Identification of a novel mechanism regulating β-cell mass: neuronal relay from the liver to pancreatic β-cells.

Recent studies have demonstrated that β-cell replication plays a central role in maintaining adult β-cell mass. β-cell proliferative activity changes dynamically to meet systemic needs throughout life. One condition in which β-cell proliferation is enhanced is obesity-related insulin resistance. However, the mechanism underlying this compensatory β-cell response is not well understood. We have identified a neuronal relay, originating in the liver, which enhances both insulin secretion and pancreatic β-cell proliferation. Blockade of this neural relay in murine obesity models inhibited pancreatic islet expansion during obesity development, showing this inter-organ communication system to be physiologically involved in compensatory β-cell proliferation. While there is controversy about which mechanism, proliferation of pre-existing β-cells or production of new β cells from progenitor cells, plays the dominant role in maintaining or regulating β-cell mass, we herein provide an example that proliferation of pre-existing β-cells contributes to a β-cell increment in obesity-related insulin resistance. Furthermore, we have shown the potential for clinical application of this inter-organ system as a therapeutic target for insulin-deficient diabetes.