The Insulin Gene Promoter: A Simplified Nomenclature

German, Michael S.; Ashcroft, S. J. H.; Docherty, Kevin; Edlund, Hanna; Edlund, Thomas; Goodison, Steven; Imura, Hiroo; Kennedy, Giulia C.; Madsen, Ole; Melloul, Danielle

doi:10.2337/diab.44.8.1002

Cited by 166 publications

(114 citation statements)

References 18 publications

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“…These percentages increase further, when considering only cargo (secretory and membrane) proteins synthesised by the beta cell. In addition, glucose stimulates proinsulin translation [20], and increases the stability of pre-proinsulin and transcription of the insulin gene [21,22], further increasing the protein load. Therefore, beta cells are highly susceptible to ER stress.…”

Section: Discussionmentioning

confidence: 99%

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Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

et al. 2011

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Aims/hypothesis Beta cell failure is caused by loss of cell mass, mostly by apoptosis, but also by simple dysfunction (decline of glucose-stimulated insulin secretion, downregulation of specific gene expression). Apoptosis and dysfunction are caused, at least in part, by lipoglucotoxicity. The mechanisms implicated are oxidative stress, increase in the hexosamine biosynthetic pathway (HBP) flux and endoplasmic reticulum (ER) stress. Oxidative stress plays a role in glucotoxicity-induced beta cell dedifferentiation, while glucotoxicity-induced ER stress has been mostly linked to beta cell apoptosis. We sought to clarify whether ER stress caused by increased HBP flux participates in a dedifferentiating response of beta cells, in the absence of relevant apoptosis. Methods We used INS-1E cells and murine islets. We analysed the unfolded protein response and the expression profile of beta cells by real-time RT-PCR and western blot. The signal transmission pathway elicited by ER stress was investigated by real-time RT-PCR and immunofluorescence. Results Glucosamine and high glucose induced ER stress, but did not decrease cell viability in INS-1E cells. ER stress caused dedifferentiation of beta cells, as shown by downregulation of beta cell markers and of the transcription factor, pancreatic and duodenal homeobox 1. Glucose-stimulated insulin secretion was inhibited. These effects were prevented by the chemical chaperone, 4-phenyl butyric acid. The extracellular signal-regulated kinase (ERK) signal transmission pathway was implicated, since its inhibition prevented the effects induced by glucosamine and high glucose. Conclusions/interpretation Glucotoxic ER stress dedifferentiates beta cells, in the absence of apoptosis, through a transcriptional response. These effects are mediated by the activation of ERK1/2.

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Section: Discussionmentioning

confidence: 99%

“…In addition, glucose stimulates proinsulin translation [20], as well as increasing the stability of pre-proinsulin and transcription of the insulin gene [21,22], further increasing the protein load. Therefore, chronic hyperglycaemia causes persistent activation of the unfolded protein response (UPR), beta cell failure and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

et al. 2011

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“…Much of what we know about the transcriptional control of beta cells stems from a wealth of studies that analysed the cis and trans elements involved in insulin gene transcription [111,112]. Three major pancreatic transcription factors were discovered precisely because of their ability to bind to several evolutionarily conserved sites in the insulin gene promoter, namely Pdx1 [113], MafA [114,115] and NeuroD1/ Beta2 [116], although these same factors were also independently cloned through other routes [117,118,119,120,121].…”

Section: Multi-input Motifs Control the Transcription Of Beta-cell-spmentioning

confidence: 99%

Transcriptional networks controlling pancreatic development and beta cell function

2004

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Transcription factors provide the genetic instructions that drive pancreatic development and enable mature beta cells to function properly. To understand fully how this is accomplished, it is necessary to unravel the regulatory networks formed by transcription factors acting on their genomic targets. This article discusses recent advances in our understanding of how transcriptional networks control early pancreas organogenesis, embryonic endocrine cell formation and the differentiated function of adult beta cells. We discuss how mutations in several transcription factor genes involved in such networks cause Maturity onset diabetes of the young (MODY). Finally, we propose that pancreatic gene programs might be manipulated to generate beta cells or to enhance the function of existing beta cells, thereby providing a possible treatment of different forms of diabetes.

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“…The transcriptional factor pancreatic duodenal homeobox 1 (PDX1) plays a pivotal role in pancreatic beta cell differentiation as well as insulin gene expression and synthesis [14][15][16][17]. Uncoupling protein 2 (UCP2) serves as a negative regulator of mitochondrial membrane potential (Δ= m ) [18], which positively correlates with glucosestimulated insulin secretion (GSIS) [19].…”

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confidence: 99%

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

et al. 2008

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Aims/hypothesis We previously observed hyperglycaemia, hyperinsulinaemia, insulin resistance and obesity in Gpx1-overexpressing mice (OE). Here we determined whether these phenotypes were eliminated by diet restriction, subsequently testing whether hyperinsulinaemia was a primary effect of Gpx1 overexpression and caused by dysregulation of pancreatic duodenal homeobox 1 (PDX1) and uncoupling protein-2 (UCP2) in islets. Methods First, 24 male OE and wild-type (WT) mice (2 months old) were given 3 g (diet-restricted) or 5 g (fullfed) feed per day for 4 months to compare their glucose metabolism. Thereafter, several mechanistic experiments were conducted with pancreas and islets of the two genotypes (2 or 6 months old) to assay for beta cell mass, reactive oxygen species (ROS) levels, mitochondrial membrane potential (Δ= m ) and expression profiles of regulatory proteins. A functional assay of islets was also performed. Results Diet restriction eliminated obesity but not hyperinsulinaemia in OE mice. These mice had greater pancreatic beta cell mass (more than twofold) and pancreatic insulin content (40%) than the WT, along with an enhanced Δ= m and glucose-stimulated insulin secretion in islets. With diminished ROS production, the OE islets displayed hyperacetylation of H3 and H4 histone in the Pdx1 promoter, elevated PDX1 and decreased UCP2. Conclusions/interpretation Overproduction of the major antioxidant enzyme, glutathione peroxidase 1, caused seemingly beneficial changes in pancreatic PDX1 and UCP2, but eventually led to chronic hyperinsulinaemia by dysregulating islet insulin production and secretion.

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The Insulin Gene Promoter: A Simplified Nomenclature

Cited by 166 publications

References 18 publications

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

Transcriptional networks controlling pancreatic development and beta cell function

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

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