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

Cell Rep. 2013 Feb 21;3(2):401-10. doi: 10.1016/j.celrep.2013.01.007. Epub 2013 Jan 31.

Abstract

Integrative 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Culture Media, Conditioned
  • Hepatocytes / cytology
  • Hepatocytes / metabolism*
  • Humans
  • Hyperplasia
  • Insulin Resistance*
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects*
  • Intercellular Signaling Peptides and Proteins / pharmacology*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology*
  • Islets of Langerhans Transplantation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptor, Insulin / deficiency
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism

Substances

  • Culture Media, Conditioned
  • Intercellular Signaling Peptides and Proteins
  • Receptor, Insulin