Glucose-dependent expansion of pancreatic beta-cells by the protein p8 in vitro and in vivo

Päth, G; Opel, Anne; Gehlen, Martin; Rothhammer, Veit; Niu, Xiaoqun; Limbert, Catarina; Romfeld, L.; Hügl, Sigrun R.; Knoll, Anita; Brendel, Matthias; Bretzel, R. G.; Seufert, Jochen

doi:10.1055/s-2007-972445

Cited by 3 publications

(7 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The reasons for the discrepancies between our current results and earlier studies in which Nupr1 was experimentally upregulated [9,11] are not immediately obvious, but could result from differences in experimental approaches and/or interpretation. For example, the increased Nupr1 expression observed in response to glucose [9] may have been stress induced, as has been reported in similar studies [29].…”

Section: Discussioncontrasting

confidence: 99%

“…Thus, its expression is upregulated by glucose and TNF-α [2], both of which are elevated in type 2 diabetes [10], and INS-1 insulinoma cells showed glucose-dependent elevations in Nupr1 gene expression [9]. The forced overexpression of Nupr1 in human islets enhanced cumulative insulin secretion in vitro and increased the insulin content of islets transplanted below the renal capsule of diabetic mice in vivo [11], consistent with beneficial effects of Nupr1 overexpression on glycaemic control. We therefore hypothesised that Nupr1 deficiency would result in reduced beta cell mass and the progressive development of type 2 diabetes, and tested this using wild-type and Nupr1 −/− C57BL/6 mice [8].…”

Section: Introductionmentioning

confidence: 66%

“…However, the in vivo function of Nupr1 in the regulation of glucose homeostasis and islet function has not yet been established. Experimental overexpression in vitro of Nupr1 in INS-1 beta cells and human islets was associated with enhanced proliferation and increased insulin content, respectively [11], suggesting that Nupr1 deletion may lead to metabolic dysregulation. However, our data using the Nupr1 −/− mouse suggest that suppression of NUPR1 expression and/or activity is associated with phenotypic effects which would be predicted to be beneficial in obesity-related type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Nupr1 deletion protects against glucose intolerance by increasing beta cell mass

et al. 2013

View full text Add to dashboard Cite

Aims/hypothesis The stress-activated nuclear protein transcription regulator 1 (NUPR1) is induced in response to glucose and TNF-α, both of which are elevated in type 2 diabetes, and Nupr1 has been implicated in cell proliferation and apoptosis cascades. We used Nupr1 −/− mice to study the role of Nupr1 in glucose homeostasis under normal conditions and following maintenance on a high-fat diet (HFD). Methods Glucose homeostasis in vivo was determined by measuring glucose tolerance, insulin sensitivity and insulin secretion. Islet number, morphology and beta cell area were assessed by immunofluorescence and morphometric analysis, and islet cell proliferation was quantified by analysis of BrdU incorporation. Islet gene expression was measured by gene arrays and quantitative RT-PCR, and gene promoter activities were monitored by measuring luciferase activity. Results Nupr1 −/− mice had increased beta cell mass as a consequence of enhanced islet cell proliferation. Nupr1-dependent suppression of beta cell Ccna2 and Tcf19 promoter activities was identified as a mechanism through which Nupr1 may regulate beta cell cycle progression. Nupr1 −/− mice maintained on a normal diet were mildly insulin resistant, but were normoglycaemic with normal glucose tolerance because of compensatory increases in basal and glucose-induced insulin secretion. Nupr1 deletion was protective against HFD-induced obesity, insulin resistance and glucose intolerance. Conclusions/interpretation Inhibition of NUPR1 expression or activity has the potential to protect against the metabolic defects associated with obesity and type 2 diabetes.

show abstract

Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Nupr1 deletion protects against glucose intolerance by increasing beta cell mass

et al. 2013

View full text Add to dashboard Cite

show abstract

“…It was also expressed by human islet ␤-cells, and the level was significantly induced by high glucose concentration (39,40). p8 Overexpression enhanced glucose-stimulated ␤-cell proliferation and insulin secretion in primary human islets.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic islet-specific overexpression of Reg3β protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus

Xiong

Wang

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

. Pancreatic islet-specific overexpression of Reg3␤ protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus. Am J Physiol Endocrinol Metab 300: E669 -E680, 2011. First published January 18, 2011; doi:10.1152/ajpendo.00600.2010.-Reg family proteins have been implicated in islet ␤-cell proliferation, survival, and regeneration. The expression of Reg3␤ (pancreatitis-associated protein) is highly induced in experimental diabetes and acute pancreatitis, but its precise role has not been established. Through knockout studies, this protein was shown to be mitogenic, antiapoptotic, and anti-inflammatory in the liver and pancreatic acinars. To test whether it can promote islet cell growth or survival against experimental damage, we developed ␤-cell-specific overexpression using rat insulin I promoter, evaluated the changes in normal islet function, gene expression profile, and the response to streptozotocin-induced diabetes. Significant and specific overexpression of Reg3␤ was achieved in the pancreatic islets of RIP-I/Reg3␤ mice, which exhibited normal islet histology, ␤-cell mass, and in vivo and in vitro insulin secretion in response to high glucose yet were slightly hyperglycemic and low in islet GLUT2 level. Upon streptozotocin treatment, in contrast to wild-type littermates that became hyperglycemic in 3 days and lost 15% of their weight, RIP-I/Reg3␤ mice were significantly protected from hyperglycemia and weight loss. To identify specific targets affected by Reg3␤ overexpression, a whole genome DNA microarray on islet RNA isolated from the transgenic mice revealed more than 45 genes significantly either up-or downregulated. Among them, isletprotective osteopontin/SPP1 and acute responsive nuclear protein p8/NUPR1 were significantly induced, a result further confirmed by real-time PCR, Western blots, and immunohistochemistry. Our results suggest that Reg3␤ is unlikely an islet growth factor but a putative protector that prevents streptozotocin-induced damage by inducing the expression of specific genes.pancreatitis-associated protein; DNA microarray; real-time polymerase chain reaction; Western blot; immunofluorescence; Reg family proteins; transgenic mice A NORMAL ␤-CELL MASS is a crucial element against the development of diabetes mellitus and is determined by at least four independent parameters, i.e., mitogenic replication, cell size expansion, neogenesis (from other pancreatic cells), and apoptosis (42). The net rate of ␤-cell growth is the balance among the rates of ␤-cell replication, hypertrophy, neogenesis, and apoptosis (10). Various growth factors such as hepatocyte growth factor and glucagon-like peptide-1 (GLP-1) have been reported to stimulate islet cell expansion (12, 13, 43). For a therapeutic purpose, ␤-cell mass could also be supplemented by islet cell transplantation where growth factors were shown to promote the survival and/or expansion of transplanted cells in rodents (8,43). Unfortunately, very few of these factors have been pr...

show abstract

“…For example, p8 may buttress defense against cell injury (Vasseur et al 2004;Malicet et al 2006b) and promote growth (Vasseur et al 1999a;Garcia-Montero et al 2001;Päth, et al 2006;Malicet et al 2006b). In contrast, p8 also inhibits cell growth and suppresses tumors (Bratland et al 2000;Vasseur et al 2002aVasseur et al , 2002bZinke et al 2002;Malicet et al 2003;Jiang et al 2005Jiang et al , 2006 while maintaining tumor phenotype by a mechanism perhaps different from growth promotion per se (Ree et al 1999;Su et al 2001;Vasseur et al 2002b;Mohammad et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Developmentally regulated synthesis of p8, a stress-associated transcription cofactor, in diapause-destined embryos of Artemia franciscana

Qiu¹,

MacRae²

2007

Cell Stress Chaper

View full text Add to dashboard Cite

Diapause-destined embryos of the crustacean Artemia franciscana arrest as gastrulae, acquire extreme stress tolerance, and enter profound metabolic dormancy. Among genes upregulated at 2 days postfertilization in these embryos is a homologue of p8, a stress-inducible transcription cofactor. Artemia p8 is smaller than vertebrate homologues but shares a basic helix-loop-helix domain and a bipartite nuclear localization signal. Probing of restriction digested DNA on Southern blots indicated a single Artemia p8 gene and 5Ј-RACE specified 2 transcription start sites. Several putative cis-acting regulatory sequences, including two heat shock elements, appeared upstream of the p8 transcription start site. Artemia p8 mRNA increased sharply at 1 day postfertilization in diapause-destined embryos and then declined, whereas p8 protein appeared 2 days postfertilization and remained relatively constant throughout development, indicating a stable protein. p8 was not detectable in nauplius-destined (nondiapause) Artemia embryos. Immunofluorescent staining revealed p8 within Artemia nuclei. The results support the idea that p8, a known stressresponsive transcription cofactor, mediates gene expression in diapause-destined Artemia embryos. p8 is the first diapause-related transcription factor identified in crustaceans and 1 of only a small number of such proteins identified in any organism undergoing diapause.

show abstract

Glucose-dependent expansion of pancreatic beta-cells by the protein p8 in vitro and in vivo

Cited by 3 publications

References 0 publications

Nupr1 deletion protects against glucose intolerance by increasing beta cell mass

Nupr1 deletion protects against glucose intolerance by increasing beta cell mass

Pancreatic islet-specific overexpression of Reg3β protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus

Developmentally regulated synthesis of p8, a stress-associated transcription cofactor, in diapause-destined embryos of Artemia franciscana

Contact Info

Product

Resources

About