Simvastatin induces activation of the serine-threonine protein kinase AKT and increases survival of isolated human pancreatic islets.
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.[1]References
- Simvastatin induces activation of the serine-threonine protein kinase AKT and increases survival of isolated human pancreatic islets. Contreras, J.L., Smyth, C.A., Bilbao, G., Young, C.J., Thompson, J.A., Eckhoff, D.E. Transplantation (2002) [Pubmed]
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