-cell phenotype can reduce cellular sensitivity to conditions that cause necrosis but not to cytokine-induced apoptosis.

Chronic Hyperglycemia Triggers Loss of Pancreatic β Cell Differentiation in an Animal Model of Diabetes

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