Postnatal Expansion of the Pancreatic \(\beta\)-Cell Mass Is Dependent on Survivin

Abstract

Objective: Diabetes results from a deficiency of functional (\beta)-cells due to both an increase in (\beta)-cell death and an inhibition of (\beta)-cell replication. The molecular mechanisms responsible for these effects in susceptible individuals are mostly unknown. The objective of this study was to determine whether a gene critical for cell division and cell survival in cancer cells, survivin, might also be important for (\beta)-cells. Research Design and Methods: We generated mice harboring a conditional deletion of survivin in pancreatic endocrine cells using mice with a Pax-6-Cre transgene promoter construct driving tissue-specific expression of Cre-recombinase in these cells. We performed metabolic studies and immunohistochemical analyses to determine the effects of a mono- and biallelic deletion of survivin. Results: Selective deletion of survivin in pancreatic endocrine cells in the mouse had no discernible effects during embryogenesis but was associated with striking decreases in (\beta)-cell number after birth, leading to hyperglycemia and early-onset diabetes by 4 weeks of age. Serum insulin levels were significantly decreased in animals lacking endocrine cell survivin, with relative stability of other hormones. Exogenous expression of survivin in mature (\beta)-cells lacking endogenous survivin completely rescued the hyperglycemic phenotype and the decrease in (\beta)-cell mass, confirming the specificity of the survivin effect in these cells. Conclusions: Our findings implicate survivin in the maintenance of (\beta)-cell mass through both replication and antiapoptotic mechanisms. Given the widespread involvement of survivin in cancer, a novel role for survivin may well be exploited in (\beta)-cell regulation in diseased states, such as diabetes.