Simvastatin induces activation of the serine-threonine protein kinase AKT and increases survival of isolated human pancreatic islets.

Academic Article

Abstract

  • BACKGROUND: Pancreatic islets are susceptible to myriad insults that occur during islet isolation and transplantation. Studies demonstrated the role of Akt in regulating pancreatic beta-cell growth and survival. Activation of Akt maintains Bad phosphorylation and prevents its binding to mitochondrial targets, decreases caspase-9 activity, and prevents the translocation of forkhead transcription factors (FKHR). Simvastatin activates Akt in mammalian cells; therefore, we investigated the role of simvastatin on human pancreatic islets (HPI) survival. METHODS: HPI were treated with simvastatin, with and without LY294002, an inhibitor of phosphoinositide 3-kinase. PI viability was examined with ethidium bromide-acridine orange, and apoptosis was examined using a quantitative assay. Akt, Bad, FKHR phosphorylation, and mitochondrial cytochrome release were analyzed by Western blots. Caspase-9 activity was assessed by a fluorometric assay. A limited number of HPI were transplanted after simvastatin treatment in diabetic NOD-SCID mice. RESULTS: Low levels of Akt phosphorylation (activation) were demonstrated early after islet isolation. Akt activation; increase in islet viability; and decrease in Bad phosphorylation, cytochrome release, caspase-9 activation, and translocation of FKHR were observed after simvastatin treatment, effects reversed by LY294002. Among recipients of islets without simvastatin, none demonstrated reversal of diabetes after the transplant. In contrast, 58% of the recipients given islets treated with simvastatin remained euglycemic 30 days after the transplant. CONCLUSIONS: Targeting the survival pathway with simvastatin exerts a cytoprotective effect on isolated PI. Activation of the Akt pathway is a potential new therapeutic approach to reduce loss of functional islet mass to bolster success in clinical islet transplantation.
  • Published In

  • Transplantation  Journal
  • Keywords

  • Animals, Carrier Proteins, Caspase 9, Caspases, Cell Survival, Cells, Cultured, Cytochrome c Group, Diabetes Mellitus, Type 1, Fas Ligand Protein, Forkhead Transcription Factors, Gene Expression, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Islets of Langerhans, Islets of Langerhans Transplantation, Male, Membrane Glycoproteins, Mice, Mice, Inbred NOD, Mice, SCID, Mitochondria, Nuclear Proteins, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Simvastatin, Transcription Factors, bcl-Associated Death Protein
  • Digital Object Identifier (doi)

    Author List

  • Contreras JL; Smyth CA; Bilbao G; Young CJ; Thompson JA; Eckhoff DE
  • Start Page

  • 1063
  • End Page

  • 1069
  • Volume

  • 74
  • Issue

  • 8