Neural relay from the liver induces proliferation of pancreatic β cells

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 β cell proliferation. Denervation experiments revealed that these interorgan (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 β 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 β cell mass and normalized blood glucose. Thus, this inter-organ system may serve as a valuable therapeutic target for diabetes by regenerating pancreatic β 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.