Glucose Stimulates Translocation of the Homeodomain Transcription Factor PDX1 from the Cytoplasm to the Nucleus in Pancreatic β-Cells

Macfarlane, Wendy M.; McKinnon, Caroline; Felton-Edkins, Zoë A.; Cragg, Helen; James, R. F. L.; Docherty, Kevin

doi:10.1074/jbc.274.2.1011

Cited by 214 publications

(181 citation statements)

References 29 publications

(34 reference statements)

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“…These data indicate that metformin rapidly stimulates an increase in IPF1 DNA binding activity in pancreatic beta cells, and that rosiglitazone has no effect over this shorter period. Probe specificity was confirmed by mutant oligonucleotide competition and antibody competition EMSA analysis (not shown) as in previous studies [13,23]. Using the same nuclear extracts, Western blotting analysis was performed to determine the level of nuclear IPF1 (Fig.…”

Section: Resultsmentioning

confidence: 60%

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Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

et al. 2006

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Aims/hypothesis: Rosiglitazone and metformin are two oral antihyperglycaemic drugs used to treat type 2 diabetes. While both drugs have been shown to improve insulin-sensitive glucose uptake, the direct effects of these drugs on pancreatic beta cells is only now beginning to be clarified. The aim of the present study was to determine the direct effects of these agents on beta cell gene expression. Methods: We used reporter gene analysis to examine the effects of rosiglitazone and metformin on the activity of the proinsulin and insulin promoter factor 1 (IPF1) gene promoters in the glucose-responsive mouse beta cell line Min6. Western blot and gel retardation analyses were used to examine the effects of both drugs on the regulation of IPF1 protein production, nuclear accumulation and DNA binding activity in both Min6 cells and isolated rat islets of Langerhans. Results: Over 24 h, rosiglitazone promoted the nuclear accumulation of IPF1 and forkhead homeobox A2 (FOXA2), independently of glucose concentration, and stimulated a two-fold increase in the activity of the Ipf1 gene promoter (p<0.01). Stimulation of the Ipf1 promoter by rosiglitazone was unaffected by the presence of the peroxisome proliferator activated receptor γ antagonist GW9662. No effect of either rosiglitazone or metformin was observed on proinsulin promoter activity. Metformin stimulated IPF1 nuclear accumulation and DNA binding activity in a time-dependent manner, with maximal effects observed after 2 h. Conclusions/interpretation: Metformin and rosiglitazone have direct effects on beta cell gene expression, suggesting that these agents may play a previously unrecognised role in the direct regulation of pancreatic beta cell function.

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Section: Resultsmentioning

confidence: 60%

“…Western blotting was carried out as previously described [23]. Protein concentrations were measured using Bio-Rad Protein Assay Kit reagent, titrated against known concentrations of bovine serum albumin.…”

Section: Western Blottingmentioning

confidence: 99%

Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

et al. 2006

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“…Although some reports in the literature have described physiologic circumstances where the distribution of Pdx1 might be cytoplasmic, it is believed that cytoplasmic sequestration may represent more a mechanism to attenuate the nuclear action of Pdx1 under physiologic or pathologic conditions, rather than to promote a specific cytoplasmic function. For example, the negative effect of fatty acids on β cell function may be related to their eventual sequestration of Pdx1 in the cytoplasm [76], whereas the positive effect of glucose on insulin transcription may be a result of its enhancement of Pdx1nuclear translocation [108]. A basic amino acid sequence with the homeodomain of Pdx1, RRMKWKK, is believed to function as the nuclear targeting sequence [109].…”

Section: Mechanism Of Pdx1 Action Posttranslational Modifications Of mentioning

confidence: 99%

“…nuclear-cytoplasmic shuttling) or function would allow for acute alterations to target gene transcription, where control on the order of seconds to minutes might be crucial. At least 3 different reversible post-translational modifications, including phosphorylation [86,108,[110][111][112][113][114], sumoylation [115], and glycosylation [116], have been proposed to explain nuclearcytoplasmic shuttling and/or other functions of Pdx1. Consistent with these modifications, different molecular weight species of Pdx1 have been described in immunoblots [115].…”

Section: Mechanism Of Pdx1 Action Posttranslational Modifications Of mentioning

confidence: 99%

“…Of the three modifications, phosphorylation is perhaps the best-studied. Elevated glucose levels have been suggested to promote Pdx1 phosphorylation through one or a combination of several pathways, including the stress-activated protein kinase (SAPK) and extracellular signalregulated kinase (ERK) 1/2 pathways [86,108,112], phosphatidylinositol 3-kinase pathway [117,118], and/or the Per-Arnt-Sim (PAS) kinase [110]. Although the role of phosphorylation of specific residues within Pdx1 has not been rigorously analyzed, phosphorylation of Ser61 and Ser66 of Pdx1 via glycogen synthase kinase 3 appears to target Pdx1 for proteosomal degradation, thereby decreasing its half-life.…”

Section: Mechanism Of Pdx1 Action Posttranslational Modifications Of mentioning

confidence: 99%

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A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Babu

Deering

Mirmira

2007

Molecular Genetics and Metabolism

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Emerging evidence over the past decade indicates a central role for transcription factors in the embryonic development of pancreatic islets and the consequent maintenance of normal glucose homeostasis. Pancreatic and duodenal homeobox 1 (Pdx1) is the best studied and perhaps most important of these factors. Whereas deletion or inactivating mutations of the Pdx1 gene causes whole pancreas agenesis in both mice and humans, even haploinsufficiency of the gene or alterations in its expression in mature islet cells causes substantial impairments in glucose tolerance and the development of a late-onset form of diabetes known as maturity onset diabetes of the young. The study of Pdx1 has revealed crucial phenotypic interrelationships of the varied cell types within the pancreas, particularly as these impinge upon cellular differentiation in the embryo and neogenesis and regeneration in the adult. In this review, we describe the actions of Pdx1 in the developing and mature pancreas and attempt to unify these actions with its known roles in modulating transcriptional complex formation and chromatin structure at the molecular genetic level.

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Arsenic Exposure and Prevalence of Type 2 Diabetes in US Adults

Navas‐Acien

Silbergeld

Pastor-Barriuso

et al. 2008

JAMA

405

255

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ContextHigh chronic exposure to inorganic arsenic in drinking water has been related to diabetes development, but the effect of exposure to low to moderate levels of inorganic arsenic on diabetes risk is unknown. In contrast, arsenobetaine, an organic arsenic compound derived from seafood intake, is considered nontoxic.Objective To investigate the association of arsenic exposure, as measured in urine, with the prevalence of type 2 diabetes in a representative sample of US adults. Design, Setting, and Participants Cross-sectional study in 788 adults aged 20 years or older who participated in the 2003-2004 National Health and Nutrition Examination Survey (NHANES) and had urine arsenic determinations.Main Outcome Measure Prevalence of type 2 diabetes across intake of arsenic. ResultsThe median urine levels of total arsenic, dimethylarsinate, and arsenobetaine were 7.1, 3.0, and 0.9 µg/L, respectively. The prevalence of type 2 diabetes was 7.7%. After adjustment for diabetes risk factors and markers of seafood intake, participants with type 2 diabetes had a 26% higher level of total arsenic (95% confidence interval [CI], 2.0%-56.0%) and a nonsignificant 10% higher level of dimethylarsinate (95% CI, −8.0% to 33.0%) than participants without type 2 diabetes, and levels of arsenobetaine were similar to those of participants without type 2 diabetes. After similar adjustment, the odds ratios for type 2 diabetes comparing participants at the 80th vs the 20th percentiles were 3.58 for the level of total arsenic (95% CI, 1.18-10.83), 1.57 for dimethylarsinate (95% CI, 0.89-2.76), and 0.69 for arsenobetaine (95% CI, 0.33-1.48). ConclusionsAfter adjustment for biomarkers of seafood intake, total urine arsenic was associated with increased prevalence of type 2 diabetes. This finding supports the hypothesis that low levels of exposure to inorganic arsenic in drinking water, a widespread exposure worldwide, may play a role in diabetes prevalence. Prospective studies in populations exposed to a range of inorganic arsenic levels are needed to establish whether this association is causal.

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Glucose Stimulates Translocation of the Homeodomain Transcription Factor PDX1 from the Cytoplasm to the Nucleus in Pancreatic β-Cells

Cited by 214 publications

References 29 publications

Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

Effects of rosiglitazone and metformin on pancreatic beta cell gene expression

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Arsenic Exposure and Prevalence of Type 2 Diabetes in US Adults

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