PANCREATIC GASTRIN STIMULATES ISLET DIFFERENTIATION OF TRANSFORMING GROWTH-FACTOR ALPHA-INDUCED DUCTULAR PRECURSOR CELLS

Gastrin is transiently expressed in fetal islets during a critical period of their development from protodifferentiated islet precursors in fetal pancreatic ducts. To examine the possible role of gastrin as an islet cell growth factor, postnatal islet growth was studied in transgenic mice which overexpress gastrin and TGFalpha in their pancreas. Overexpression of a TGFalpha transgene causes metaplastic ductules containing numerous insulin expressing cells that resemble protodifferentiated precursors of the fetal pancreas. However, islet mass of the TGFalpha transgenic mice was not increased. Pancreatic overexpression of gastrin from a chimeric insulin/gastrin transgene transcribed from the insulin promoter markedly decreased the TGFalpha-stimulated increase in pancreatic duct mass. Furthermore, pancreatic coexpression of both gastrin and TGFalpha significantly increased islet mass in mice expressing both transgenes. These findings indicate that TGFalpha and gastrin can act synergistically to stimulate islet growth, although neither peptide alone is sufficient. Islet growth may possibly be stimulated through gastrin promoting the differentiation of insulin-positive cells in the TGFalpha-induced metaplastic ducts. This transgenic study suggests that islet neogenesis can be reactivated in the ductular epithelium of the adult pancreas by local expression of two growth factors, gastrin and TGFalpha.