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. 2009 Sep;297(3):E695-707.
doi: 10.1152/ajpendo.00082.2009. Epub 2009 Jul 14.

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

Richard W Gelling  1 , Patricia M Vuguin, Xiu Quan Du, 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
Affiliations

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

Richard W Gelling et al. Am J Physiol Endocrinol Metab. 2009 Sep.

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 beta-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. beta-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 beta-cell expression of the Gcgr increased insulin secretion, pancreatic insulin content, beta-cell mass, and, when mice were fed a HFD, partially protected against hyperglycemia and IGT.

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Figures

Fig. 1.
Fig. 1.
Generation of transgenic mice overexpressing the glucagon receptor (Gcgr) specifically on pancreatic β-cells (RIP-Gcgr). A: schematic drawing of the RIP-Gcgr-pA transgene. The rat insulin promoter (RIP, gray shaded box) was used to direct murine Gcgr overexpression in β-cells. White boxes represent noncoding regions, and black boxes represent coding regions of Gcgrs exons 1 to 13. The 847-bp hybrid SV40 intron/polyadenylation signal sequence is indicated. Primers used to screen for transgene are indicated by arrowheads a and b. B: quantitiative PCR analysis of total islet RNA from mice overexpressing the Gcgr gene. Mice were age (11–14 wk)- and sex-matched (males) controls (***P < 0.001, n = 3). WT, wild type. C and D: daily blood glucose profiles in RIP-Gcgr3 mice. Blood glucose levels were determined from tail blood throughout the day for male (C) and female (D) mice. Data represent means ± SE; n = 6–10 mice. *P < 0.05.
Fig. 2.
Fig. 2.
A: glucagon-stimulated insulin release from isolated islets. Islets from RIP-Gcgr mice responded to a dose of glucagon (0.3 nM) that was subthreshold for that of control islets, whereas 20 nM glucagon increased insulin release from both RIP-Gcgr and control islets. Data represent means ± SE; n = 4 mice. **P < 0.01. Glucagon-stimulated insulin response (B) and plasma glucose (C) and arginine-stimulated insulin release (D) from control and RIP-Gcgr3 male transgenic mice. Anesthetized mice were challenged with 16 μg/kg glucagon ip after a 6-h fast or 0.25 g/kg arginine iv after a 12-h fast. Data represent means ± SE; n = 7–13. *P < 0.05.
Fig. 3.
Fig. 3.
Insulin secretion from the isolated perfused mouse pancreas in response to glucose is increased in RIP-Gcgr mice. The insulin response of male RIP-Gcgr mice (22 wk) to 16.7 mM glucose was increased compared with littermate controls (A and C). The integrated insulin response [area under the curve (AUC) in μU insulin over 40 min] was approximately two times that seen in control mice (B and D). Data represent means ± SE; n = 5–9. **P < 0.01.
Fig. 4.
Fig. 4.
Glucose homeostasis in RIP-Gcgr mice. Intraperitoneal glucose tolerance test (IPGTT) of RIP-Gcgr3 males (A) and RIP-Gcgr6 females (C). Both the peak glucose levels and duration of the glucose excursion (AUC in mM of glucose over 90 min) (B and D) were decreased in the RIP-Gcgr mice compared with littermate controls. RIP-Gcgr mice have normal insulin tolerance. No difference was observed in the insulin-induced glucose excursion obtained from RIP-Gcgr3 male (E) and RIP-Gcgr6 female (F) mice compared with littermate controls (14–20 wk). Data represent means ± SE; n = 5–9. *P < 0.05 and **P < 0.01.
Fig. 5.
Fig. 5.
RIP-Gcgr mice have increased pancreatic insulin content (A) and β-cell mass (B), but normal islet architecture (C and D). The pancreatic insulin content of RIP-Gcgr mice was ∼1.5 times that of age- and sex-matched controls. Quantification of islet cell mass by point counting morphometry indicated that the β-cell volume was increased ∼20% in male RIP-Gcgr mice 16 wk of age. Photomicrographs of islets from 3-mo-old mice immunostained for insulin (red) and glucagon (green). Control (C) and RIP-Gcgr (B) mice. Bar: 40 μm. Data represent means ± SE; n = 5–7. *P < 0.05 and **P < 0.01.
Fig. 6.
Fig. 6.
Effect of high-fat diet (HFD) on body weight (A), fasting blood glucose (B), plasma insulin (C), and leptin levels (D). Mice were weaned on diets consisting of either 58% (HFD) or 10.5% [low-fat diet (LFD)] of total calories derived from fat for 12 wk. Data represent means ± SE; n = 33–32 for body weight and n = 7–8 for all other measurements. *P at least <0.05 vs. control LFD; #P at least <0.05 vs. Rip-Gcgr3 LFD; ΨP at least <0.05 vs. control HFD.
Fig. 7.
Fig. 7.
Effect of HFD on glucose homeostasis in RIP-Gcgr3 and control mice. Insulin tolerance test (ITT; A) and IPGTT (C) were carried out on mice after 12 wk of being fed either a HFD or LFD. Control and RIP-Gcgr3 mice displayed a similar decrease in insulin sensitivity compared with mice fed the LFD as was reflected in the AUC (D). Both the peak glucose levels and duration of the glucose excursion (AUC in mM of glucose over 90 min) (C and D) were decreased in the RIP-Gcgr3 mice compared with littermate controls when fed a HFD. E and F: in anesthetized animals, insulin release was increased in RIP-Gcgr3 compared with controls when fed a LFD. Rip-Gcgr3 mice fed a HFD displayed a further increase in insulin release that was greater than that seen in both LFD-fed groups as well as controls fed a HFD. Data are means ± SE; n = 6–8. *P at least <0.05 vs. control LFD; #P at least <0.05 vs. Rip-Gcgr3 LFD; ΨP at least <0.05 vs. control HF.
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