Trefoil factor 3 stimulates human and rodent pancreatic islet β-cell replication with retention of function

Patrick T. Fueger, Jonathan C. Schisler, Danhong Lu, Daniella A. Babu, Raghavendra G. Mirmira, Christopher B. Newgard, Hans E. Hohmeier

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Both major forms of diabetes involve a decline in β-cell mass, mediated by autoimmune destruction of insulin-producing cells in type 1 diabetes and by increased rates of apoptosis secondary to metabolic stress in type 2 diabetes. Methods for controlled expansion of β-cell mass are currently not available but would have great potential utility for treatment of these diseases. In the current study, we demonstrate that overexpression of trefoil factor 3 (TFF3) in rat pancreatic islets results in a 4- to 5-fold increase in [3H]thymidine incorporation, with full retention of glucose-stimulated insulin secretion. This increase was almost exclusively due to stimulation of β-cell replication, as demonstrated by studies of bromodeoxyuridine incorporation and co-immunofluorescence analysis with anti-bromodeoxyuridine and antiinsulin or antiglucagon antibodies. The proliferative effect of TFF3 required the presence of serum or 0.5 ng/ml epidermal growth factor. The ability of TFF3 overexpression to stimulate proliferation of rat islets in serum was abolished by the addition of epidermal growth factor receptor antagonist AG1478. Furthermore, TFF3-induced increases in [3H]thymidine incorporation in rat islets cultured in serum was blocked by overexpression of a dominant-negative Akt protein or treatment with triciribine, an Akt inhibitor. Finally, overexpression of TFF3 also caused a doubling of [3H]thymidine incorporation in human islets. In summary, our findings reveal a novel TFF3-mediated pathway for stimulation of β-cell replication that could ultimately be exploited for expansion or preservation of islet β-cell mass.

Original languageEnglish (US)
Pages (from-to)1251-1259
Number of pages9
JournalMolecular Endocrinology
Volume22
Issue number5
DOIs
StatePublished - May 1 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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