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

Abstract

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.

• Authors: Christine Longuet, Ana M Robledo, E Danielle Dean, Chunhua Dai, Safina Ali, Ian McGuinness, Vincent de Chavez, Patricia M Vuguin, Maureen J Charron, Alvin C Powers, Daniel J Drucker
• Journal: Diabetes (Diabetes) Vol. 62 Issue 4 Pg. 1196-205 (Apr 2013) ISSN: 1939-327X [Electronic] United States
• PMID: 23160527 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Intercellular Signaling Peptides and Proteins
• Receptors, Glucagon
• Glucagon
• Glucose

Topics

• Animals
• Blood Glucose
• Female
• Glucagon (administration & dosage, blood)
• Glucagon-Secreting Cells (cytology, pathology, physiology)
• Glucose (metabolism)
• Hepatocytes (drug effects, metabolism)
• Hyperplasia
• Insulin Resistance
• Intercellular Signaling Peptides and Proteins (physiology)
• Islets of Langerhans (cytology, metabolism, pathology)
• Liver (cytology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Receptors, Glucagon (genetics, metabolism)
• Signal Transduction