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Postnatal expansion of the pancreatic β-cell mass is dependent on survivin

¹The Research Institute at Nationwide Children's Hospital, Columbus OH 43205, USA
²Joslin Diabetes Center, Harvard Medical School, Boston MA 02215, USA
³Department of Veterinary Biosciences, The Ohio State University, Columbus OH 43210, USA
⁴Department of Pediatrics, Brown University, Providence RI 02903, USA
⁵Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
⁶ Department of Pathology and Laboratory Medicine, Brown University, Providence RI 02903, USA
⁷Department of Zoology, Miami University, Oxford OH 45056, USA

Objective: Diabetes results from a deficiency of functional β-cells due to both an increase in β-cell death and an inhibition of β-cell replication. The molecular mechanisms responsible for these effects in susceptible individuals are mostly unknown. The objective of this study was to determine if a gene critical for cell division and cell survival in cancer cells, survivin, might also be important for β-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 bi-allelic 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 β-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 β-cells lacking endogenous survivin completely rescued the hyperglycemic phenotype and the decrease in β-cell mass, confirming the specificity of the survivin effect in these cells.

Conclusions: Our findings implicate survivin in the maintenance of β-cell mass through both replication and anti-apoptotic mechanisms. Given the widespread involvement of survivin in cancer, a novel role for survivin may well be exploited in β-cell regulation in diseased states, such as diabetes.

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