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 alpha-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 alpha-cell hyperplasia. To investigate mechanisms by which signaling through the Gcgr regulates alpha-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 alpha-cell proliferation and expansion of alpha-cell area, consistent with changes exhibited by endogenous alpha-cells in Gcgr(-/-) and Gcgr(Hep-/-) pancreata. These results suggest that a circulating factor generated after disruption of hepatic Gcgr signaling can increase alpha-cell proliferation independent of direct pancreatic input. Identification of novel factors regulating alpha-cell proliferation and mass may facilitate the generation and expansion of alpha-cells for transdifferentiation into beta-cells and the treatment of diabetes. Diabetes 62:1196-1205, 2013