Enhanced expression of PDX-1 and Ngn3 by exendin-4 during β cell regeneration in STZ-treated mice

Kodama, Shintaro; Toyonaga, Tetsushi; Kondo, Tatsuya; Matsumoto, Kazuya; Tsuruzoe, Kaku; Kawashima, Junji; Goto, Hideo; Kume, Kazuhiko; Kume, Shoen; Sakakida, Michiharu; Araki, Eiichi

doi:10.1016/j.bbrc.2004.12.120

Cited by 81 publications

(66 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Consistent with published findings (12,13), Neurog3 transcripts were readily detected by RT-PCR in the WT adult islet cells ( Fig. 2A).…”

Section: Neurog3 Mrna and Protein Can Be Detected In Hormone-expressingsupporting

confidence: 91%

“…Several reports have shown Neurog3 expression in WT adult islet cells (2,(12)(13)(14), and this expression is enhanced by regenerative conditions (11)(12)(13). Yet these analyses have failed to establish whether Neurog3 expression is restricted to only a few putative endocrine progenitor cells at a high level, or whether Neurog3 is also present in differentiated islet cells at a low level.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function

Wang¹,

Jensen

Seymour

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

147

143

View full text Add to dashboard Cite

Neurog3 (Neurogenin 3 or Ngn3) is both necessary and sufficient to induce endocrine islet cell differentiation from embryonic pancreatic progenitors. Since robust Neurog3 expression has not been detected in hormone-expressing cells, Neurog3 is used as an endocrine progenitor marker and regarded as dispensable for the function of differentiated islet cells. Here we used 3 independent lines of Neurog3 knock-in reporter mice and mRNA/protein-based assays to examine Neurog3 expression in hormone-expressing islet cells. Neurog3 mRNA and protein are detected in hormoneproducing cells at both embryonic and adult stages. Significantly, inactivating Neurog3 in insulin-expressing ␤ cells at embryonic stages or in Pdx1-expressing islet cells in adults impairs endocrine function, a phenotype that is accompanied by reduced expression of several Neurog3 target genes that are essential for islet cell differentiation, maturation, and function. These findings demonstrate that Neurog3 is required not only for initiating endocrine cell differentiation, but also for promoting islet cell maturation and maintaining islet function.endocrine progenitor ͉ maintenance ͉ pancreas ͉ diabetes ͉ sugar metabolism

show abstract

“…Consistent with published findings (12,13), Neurog3 transcripts were readily detected by RT-PCR in the WT adult islet cells ( Fig. 2A).…”

Section: Neurog3 Mrna and Protein Can Be Detected In Hormone-expressingsupporting

confidence: 91%

mentioning

confidence: 99%

Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function

Wang¹,

Jensen

Seymour

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

147

143

View full text Add to dashboard Cite

show abstract

“…In the present study, continuous infusion of GLP-1 induced translocation of FOXO1 to the cytoplasm in many beta cells, while FOXO1 was predominantly localised in the nucleus of insulinpositive cells in untreated NOD mice or saline-treated mice. It has been reported that FOXO1 and PDX1 demonstrate mutually exclusive nuclear localisation in beta cells and that nuclear localisation of FOXO1 is associated with weak or negative PDX1 localisation [9]. Therefore, it can be suggested that beta cell proliferation in GLP-1-treated mice was associated with the induction of cytoplasmic FOXO1 translocation, although we were unable to find a clear relationship between the localisation of FOXO1 and PDX1 (data not shown).…”

Section: Discussioncontrasting

confidence: 58%

“…It has also been demonstrated that GLP-1 agonists stimulate beta cell proliferation and neogenesis in rats, along with increased islet expression of pancreatic and duodenal homeobox gene 1 (Pdx1), Glut2 (also known as solute carrier family 2 [facilitated glucose transporter], member 2 [Slc2a2]) and glucokinase genes, as well as upregulation of insulin mRNA [8]. The translocation of forkhead box O1 (FOXOl) from the nucleus to the cytoplasm results in upregulation of Pdx1 expression through insulin receptor substrate 2 (IRS2)-mediated activation of the phosphatidylinositol 3-kinase (PI3-K)-protein kinase B (PKB) pathway [9]. More recent studies have demonstrated that administration of GLP-1 inhibits beta cell apoptosis via the PI3-K-PKB signalling pathway [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Continuous stimulation of human glucagon-like peptide-1 (7–36) amide in a mouse model (NOD) delays onset of autoimmune type 1 diabetes

et al. 2007

View full text Add to dashboard Cite

Aims/hypothesis We examined the effect of glucagon-like peptide-1 (GLP-1) on the development of diabetes and islet morphology in NOD mice by administering GLP-1 to prediabetic mice. Methods Eight-week-old female NOD mice were infused subcutaneously with human GLP-1 via a mini-osmotic pump for 4 or 8 weeks. In mice treated with GLP-1 for 4 weeks, blood glucose levels and body weight were measured. An intraperitoneal glucose tolerance test (IPGTT) and evaluation of insulitis score were also performed. Beta cell area, proliferation, apoptosis, neogenesis from ducts and subcellular localisation of forkhead box O1 (FOXO1) were examined by histomorphometrical, BrdU-labelling, TUNEL, insulin/cytokeratin and FOXO1/ insulin double-immunostaining methods, respectively.Results Mice treated with human GLP-1 for 4 weeks had lower blood glucose levels until 2 weeks after completion of treatment, showing improved IPGTT data and insulitis score. This effect continued even after cessation of the treatment. In addition to the increase of beta cell neogenesis, BrdU labelling index was elevated (0.24 vs 0.13%, p<0.001), while apoptosis was suppressed by 54.2% (p<0.001) in beta cells. Beta cell area was increased in parallel with the translocation of FOXO1 from the nucleus to the cytoplasm. The onset of diabetes was delayed in mice treated with GLP-1 for 4 weeks, while mice treated with GLP-1 for 8 weeks did not develop diabetes by age 21 weeks compared with a 60% diabetes incidence in control mice at this age. Conclusions/interpretation Continuous infusion of human GLP-1 to prediabetic NOD mice not only induces beta cell proliferation and neogenesis, but also suppresses beta cell apoptosis and delays the onset of type 1 diabetes.

show abstract

“…Expression of Neurog3 was reported in dedifferentiated in-vitro-expanded human beta cells along with an accompanying loss of expression of genes characteristic of beta cell differentiation. Similarly, in an adult mouse model of beta cell regeneration, intra-islet endocrine progenitor cells transiently expressed Neurog3 mRNA, implicating reactivation of endogenous Neurog3 during regeneration of beta cells [24]. However, a recent report by Lee et al found beta cell regeneration after partial pancreatectomy does not involve Neurog3 gene reactivation [25].…”

Section: Discussionmentioning

confidence: 99%

Ectopic expression of neurogenin 3 in neonatal pig pancreatic precursor cells induces (trans)differentiation to functional alpha cells

et al. 2006

View full text Add to dashboard Cite

Aims/hypothesis: Neurogenin 3 (NEUROG3), a basic helix-loop-helix transcription factor that is needed for endocrine cell development in the embryonic pancreas, has been shown to induce transdifferentiation of duct cells from adult pancreas towards a neuro-endocrine phenotype. Our study explored the endocrine transdifferentiation potential of NEUROG3 in neonatal pancreatic precursor cells. Materials and methods: A replication-deficient adenovirus expressing Neurog3 and green fluorescent protein (GFP) (Ad-NEUROG3) was used to infect neonatal pig pancreatic cell preparations enriched for endocrine islet and cytokeratin-positive precursor cells. GFP-positive cells were sorted using flow cytometry on days 3 and 8 after infection and characterised at the transcript and protein level. For in vivo experiments, the total population of Ad-NEUROG3-infected pancreatic cells was transplanted, then later removed for determination of graft hormone content and immunohistochemistry. Results: Among the GFPpositive cells, the fraction of precursor cells decreased by more than 85% at day 8 after infection, while the fraction of glucagon-positive cells increased 2.5-fold and the beta cell number remained the same. Transplantation of the Ad-NEUROG3-infected pancreatic cell preparation failed to reverse streptozotocin-induced hyperglycaemia, while noninfected cells and a control cell preparation infected with replication-deficient adenovirus expressing only GFP were able to do so. At day 109 after transplantation, kidneys grafted with Ad-NEUROG3-infected pancreatic cells contained significantly decreased insulin and increased glucagon levels. Abundant glucagon-immunopositive cells were seen in Ad-NEUROG3-infected grafts, which were virtually devoid of proliferating insulin-positive cells. Conclusions/interpretation: In summary, adenoviral delivery of NEUROG3 to pancreatic precursor cells from neonatal pig pancreas promotes alpha cell differentiation in vitro and in vivo.

show abstract

Enhanced expression of PDX-1 and Ngn3 by exendin-4 during β cell regeneration in STZ-treated mice

Cited by 81 publications

References 29 publications

Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function

Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function

Continuous stimulation of human glucagon-like peptide-1 (7–36) amide in a mouse model (NOD) delays onset of autoimmune type 1 diabetes

Ectopic expression of neurogenin 3 in neonatal pig pancreatic precursor cells induces (trans)differentiation to functional alpha cells

Contact Info

Product

Resources

About