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BMC Genomics. 2009; 10: 406.
Published online Aug 28, 2009. doi:  10.1186/1471-2164-10-406
PMCID: PMC2741493
Molecular mechanisms of tungstate-induced pancreatic plasticity: a transcriptomics approach
Jordi Altirriba,1,2 Albert Barbera,1 Héctor Del Zotto,3 Belen Nadal,1,2 Sandra Piquer,1,2 Alex Sánchez-Pla,4,5 Juan J Gagliardino,3 and Ramon Gomiscorresponding author1,2
1Diabetes and Obesity Laboratory, Endocrinology and Nutrition Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona, Barcelona, Spain
2Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
3Centro de Endocrinología Experimental y Aplicada (CENEXA), Universidad Nacional de La Plata – Consejo Nacional de Investigaciones Científicas y Técnicas (UNLP-CONICET), Facultad de Ciencias Médicas, UNLP, La Plata, Argentina
4Department of Statistics, University of Barcelona, Barcelona, Spain
5Statistics and Bioinformatics Unit, Institut de Recerca Hospital Universitari Vall d'Hebron, Barcelona, Spain
corresponding authorCorresponding author.
Jordi Altirriba: jaltirri/at/clinic.ub.es; Albert Barbera: abarbera/at/clinic.ub.es; Héctor Del Zotto: hdelzotto/at/yahoo.com.ar; Belen Nadal: bnadal/at/ub.edu; Sandra Piquer: spiquer/at/clinic.ub.es; Alex Sánchez-Pla: asanchez/at/ub.edu; Juan J Gagliardino: cenexa/at/speedy.com.ar; Ramon Gomis: rgomis/at/clinic.ub.es
Received January 7, 2009; Accepted August 28, 2009.
Abstract
Background
Sodium tungstate is known to be an effective anti-diabetic agent, able to increase beta cell mass in animal models of diabetes, although the molecular mechanisms of this treatment and the genes that control pancreas plasticity are yet to be identified. Using a transcriptomics approach, the aim of the study is to unravel the molecular mechanisms which participate in the recovery of exocrine and endocrine function of streptozotocin (STZ) diabetic rats treated with tungstate, determining the hyperglycemia contribution and the direct effect of tungstate.
Results
Streptozotocin (STZ)-diabetic rats were treated orally with tungstate for five weeks. Treated (STZ)-diabetic rats showed a partial recovery of exocrine and endocrine function, with lower glycemia, increased insulinemia and amylasemia, and increased beta cell mass achieved by reducing beta cell apoptosis and raising beta cell proliferation. The microarray analysis of the pancreases led to the identification of three groups of differentially expressed genes: genes altered due to diabetes, genes restored by the treatment, and genes specifically induced by tungstate in the diabetic animals. The results were corroborated by quantitative PCR. A detailed description of the pathways involved in the pancreatic effects of tungstate is provided in this paper. Hyperglycemia contribution was studied in STZ-diabetic rats treated with phloridzin, and the direct effect of tungstate was determined in INS-1E cells treated with tungstate or serum from untreated or treated STZ-rats, observing that tungstate action in the pancreas takes places via hyperglycemia-independent pathways and via a combination of tungstate direct and indirect (through the serum profile modification) effects. Finally, the MAPK pathway was evaluated, observing that it has a key role in the tungstate-induced increase of beta cell proliferation as tungstate activates the mitogen-activated protein kinase (MAPK) pathway directly by increasing p42/p44 phosphorylation and indirectly by decreasing the expression of raf kinase inhibitor protein (Rkip), a negative modulator of the pathway.
Conclusion
In conclusion, tungstate improves pancreatic function through a combination of hyperglycemia-independent pathways and through its own direct and indirect effects, whereas the MAPK pathway has a key role in the tungstate-induced increase of beta cell proliferation.
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