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This Article Full Text Full Text (PDF) Supplemental Figures Supplemental Figures All Versions of this Article: 297/3/E695    most recent 00082.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gelling, R. W. Articles by Charron, M. J. PubMed PubMed Citation Articles by Gelling, R. W. Articles by Charron, M. J.

Pancreatic β-cell overexpression of the glucagon receptor gene results in enhanced β-cell function and mass

Department of ¹Biochemistry and ⁶Medicine and ³Department of Pediatrics, Pediatric Endocrinology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York; ²Department of Diabetes Biology and ⁴Pharmacological Research 4, ⁸Pharmacological Research 2, and ⁹Pharmacological Research 3, Novo Nordisk, Bagsværd, Denmark; ⁵Department of Physiology, University of British Columbia, Vancouver, British Columbia, Canada; ⁷Department of Medical Physiology, Panum Institute, Copenhagen, Denmark

Submitted 10 February 2009 ; accepted in final form 6 July 2009

In addition to its primary role in regulating glucose production from the liver, glucagon has many other actions, reflected by the wide tissue distribution of the glucagon receptor (Gcgr). To investigate the role of glucagon in the regulation of insulin secretion and whole body glucose homeostasis in vivo, we generated mice overexpressing the Gcgr specifically on pancreatic β-cells (RIP-Gcgr). In vivo and in vitro insulin secretion in response to glucagon and glucose was increased 1.7- to 3.9-fold in RIP-Gcgr mice compared with controls. Consistent with the observed increase in insulin release in response to glucagon and glucose, the glucose excursion resulting from both a glucagon challenge and intraperitoneal glucose tolerance test (IPGTT) was significantly reduced in RIP-Gcgr mice compared with controls. However, RIP-Gcgr mice display similar glucose responses to an insulin challenge. β-Cell mass and pancreatic insulin content were also increased (20 and 50%, respectively) in RIP-Gcgr mice compared with controls. When fed a high-fat diet (HFD), both control and RIP-Gcgr mice developed similar degrees of obesity and insulin resistance. However, the severity of both fasting hyperglycemia and impaired glucose tolerance (IGT) were reduced in RIP-Gcgr mice compared with controls. Furthermore, the insulin response of RIP-Gcgr mice to an IPGTT was twice that of controls when fed the HFD. These data indicate that increased pancreatic β-cell expression of the Gcgr increased insulin secretion, pancreatic insulin content, β-cell mass, and, when mice were fed a HFD, partially protected against hyperglycemia and IGT.

glucagon receptor signaling; pancreatic islet cells; insulin secretion