Liver-Derived Systemic Factors Drive β Cell Hyperplasia in Insulin-Resistant States

SummaryIntegrative organ crosstalk regulates key aspects of energy homeostasis, and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that crosstalk between the liver and pancreatic islets modulates β cell growth in response to insulin resistance, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, as well as in vitro islet culture approaches, we demonstrate that humoral, nonneural, non-cell-autonomous factor(s) induces β cell proliferation in LIRKO mice. Furthermore, we report that a hepatocyte-derived factor(s) stimulates mouse and human β cell proliferation in ex vivo assays, independent of ambient glucose and insulin levels. These data implicate the liver as a critical source of β cell growth factor(s) in insulin-resistant states.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Circulating nonneuronal factors drive β cell replication in LIRKO mice ► LIRKO serum increases mouse and human islet β cell replication in vitro ► LIRKO serum induces selective β cell replication in vivo ► Hepatocyte-derived factors stimulate mouse and human β cell replication in vitro