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. GcgrHep-/- 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, GcgrHep-/- 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 GcgrHep-/- mice. Wild-type islets beneath the renal capsule of Gcgr-/- or GcgrHep-/- 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 GcgrHep-/- 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.
|Original language||English (US)|
|Number of pages||10|
|State||Published - Apr 2013|
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism