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

Richard W. Gelling, Patricia M. Vuguin, Quan Du Xiu, Lingguang Cui, John Rømer, Raymond A. Pederson, Margarita Leiser, Heidi Sørensen, Jens J. Holst, Christian Fledelius, Peter B. Johansen, Norman Fleischer, Christopher H S McIntosh, Erica Nishimura, Maureen J. Charron

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume297
Issue number3
DOIs
StatePublished - Sep 2009

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Glucagon Receptors
Insulin
Glucagon
Genes
Glucose
High Fat Diet
Glucose Intolerance
Glucose Tolerance Test
Hyperglycemia
Tissue Distribution
Insulin Resistance
Fasting

Keywords

  • Glucagon receptor signaling
  • Insulin secretion
  • Pancreatic islet cells

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

Pancreatic β-cell overexpression of the glucagon receptor gene results in enhanced β-cell function and mass. / Gelling, Richard W.; Vuguin, Patricia M.; Xiu, Quan Du; Cui, Lingguang; Rømer, John; Pederson, Raymond A.; Leiser, Margarita; Sørensen, Heidi; Holst, Jens J.; Fledelius, Christian; Johansen, Peter B.; Fleischer, Norman; McIntosh, Christopher H S; Nishimura, Erica; Charron, Maureen J.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 297, No. 3, 09.2009.

Research output: Contribution to journalArticle

Gelling, RW, Vuguin, PM, Xiu, QD, Cui, L, Rømer, J, Pederson, RA, Leiser, M, Sørensen, H, Holst, JJ, Fledelius, C, Johansen, PB, Fleischer, N, McIntosh, CHS, Nishimura, E & Charron, MJ 2009, 'Pancreatic β-cell overexpression of the glucagon receptor gene results in enhanced β-cell function and mass', American Journal of Physiology - Endocrinology and Metabolism, vol. 297, no. 3. https://doi.org/10.1152/ajpendo.00082.2009
Gelling, Richard W. ; Vuguin, Patricia M. ; Xiu, Quan Du ; Cui, Lingguang ; Rømer, John ; Pederson, Raymond A. ; Leiser, Margarita ; Sørensen, Heidi ; Holst, Jens J. ; Fledelius, Christian ; Johansen, Peter B. ; Fleischer, Norman ; McIntosh, Christopher H S ; Nishimura, Erica ; Charron, Maureen J. / Pancreatic β-cell overexpression of the glucagon receptor gene results in enhanced β-cell function and mass. In: American Journal of Physiology - Endocrinology and Metabolism. 2009 ; Vol. 297, No. 3.
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