liver-Specific Disruption of the Murine Glucagon Receptor Produces a-Cell Hyperplasia

摘要

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~(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 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~(Hep-/-) mice. Wild-type islets beneath the renal capsule of Gcgr~(-/-) or Gcgr~(Hep-/-) 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~(Hep-/-) 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 α-cells for transdifferentiation into β-cells and the treatment of diabetes.