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- Title
Trefoil Factor 3-Induced Islet Proliferation Requires EGF Receptor Signaling.
- Authors
Fueger, Patrick T.; Schisler, Jonathan C.; Lu, Danhong; Hohmeier, Hans E.; Newgard, Christopher B.
- Abstract
The limited availability of pancreatic islets from cadaver donors has hindered the broad application of islet transplantation as a cure for type 1 diabetes. Because of this, it is important to develop methods to stimulate islet proliferation. We have recently discovered that trefoil factor 3 (TFF3) can stimulate primary rat islet proliferation in vitro and that this effect requires the presence of serum. We therefore sought to determine what component of serum was required for enabling TFF3-stimulated islet proliferation. We transduced islets with adenoviruses expressing either beta-galactosidase (AdCMV-BetaGal) or TFF3 (AdCMV-TFF3) in both the presence and absence of serum. Without serum, AdCMV-TFF3 could not increase [³H]-thymidine incorporation. However, addition of 0.5 ng/ml of epidermal growth factor (EGF), while having minimal proliferative effect alone, induced proliferation (by ∼fourfold) in serum free, AdCMV-TFF3-treated islets to the same extent as AdCMV-TFF3-treated islets cultured in the presente of serum. Importantly, the ability of AdCMV-TFF3 to stimulate proliferation in isolated rat islets cultured in serum could be abolished by the addition of 10 µM AG1478 (an EGF receptor tyrosine kinase inhibitor). In a similar manner, AdCMV-TFF3-induced increases in [³H]-thymidine incorporation in rat islets cultured in serum could be blocked by overexpressing a dominant negative Akt protein (AdCMV-dnAkt) or treating with 10/µM Triciribine (an Akt pharmacological inhibitor). Finally, glucose-stimulated insulin secretion was not impaired by AdCMV-TFF3 or EGF treatment. In summary, TFF3 signaling appears to be dependent on EGF receptor signaling and the downstream effector Akt, as TFF3-induced proliferation can be blocked by inhibiting the function of either kinase. Therefore, it is possible that culturing isolated islets in the combination of TFF3 and EGF might be a viable means for increasing islet mass.
- Subjects
CELL proliferation; ISLANDS of Langerhans transplantation; EPIDERMAL growth factor; TREATMENT of diabetes; ADENOVIRUSES; SERUM; MECHANISM of action for insulin
- Publication
Diabetes, 2007, Vol 56, pA424
- ISSN
0012-1797
- Publication type
Article