Neural relay from the liver induces proliferation of pancreatic beta cells: a path to regenerative medicine using the self-renewal capabilities.

Systemic homeostasis requires coordinated metabolic regulation among multiple tissues/organs via inter-organ communication. We have reported that neuronal signaling plays important roles in this inter-organ metabolic communication. First, we found that liver-selective extracellular signal-regulated kinase (ERK) activation induces insulin hypersecretion and pancreatic beta cell proliferation. Denervation experiments revealed that these inter- organ (liver-to-pancreas) effects are mediated by a neural relay consisting of splanchnic afferents (from the liver) and vagal efferents (to the pancreas). The central nervous system also participates in this inter-organ communication. This neural relay system originating in the liver is physiologically involved in the anti-diabetes mechanism whereby, during obesity development, insulin hypersecretion and pancreatic beta cell hyperplasia occur in response to insulin resistance. This indicates the pathophysiological importance of this system in diabetes prevention and hyperinsulinemia development. Furthermore, when applied to mouse models of insulin-deficient diabetes, both type 1 and type 2, hepatic activation of ERK signaling increased pancreatic beta cell mass and normalized blood glucose. Thus, this inter-organ system may serve as a valuable therapeutic target for diabetes by regenerating pancreatic beta cells. The concept that manipulation of an endogenous mechanism can regenerate a damaged tissue in vivo may open a new paradigm for regenerative trreatments for degenerative disorders.