Trefoil Factor 3 Stimulates Human and Rodent Pancreatic Islet β-Cell Replication with Retention of Function

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2008-05, Vol.22 (5), p.1251-1259
• Main Authors: Fueger, Patrick T, Schisler, Jonathan C, Lu, Danhong, Babu, Daniella A, Mirmira, Raghavendra G, Newgard, Christopher B, Hohmeier, Hans E
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cell Proliferation - drug effects; Cells, Cultured; Epidermal Growth Factor - pharmacology; Humans; Immunoblotting; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Islets of Langerhans - cytology; Islets of Langerhans - metabolism; Male; Neuropeptides - genetics; Neuropeptides - metabolism; Neuropeptides - physiology; Oncogene Protein v-akt - metabolism; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Thymidine - metabolism; Transfection; Trefoil Factor-3
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2007-0500

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.