Combined gastrin and epidermal growth factor treatment induces islet regeneration and restores normoglycaemia in C57BI6/J mice treated with alloxan

Abstract

Aims/hypothesis. Increasing beta-cell mass and/or function could restore glucose homeostasis in diabetes mellitus. Hitherto, trophic factors for beta-cell regeneration after toxic events have been difficult to identify. We evaluated the application of gastrin and epidermal growth factor after alloxan-induced pancreatic beta-cell damage. Methods. After alloxan treatment (70 mg/kg), mice were implanted with Alzet osmotic minipumps releasing gastrin and epidermal growth factor for one week. We monitored glycaemia, did histological analyses of the pancreata and quantified pancreatic beta-cell mass and insulin content. Results. Alloxan treatment alone resulted in a persisting hyperglycaemic state. Combined gastrin and epidermal growth factor treatment restored normoglycaemia in 3 days, an effect which seemed permanent. Glucose tolerance tests showed normal glucose responsiveness. Gastrin on its own and epidermal growth factor on its own did not alleviate hyperglycaemia. Islet mass, islet density and pancreatic insulin content were higher in mice treated with gastrin and epidermal growth factor than in untreated mice with persisting hyperglycaemia. In normoglycaemic control mice treatment with gastrin and epidermal growth factor did not affect these parameters. We detected transitional cytokeratin-positive ductal to endocrine insulin-expressing cells and noted increased ductal but not beta-cell proliferation. Conclusions/ interpretation. Our results show that combined treatment with gastrin and epidermal growth factor can induce sufficient regeneration of a functional islet mass to restore glucose homeostasis.