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Transplantation. 2002 Oct 27;74(8):1063-9.

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

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Transplant Center, Division of Transplantation, University of Alabama at Birmingham, 748 Lyons-Harrison Research Building, 701 19th Street South, Birmingham, AL 35294, USA.



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.


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.


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.


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.

[Indexed for MEDLINE]

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