This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suarez-Pinzon, W. L. Articles by Rabinovitch, A. Search for Related Content PubMed PubMed Citation Articles by Suarez-Pinzon, W. L. Articles by Rabinovitch, A. Related Collections Diabetes and Insulin

Combination Therapy with Epidermal Growth Factor and Gastrin Induces Neogenesis of Human Islet ß-Cells from Pancreatic Duct Cells and an Increase in Functional ß-Cell Mass

Departments of Medicine (W.L.S.-P., A.R.) and Surgery (J.R.T.L.), University of Alberta, Edmonton, Canada T6G 2S2; and Waratah Pharmaceuticals (S.J.B.), Woburn, Massachusetts 01801

Address all correspondence and requests for reprints to: Dr. Alex Rabinovitch, 430 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. E-mail: alex.rabinovitch{at}ualberta.ca.

Pancreatic islet transplantation is a viable treatment for type 1 diabetes, but is limited by human donor tissue availability. The combination of epidermal growth factor (EGF) and gastrin induces islet ß-cell neogenesis from pancreatic exocrine duct cells in rodents. In this study we investigated whether EGF and gastrin could expand the ß-cell mass in adult human isolated islets that contain duct as well as endocrine cells. Human islet cells were cultured for 4 wk in serum-free medium (control) or in medium with EGF (0.3 µg/ml), gastrin (1.0 µg/ml), or the combination of EGF and gastrin. ß-Cell numbers were increased in cultures with EGF plus gastrin (+118%) and with EGF (+81%), but not in cultures with gastrin (–3%) or control medium (–62%). After withdrawal of EGF and gastrin and an additional 4 wk in control medium, ß-cell numbers continued to increase only in cultures previously incubated with both EGF and gastrin (+232%). EGF plus gastrin also significantly increased cytokeratin 19-positive duct cells (+678%) in the cultures. Gastrin, alone or in combination with EGF, but not EGF alone, increased the expression of pancreatic and duodenal homeobox factor-1 as well as insulin and C peptide in the cytokeratin 19-positive duct cells. Also, EGF plus gastrin significantly increased ß-cells and insulin content in human islets implanted in immunodeficient nonobese diabetic-severe combined immune deficiency mice as well as insulin secretory responses of the human islet grafts to glucose challenge. In conclusion, combination therapy with EGF and gastrin increases ß-cell mass in adult human pancreatic islets in vitro and in vivo, and this appears to result from the induction of ß-cell neogenesis from pancreatic exocrine duct cells.

This article has been cited by other articles:

				D. Bresson and M. von Herrath Immunotherapy for the Prevention and Treatment of Type 1 Diabetes: Optimizing the path from bench to bedside Diabetes Care, October 1, 2009; 32(10): 1753 - 1768. [Full Text] [PDF]

				L. R. Nielsen, J. F. Rehfeld, U. Pedersen-Bjergaard, P. Damm, and E. R. Mathiesen Pregnancy-Induced Rise in Serum C-Peptide Concentrations in Women With Type 1 Diabetes Diabetes Care, June 1, 2009; 32(6): 1052 - 1057. [Abstract] [Full Text] [PDF]

				W. L. Suarez-Pinzon, R. F. Power, Y. Yan, C. Wasserfall, M. Atkinson, and A. Rabinovitch Combination Therapy With Glucagon-Like Peptide-1 and Gastrin Restores Normoglycemia in Diabetic NOD Mice Diabetes, December 1, 2008; 57(12): 3281 - 3288. [Abstract] [Full Text] [PDF]

				N. M. Fiaschi-Taesch, D. M. Berman, B. M. Sicari, K. K. Takane, A. Garcia-Ocana, C. Ricordi, N. S. Kenyon, and A. F. Stewart Hepatocyte Growth Factor Enhances Engraftment and Function of Nonhuman Primate Islets Diabetes, October 1, 2008; 57(10): 2745 - 2754. [Abstract] [Full Text] [PDF]

				D. A. Taylor-Fishwick, A. Bowman, M. Korngiebel-Rosique, and A. I. Vinik Pancreatic Islet Immunoreactivity to the Reg Protein INGAP J. Histochem. Cytochem., February 1, 2008; 56(2): 183 - 191. [Abstract] [Full Text] [PDF]

				R. Mussmann, M. Geese, F. Harder, S. Kegel, U. Andag, A. Lomow, U. Burk, D. Onichtchouk, C. Dohrmann, and M. Austen Inhibition of GSK3 Promotes Replication and Survival of Pancreatic Beta Cells J. Biol. Chem., April 20, 2007; 282(16): 12030 - 12037. [Abstract] [Full Text] [PDF]

				R. Gianani The Multiple Endocrine Neoplasia Type-1 (MEN-1) Syndrome and Its Effect on the Pancreas J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 811 - 812. [Full Text] [PDF]

				K. Robertson, J. J. Kopchick, and J.-L. Liu Growth hormone receptor gene deficiency causes delayed insulin responsiveness in skeletal muscles without affecting compensatory islet cell overgrowth in obese mice Am J Physiol Endocrinol Metab, September 1, 2006; 291(3): E491 - E498. [Abstract] [Full Text] [PDF]

				W. L. Suarez-Pinzon, Y. Yan, R. Power, S. J. Brand, and A. Rabinovitch Combination Therapy With Epidermal Growth Factor and Gastrin Increases {beta}-Cell Mass and Reverses Hyperglycemia in Diabetic NOD Mice Diabetes, September 1, 2005; 54(9): 2596 - 2601. [Abstract] [Full Text] [PDF]