Liver-Specific Disruption of the Murine Glucagon Receptor Produces  -Cell Hyperplasia: Evidence for a Circulating  -Cell Growth Factor

Glucagon is a critical regulator of glucose homeostasis; however, mechanisms regulating glucagon action and a-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 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 mice developed hyperglucagonemia and a-cell hyperplasia. To investigate mechanisms by which signaling through the Gcgr regulates a-cell mass, wild-type islets were transplanted into Gcgr or Gcgr mice. Wild-type islets beneath the renal capsule of Gcgr or Gcgr mice exhibited an increased rate of a-cell proliferation and expansion of a-cell area, consistent with changes exhibited by endogenous a-cells in Gcgr and Gcgr pancreata. These results suggest that a circulating factor generated after disruption of hepatic Gcgr signaling can increase a-cell proliferation independent of direct pancreatic input. Identification of novel factors regulating a-cell proliferation and mass may facilitate the generation and expansion of a-cells for transdifferentiation into b-cells and the treatment of diabetes.