title: Inhibition of beta cell growth and function by bone morphogenetic proteins.
abstract: OBJECTIVE
  Impairment of beta cell mass and function is evident in both type 1 and type 2 diabetes. In healthy physiological conditions pancreatic beta cells adapt to the body's increasing insulin requirements by proliferation and improved function. We hypothesised that during the development of diabetes, there is an increase in the expression of inhibitory factors that prevent the beta cells from adapting to the increased need for insulin. We evaluated the effects of bone morphogenetic protein (BMP) 2 and -4 on beta cells.
  
  
  METHODS
  The effects of BMP2 and -4 on beta cell proliferation, apoptosis, gene expression and insulin release were studied in isolated islets of Langerhans from rats, mice and humans. The expression of BMPs was analysed by immunocytochemistry and real-time PCR. The role of endogenous BMP was investigated using a soluble and neutralising form of the BMP receptor 1A.
  
  
  RESULTS
  BMP2 and -4 were found to inhibit basal as well as growth factor-stimulated proliferation of primary beta cells from rats and mice. Bmp2 and Bmp4 mRNA and protein were expressed in islets and regulated by inflammatory cytokines. Neutralisation of endogenous BMP activity resulted in enhanced proliferation of rodent beta cells. The expression of Id mRNAs was induced by BMP4 in rat and human islets. Finally, glucose-induced insulin secretion was significantly impaired in rodent and human islets pre-treated with BMP4, and inhibition of BMP activity resulted in enhanced insulin release.
  
  
  CONCLUSIONS
  These data show that BMP2 and -4 exert inhibitory actions on beta cells in vitro and suggest that BMPs exert regulatory roles of beta cell growth and function.
authors.affiliation: Hagedorn Research Institute, Gentofte, Denmark.
authors.forename: Christine
authors.initials: C
authors.lastname: Bruun
authors.forename: Gitte L
authors.initials: GL
authors.lastname: Christensen
authors.forename: Marie L B
authors.initials: ML
authors.lastname: Jacobsen
authors.forename: Marianne B
authors.initials: MB
authors.lastname: Kanstrup
authors.forename: Pernille R
authors.initials: PR
authors.lastname: Jensen
authors.forename: Helle
authors.initials: H
authors.lastname: Fjordvang
authors.forename: Thomas
authors.initials: T
authors.lastname: Mandrup-Poulsen
authors.forename: Nils
authors.initials: N
authors.lastname: Billestrup
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D007328:Insulin