Mice Deficient for Glucagon Gene-Derived Peptides Display Normoglycemia and Hyperplasia of Islet α-Cells But Not of Intestinal L-cells

Hayashi, Yoshitaka; Yamamoto, Motoshi; Mizoguchi, Hideaki; Watanabe, Chika; Itô, Ryôichi; Yamamoto, Seishi; Sun, Xiaoyang; Murata, Yoshiharu

doi:10.1210/jcem.94.11.9994

Cited by 29 publications

(71 citation statements)

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“…Conversely, the expansion of α cell mass was associated with increased α cell proliferation and neogenesis from ductassociated progenitors (supplementary material Fig. S14), consistent with the endocrine phenotypes reported in mutant mice deficient in the glucagon pathway (Prasadan et al, 2002;Webb et al, 2002;Gelling et al, 2003;Hayashi et al, 2009).…”

Section: Results β Cell Regeneration Occurs By Neogenesis In Zebrafishsupporting

confidence: 80%

“…In regenerating islets, gcga knockdown phenocopies the loss of α cells observed in the arxa knockdown, providing strong evidence that peptides derived from the glucagon gene are crucial regulators of α cell conversion. As in murine disruptions of the glucagon signaling pathway (Gelling et al, 2003;Hayashi et al, 2009;Vuguin and Charron, 2011;Longuet et al, 2013), we found that α cell mass was not only maintained, but also expanded through proliferation and neogenesis. That the number of potential α cell progenitors of β cells was expanded, yet β cell regeneration was depressed, further underscores the importance of glucagon for cell fate switching.…”

Section: Discussionmentioning

confidence: 61%

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glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis

et al. 2015

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The interconversion of cell lineages via transdifferentiation is an adaptive mode of tissue regeneration and an appealing therapeutic target. However, its clinical exploitation is contingent upon the discovery of contextual regulators of cell fate acquisition and maintenance. In murine models of diabetes, glucagon-secreting alpha cells transdifferentiate into insulin-secreting beta cells following targeted beta cell depletion, regenerating the form and function of the pancreatic islet. However, the molecular triggers of this mode of regeneration are unknown. Here, using lineage-tracing assays in a transgenic zebrafish model of beta cell ablation, we demonstrate conserved plasticity of alpha cells during islet regeneration. In addition, we show that glucagon expression is upregulated after injury. Through gene knockdown and rescue approaches, we also find that peptides derived from the glucagon gene are necessary for alpha-to-beta cell fate switching. Importantly, whereas beta cell neogenesis was stimulated by glucose, alpha-to-beta cell conversion was not, suggesting that transdifferentiation is not mediated by glucagon/GLP-1 control of hepatic glucose production. Overall, this study supports the hypothesis that alpha cells are an endogenous reservoir of potential new beta cells. It further reveals that glucagon plays an important role in maintaining endocrine cell homeostasis through feedback mechanisms that govern cell fate stability.

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Section: Results β Cell Regeneration Occurs By Neogenesis In Zebrafishsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 61%

glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis

et al. 2015

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“…The low fasting plasma glucose can also directly be explained by the decreased circulating glucagon levels causing decreased glycogenolysis and gluconeogenesis. In agreement with this concept, the GCG knockout mouse manifests with lower blood glucose and lower serum insulin levels, as well as higher insulin sensitivity, compared with wild-type mice [23]. The lower height among homozygous carriers compared with wild-type carriers may be due to the low serum insulin levels with reduced anabolic effects of insulin, probably starting in the fetus.…”

Section: Discussionmentioning

confidence: 65%

Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1

Torekov

Grarup

et al. 2011

Diabetologia

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Aims/hypothesis The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits. Methods GCG was re-sequenced as a candidate gene in 865 European individuals. Twenty-nine variants were identified. Four variants that were considered to have a likelihood for altered functionality: rs4664447, rs7581952, Ile158Val and Trp169Ter, were genotyped in 17,584 Danes. Results When examined in 5,760 treatment-naive individuals, homozygous carriers of the low frequency (minor allele frequency 2.3%) G allele of rs4664447, predicted to disrupt an essential splice enhancer binding site, had lower levels of fasting plasma glucose (mean ± SD, 4.8 ± 1.2 vs 5.5 ± 0.8 mmol/l, p=0.004); fasting serum insulin (22±14 vs 42±27 pmol/l, p=0.04); glucose-stimulated serum insulin (159±83 vs 290±183 pmol/l, p=0.01) and adult height (165±10 vs 172±9 cm, p=0.0009) compared with A allele carriers. During oral glucose tolerance and hyperglycaemic arginine stimulation tests, the plasma AUC for GLP-1 (730±69 vs 1,334±288 pmol/l×min, p=0.0002) and basal and stimulated levels of serum insulin and plasma glucagon were ∼50% decreased (p<0.001) among three homozygous carriers compared with nine matched wild-type Electronic supplementary material The online version of this article (doi:10.1007/s00125-011-2265-7) contains peer-reviewed but unedited supplementary material, including a list of the GIANT Consortium members, which is available to authorised users.

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“…Since the intestine of mice with ablation of the glucagon gene (GcgÀ/À) (Hayashi et al, 2009), PC2 (Furuta et al, 2001;Grigoryan et al, 2008), Gcgr (Grigoryan et al, 2012), or the GLP-1 receptor (Hansotia and Drucker, 2005) appeared to be morphologically normal, the presence of glucagon and GLP-1 in the embryonic small intestine is intriguing. One possibility is that products of the glucagon gene are involved in a regulatory loop that controls the number of cells expressing the gene.…”

Section: Discussionmentioning

confidence: 99%

“…One possibility is that products of the glucagon gene are involved in a regulatory loop that controls the number of cells expressing the gene. In adults, mutant mice lacking glucagon display alpha but not L cell hyperplasia (Furuta et al, 1997;Grigoryan et al, 2008;Hayashi et al, 2009) and restoration of glucagon to PC2 KO mice normalizes alpha cell number (Webb et al, 2002). The number of L cells is positively correlated with plasma level of GLP-1, which was high in GcgrÀ/À mice (Gelling et al, 2003) but was normal in PC2À/À mice (Furuta et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Phenotype of entero‐endocrine L cells becomes restricted during development

Grigoryan

Kedees

Guz

et al. 2012

Developmental Dynamics

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Mice Deficient for Glucagon Gene-Derived Peptides Display Normoglycemia and Hyperplasia of Islet α-Cells But Not of Intestinal L-cells

Cited by 29 publications

References 0 publications

glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis

glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis

Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1

Phenotype of entero‐endocrine L cells becomes restricted during development

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