Maintenance of glucose metabolism homeostasis by regulating pancreatic β-cells through interoceptive signals from the liver

Abstract

Pancreatic β-cells adaptively proliferate in insulin-resistant states to increase insulin production and release. The proliferation is a compensatory mechanism aimed at maintaining glucose homeostasis. We previously discovered an inter-organ neuronal relay system, consisting of the afferent splanchnic nerve, central nervous system and efferent vagus, which is involved in adaptive β-cell proliferation. Interoceptive signals from the liver appear to function as the trigger for stimulating this inter-organ neuronal network system. We further elucidated the underlying molecular mechanisms governing this system which involve neurotransmitters from the vagus and activation of the β-cell FoxM1 pathway. However, whether activation of efferent vagal nerves in vivo alone is sufficient to promote meaningful β-cell proliferation was unclear. To address this issue, we newly developed an optogenetic vagal nerve stimulation (oVNS) system and examined the effects of vagal nerve stimulation on β-cells. Employing this system, we demonstrated that selective oVNS in the pancreas dramatically promoted β-cell proliferation. In addition, oVNS suppressed the development of hyperglycemia in insulin-deficient model mice. Thus, vagal nerve signals are not only necessary but also sufficient to induce β-cell proliferation, thereby increasing functional β-cell mass. These results enhance our understanding of the adaptation systems of organs/tissues as well as providing novel clues for developing tissue regeneration strategies based on endogenous biological systems.