Liver-Specific Disruption of the Murine Glucagon Receptor Produces α-Cell Hyperplasia

Evidence for a Circulating α-Cell Growth Factor

  1. Daniel J. Drucker1
  1. 1Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, The University of Toronto, Toronto, Ontario, Canada
  2. 2Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  3. 3Division of Pediatric Endocrinology, Steven & Alexandra Cohen Children’s Medical Center of New York, Long Island, New York
  4. 4Albert Einstein College of Medicine, Departments of Biochemistry, Medicine, and Obstetrics & Gynecology, Bronx, New York
  5. 5Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee
  6. 6VA Tennessee Valley Healthcare System, Nashville, Tennessee.
  1. Corresponding author: Alvin C. Powers, al.powers{at}vanderbilt.edu, or Daniel J. Drucker, drucker{at}lunenfeld.ca.
  1. C.L., A.M.R., and E.D.D. contributed equally to this study.

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.

Footnotes

  • Received November 17, 2011.
  • Accepted September 25, 2012.

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  1. Diabetes vol. 62 no. 4 1196-1205
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