title: Molecular mechanisms of tungstate-induced pancreatic plasticity: a transcriptomics approach.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Diabetes and Obesity Laboratory, Endocrinology and Nutrition Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona, Barcelona, Spain. jaltirri@clinic.ub.es
authors.forename: Jordi
authors.initials: J
authors.lastname: Altirriba
authors.forename: Albert
authors.initials: A
authors.lastname: Barbera
authors.forename: Héctor
authors.initials: H
authors.lastname: Del Zotto
authors.forename: Belen
authors.initials: B
authors.lastname: Nadal
authors.forename: Sandra
authors.initials: S
authors.lastname: Piquer
authors.forename: Alex
authors.initials: A
authors.lastname: Sánchez-Pla
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Gagliardino
authors.forename: Ramon
authors.initials: R
authors.lastname: Gomis
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D020869:Gene Expression Profiling; D006943:Hyperglycemia / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D010695:Phlorhizin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D017973:Tungsten Compounds / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D017973:Tungsten Compounds; D013311:Streptozocin; C025399:sodium tungstate(VI); D010695:Phlorhizin; D020928:Mitogen-Activated Protein Kinases