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

  1. Yuying Jiang1,
  2. Wataru Nishimura2,
  3. Deborah Devor-Henneman3,
  4. Donna Kusewitt3,
  5. Haijuan Wang4,
  6. Michael P. Holloway14,
  7. Takehiko Dohi5,
  8. Edmond Sabo6,
  9. Michael L. Robinson7,
  10. Dario C. Altieri5,
  11. Arun Sharma2 and
  12. Rachel A. Altura14
  1. 1The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
  2. 2Joslin Diabetes Center, Harvard Medical School, Boston Massachusetts
  3. 3Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio
  4. 4Department of Pediatrics, Brown University, Providence, Rhode Island
  5. 5Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts
  6. 6Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island
  7. 7Department of Zoology, Miami University, Oxford, Ohio
  1. Corresponding author: Rachel A. Altura, rachel_altura{at}brown.edu

Abstract

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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 3 July 2008.

    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted June 26, 2008.
    • Received February 6, 2008.
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  1. Diabetes vol. 57 no. 10 2718-2727
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