Transgenic overexpression of active calcineurin in β-cells results in decreased β-cell mass and hyperglycemia

Ernesto Bernal-Mizrachi, Corentin Cras-Méneur, Bo Ra Ye, James D. Johnson, M. Alan Permutt

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Background: Glucose modulates β-cell mass and function through an initial depolarization and Ca2+ influx, which then triggers a number of growth regulating signaling pathways. One of the most important downstream effectors in Ca2+ signaling is the calcium/Calmodulin activated serine threonine phosphatase, calcineurin. Recent evidence suggests that calcineurin/NFAT is essential for β-cell proliferation, and that in its absence loss of β-cells results in diabetes. We hypothesized that in contrast, activation of calcineurin might result in expansion of β-cell mass and resistance to diabetes. Methodology/Principal Findings: To determine the role of activation of calcineurin signaling in the regulation of pancreatic β-cell mass and proliferation, we created mice that expressed a constitutively active form of calcineurin under the insulin gene promoter (caCn RIP). To our surprise, these mice exhibited glucose intolerance. In vitro studies demonstrated that while the second phase of Insulin secretion is enhanced, the overall insulin secretory response was conserved. Islet morphometric studies demonstrated decreased β-cell mass suggesting that this was a major component responsible for altered Insulin secretion and glucose intolerance in caCn RIP mice. The reduced β-cell mass was accompanied by decreased proliferation andenhanced apoptosis.Conclusions: Our studies identify calcineurin as an important factor in controlling glucose homeostasis and indicate that chronic depolarization leading to increased calcineurin activity may contribute, along with other genetic and environmental factors, to β-cell dysfunction and diabetes.

Original languageEnglish (US)
Article numbere11969
JournalPloS one
Volume5
Issue number8
DOIs
StatePublished - Oct 15 2010
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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