Partial hepatectomy promotes pancreatic regeneration through HGF/Gab1 pathway in db/db mice

Both the liver and the pancreas of terrestrial vertebrates are developed from endodermal epithelial cells in the embryonic foregut. Some studies showed that there was an interaction between liver and pancreas regeneration. In the present study, we first examined the effects of partial hepatectomy on β-cell mass, insulin and pancreas weight. Partial hepatectomy significantly improved β-cell proliferation, insulin secretion and pancreas growth. Next, we measured the changes of fasting plasma glucose (FPG) and blood glucose inoral glucose tolerance test (OGTT) in the presence of partial hepatectomy. The results suggested that partial hepatectomy significantly improve carbohydrate metabolism, indicated by the decrease of FPG level and blood glucose in OGTT. The serum hepatocyte growth factor (HGF) in mice gradually increased after partial hepatectomy. The pancreatic HGF expression and Grb2 associated binder 1 (Gab1) activation were also dramatically increased by partial hepatectomy. To further identify the role of HGF and Gab1, we treated mice with PHA-665752, a specific inhibitor of c-Met, the HGF receptor, and found that the ratio of β-cells to non-β endocrine cells, insulin secretion and pancreas weight and Gab1 activation were all decreased by PHA-665752. Furthermore, PHA-665752 significantly increased the FPG levels and blood glucose levels in OGTT compared to Hepatectomy group. These results revealed a positive effect of partial hepatectomy on pancreatic regeneration and a novel mechanism involving HGF/Gab1 signaling.