Liver-specific disruption of the murine glucagon receptor produces ?-cell hyperplasia: evidence for a circulating ?-cell growth factor.

ABSTRACT: Glucagon is a critical regulator of glucose homeostasis; however, mechanisms regulating glucagon action and ?-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 ?-cell hyperplasia. To investigate mechanisms by which signaling through the Gcgr regulates ?-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 ?-cell proliferation and expansion of ?-cell area, consistent with changes exhibited by endogenous ?-cells in Gcgr(-/-) and Gcgr(Hep)(-/-) pancreata. These results suggest that a circulating factor generated after disruption of hepatic Gcgr signaling can increase ?-cell proliferation independent of direct pancreatic input. Identification of novel factors regulating ?-cell proliferation and mass may facilitate the generation and expansion of ?-cells for transdifferentiation into ?-cells and the treatment of diabetes.

SUBMITTER: Longuet C 

PROVIDER: S-EPMC3609565 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature