Synergistic effect of hyperglycemia and p27 ^kip1 suppression on adult mouse islet beta cell replication

The complementary role of hyperglycemia and p27 ^kip1 suppression on islet beta cell regeneration was investigated in a syngeneic mouse model. p27 ^kip1 gene silencing was performed by infecting islets of C57BL/6 with shRNA lentiviral particles. At 54 hours after viral infection, p27 ^kip1 protein content in cultured targeting islets was 22% of that in freshly isolated islets. Six days after transplantation to diabetic mice, targeting islet graft had considerably more cells with Ki67-staining nuclei than nontargeting islets. The mice in the targeting-islet group had a significantly shorter duration of temporary hyperglycaemia than mice in the non-targeting-islet group. The long-term ex vivo beneficial effect of p27 ^kip1 silencing on graft function was also indicated by the significantly higher cumulative cure rate for diabetes in mice receiving 200 targeting islets than that in mice receiving 200 non-targeting islets. Our data suggest that hyperglycemia and persistent p27 ^kip1 suppression have a synergistic effect on islet beta cell replication in adult mice.