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

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

doi:10.1152/ajpendo.00082.2009

Cited by 60 publications

(44 citation statements)

References 57 publications

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“…The critical role of glucagon in maintaining beta cell function is also supported by the observations in Gcgr −/− mice, which displayed impaired beta cell function due to the lack of glucagon action [34]. Consistently, this perception is further supported by another study showing that beta cell specific over-production of GCGR enhanced glucose-competent insulin secretion and increased beta cell mass [35].…”

Section: Discussionsupporting

confidence: 63%

Ectopic expression of glucagon receptor in skeletal muscles improves glucose homeostasis in a mouse model of diabetes

et al. 2012

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Aims/hypothesis Excessive secretion of glucagon partially contributes to the development of diabetic hyperglycaemia. However, complete blocking of glucagon action will lead to adverse effects, since glucagon exerts certain beneficial effects via its receptor in many organs. We aimed to study the effects of a 'decoy receptor' for circulating glucagon on modulating beta cell function and glucose homeostasis in mice by over-producing the glucagon receptor (GCGR) in skeletal muscles. Methods We generated transgenic mice in which the expression of Gcgr is driven by the muscle specific creatine kinase (Mck) promoter, and assessed the effects of glucagon on the modulation of glucose homeostasis under conditions of extremes of glucose influx or efflux.Results Mck/Gcgr mice showed increased circulating levels of glucagon and insulin, resulting in an unchanged ratio of glucagon-to-insulin. The levels of hepatic glucose-6-phosphatase (G6PC) and fructose-1,6-bisphosphatase (F1,6P2ase) were significantly decreased, whereas the phosphorylation level of pancreatic cAMP-response-element-binding-protein (CREB) was significantly increased in these transgenic mice. Under basal conditions, the mice displayed normal blood glucose levels and unchanged glucose tolerance and insulin sensitivity when compared with their age-matched wild-type (WT) littermates. However, following multiple lowdose streptozotocin injections, Mck/Gcgr mice exhibited a delay in the onset of hyperglycaemia compared with the WT controls. This was associated with preserved beta cell mass and beta cell secretory capacity in response to glucose challenge.A. Maharaj and L. Zhu contributed equally to this study. Electronic supplementary material The online version of this article

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Section: Discussionsupporting

confidence: 63%

Ectopic expression of glucagon receptor in skeletal muscles improves glucose homeostasis in a mouse model of diabetes

et al. 2012

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“…Overexpression of Gcgr in b-cells increased glucagon-stimulated insulin release and significantly increased b-cell volume, suggesting a role for Gcgr receptor in increased insulin cell competency (Gelling et al 2009). These data are strengthened by the findings of low levels of PDX1, GLUT2, and MafA, molecules involved in the regulation of insulin expression, in insulin cells of Gcgr K/K mice (Vuguin et al 2006).…”

Section: Role Of Glucagon In B (Insulin) Cell Functionmentioning

confidence: 99%

Lack of glucagon receptor signaling and its implications beyond glucose homeostasis

Charron¹,

Vuguin²

2015

Journal of Endocrinology

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Glucagon action is transduced by a G protein-coupled receptor located in liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart, pancreatic b-cells, and placenta. Genetically modified animal models have provided important clues about the role of glucagon and its receptor (Gcgr) beyond glucose control. The PubMed database was searched for articles published between 1995 and 2014 using the key terms glucagon, glucagon receptor, signaling, and animal models. Lack of Gcgr signaling has been associated with: i) hypoglycemic pregnancies, altered placentation, poor fetal growth, and increased fetal-neonatal death; ii) pancreatic glucagon cell hyperplasia and hyperglucagonemia; iii) altered body composition, energy state, and protection from diet-induced obesity; iv) impaired hepatocyte survival; v) altered glucose, lipid, and hormonal milieu; vi) altered metabolic response to prolonged fasting and exercise; vii) reduced gastric emptying and increased intestinal length; viii) altered retinal function; and ix) prevention of the development of diabetes in insulin-deficient mice. Similar phenotypic findings were observed in the hepatocyte-specific deletion of Gcgr. Glucagon action has been involved in the modulation of sweet taste responsiveness, inotropic and chronotropic effects in the heart, satiety, glomerular filtration rate, secretion of insulin, cortisol, ghrelin, GH, glucagon, and somatostatin, and hypothalamic signaling to suppress hepatic glucose production. Glucagon (a) cells under certain conditions can transdifferentiate into insulin (b) cells. These findings suggest that glucagon signaling plays an important role in multiple organs. Thus, treatment options designed to block Gcgr activation in diabetics may have implications beyond glucose homeostasis.

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“…Glucagon directly stimulates insulin secretion in the rat pancreas independent of GLP-1 receptor action (45), and transgenic Gcgr expression in murine β cells significantly augments glucose-stimulated insulin secretion and reduces random glycemia in RIP-Gcgr transgenic mice (46). Moreover, the glucagon antagonist des-His1-[Glu9]-glucagon-amide significantly reduced glucose-stimulated insulin release in human islets (47).…”

Section: Figurementioning

confidence: 99%

Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis

Ali

Lamont

Charron³

et al. 2011

J. Clin. Invest.

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Disordered glucagon secretion contributes to the symptoms of diabetes, and reduced glucagon action is known to improve glucose homeostasis. In mice, genetic deletion of the glucagon receptor (Gcgr) results in increased levels of the insulinotropic hormone glucagon-like peptide 1 (GLP-1), which may contribute to the alterations in glucose homeostasis observed in Gcgr -/-mice. Here, we assessed the contribution of GLP-1 receptor (GLP-1R) signaling to the phenotype of Gcgr -/-mice by generating Gcgr -/-Glp1r -/-mice. Although insulin sensitivity was similar in all genotypes, fasting glucose was increased in Gcgr -/-Glp1r -/-mice. Elimination of the Glp1r normalized gastric emptying and impaired intraperitoneal glucose tolerance in Gcgr -/-mice. Unexpectedly, deletion of Glp1r in Gcgr -/-mice did not alter the improved oral glucose tolerance and increased insulin secretion characteristic of that genotype. Although Gcgr -/-Glp1r -/-islets exhibited increased sensitivity to the incretin glucose-dependent insulinotropic polypeptide (GIP), mice lacking both Glp1r and the GIP receptor (Gipr) maintained preservation of the enteroinsular axis following reduction of Gcgr signaling. Moreover, Gcgr -/-Glp1r -/-islets expressed increased levels of the cholecystokinin A receptor (Cckar) and G protein-coupled receptor 119 (Gpr119) mRNA transcripts, and Gcgr -/-Glp1r -/-mice exhibited increased sensitivity to exogenous CCK and the GPR119 agonist AR231453. Our data reveal extensive functional plasticity in the enteroinsular axis via induction of compensatory mechanisms that control nutrient-dependent regulation of insulin secretion.

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

Abstract: MJ. Pancreatic ␤-cell overexpression of the glucagon receptor gene results in enhanced ␤-cell function and mass.

Cited by 60 publications

References 57 publications

Ectopic expression of glucagon receptor in skeletal muscles improves glucose homeostasis in a mouse model of diabetes

Ectopic expression of glucagon receptor in skeletal muscles improves glucose homeostasis in a mouse model of diabetes

Lack of glucagon receptor signaling and its implications beyond glucose homeostasis

Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis

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