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

Sarah W. Stedman Nutrition and Metabolism Center (P.T.F., J.C.S., D.L., C.B.N., H.E.H.), Department of Pharmacology and Cancer Biology, and Department of Medicine, Division of Endocrinology, Nutrition, and Metabolism, Duke University Medical Center, Durham, North Carolina 27704; and Department of Internal Medicine (D.A.B., R.G.M.), Division of Endocrinology and Metabolism, University of Virginia Health System, Charlottesville, Virginia 22903

Address all correspondence and requests for reprints to: Christopher B. Newgard, Ph.D., Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Duke Independence Park Facility, 4321 Medical Park Drive, Suite 200, Durham, North Carolina 27704. E-mail: newga002{at}mc.duke.edu.

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.