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

• Published in: Diabetes (New York, N.Y.) Vol. 62; no. 4; pp. 1196 - 1205
• Main Authors: Longuet, Christine, Robledo, Ana M, Dean, E Danielle, Dai, Chunhua, Ali, Safina, McGuinness, Ian, de Chavez, Vincent, Vuguin, Patricia M, Charron, Maureen J, Powers, Alvin C, Drucker, Daniel J
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.04.2013
• Subjects: Animals; Blood Glucose; Female; Glucagon - administration & dosage; Glucagon - blood; Glucagon-Secreting Cells - cytology; Glucagon-Secreting Cells - pathology; Glucagon-Secreting Cells - physiology; Glucose - metabolism; Hepatocytes - drug effects; Hepatocytes - metabolism; Hyperplasia; Insulin Resistance; Intercellular Signaling Peptides and Proteins - physiology; Islets of Langerhans - cytology; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Liver - cytology; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Original Research; Receptors, Glucagon - genetics; Receptors, Glucagon - metabolism; Signal Transduction
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db11-1605

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. 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 α-cell hyperplasia. To investigate mechanisms by which signaling through the Gcgr regulates α-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 α-cell proliferation and expansion of α-cell area, consistent with changes exhibited by endogenous α-cells in Gcgr(-/-) and Gcgr(Hep)(-/-) 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.