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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.

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