Liver-specific disruption of the murine glucagon receptor produces α-cell hyperplasia evidence for a circulating α-Cell Growth Factor

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

Research output: Contribution to journalArticle

95 Scopus citations

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. 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 languageEnglish (US)
Pages (from-to)1196-1205
Number of pages10
JournalDiabetes
Volume62
Issue number4
DOIs
StatePublished - Apr 2013

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Longuet, C., Robledo, A. M., Dean, E. D., Dai, C., Ali, S., McGuinness, I., De Chavez, V., Vuguin, P. M., Charron, M. J., Powers, A. C., & Drucker, D. J. (2013). Liver-specific disruption of the murine glucagon receptor produces α-cell hyperplasia evidence for a circulating α-Cell Growth Factor. Diabetes, 62(4), 1196-1205. https://doi.org/10.2337/db11-1605