Liver-specific disruption of the murine glucagon receptor produces α-cell hyperplasia evidence for a circulating α-Cell Growth Factor

Glucagon is a critical regulator of glucose homeostasis; however, mechanisms regulating glucagon action and α-Cell function and number are incompletely understood. To elucidate the role of the hepatic glucagon receptor (Gcgr) in glucagon action, we generated mice with hepatocyte-specific deletion of the glucagon receptor. Gcgr^Hep-/- mice exhibited reductions in fasting blood glucose and improvements in insulin sensitivity and glucose tolerance compared with wild-type controls, similar in magnitude to changes observed in Gcgr^-/- mice. Despite preservation of islet Gcgr signaling, Gcgr^Hep-/- mice developed hyperglucagonemia and α-Cell hyperplasia. To investigate mechanisms by which signaling through the Gcgr regulates α-Cell mass, wild-type islets were transplanted into Gcgr^-/- or Gcgr^Hep-/- mice. Wild-type islets beneath the renal capsule of Gcgr^-/- or Gcgr^Hep-/- mice exhibited an increased rate of α-Cell proliferation and expansion of α-Cell area, consistent with changes exhibited by endogenous α-Cells in Gcgr ^-/- and Gcgr^Hep-/- pancreata. These results suggest that a circulating factor generated after disruption of hepatic Gcgr signaling can increase α-Cell proliferation independent of direct pancreatic input. Identification of novel factors regulating α-Cell proliferation and mass may facilitate the generation and expansion of α-Cells for transdifferentiation into β-cells and the treatment of diabetes.