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Postnatal Expansion of the Pancreatic β-Cell Mass Is Dependent on Survivin

¹ The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
² Joslin Diabetes Center, Harvard Medical School, Boston Massachusetts
³ Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio
⁴ Department of Pediatrics, Brown University, Providence, Rhode Island
⁵ Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts
⁶ Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island
⁷ Department of Zoology, Miami University, Oxford, Ohio

Corresponding author: Rachel A. Altura, rachel_altura{at}brown.edu

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 whether 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 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 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 antiapoptotic 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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