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Glucagon receptor inactivation leads to ?-cell hyperplasia in zebrafish.

ABSTRACT: Glucagon antagonism is a potential treatment for diabetes. One potential side effect is ?-cell hyperplasia, which has been noted in several approaches to antagonize glucagon action. To investigate the molecular mechanism of the ?-cell hyperplasia and to identify the responsible factor, we created a zebrafish model in which glucagon receptor (gcgr) signaling has been interrupted. The genetically and chemically tractable zebrafish, which provides a robust discovery platform, has two gcgr genes (gcgra and gcgrb) in its genome. Sequence, phylogenetic, and synteny analyses suggest that these are co-orthologs of the human GCGR. Similar to its mammalian counterparts, gcgra and gcgrb are mainly expressed in the liver. We inactivated the zebrafish gcgra and gcgrb using transcription activator-like effector nuclease (TALEN) first individually and then both genes, and assessed the number of ?-cells using an ?-cell reporter line, Tg(gcga:GFP). Compared to WT fish at 7 days postfertilization, there were more ?-cells in gcgra-/-, gcgrb-/-, and gcgra-/-;gcgrb-/- fish and there was an increased rate of ?-cell proliferation in the gcgra-/-;gcgrb-/- fish. Glucagon levels were higher but free glucose levels were lower in gcgra-/-, gcgrb-/-, and gcgra-/-;gcgrb-/- fish, similar to Gcgr-/- mice. These results indicate that the compensatory ?-cell hyperplasia in response to interruption of glucagon signaling is conserved in zebrafish. The robust ?-cell hyperplasia in gcgra-/-;gcgrb-/- larvae provides a platform to screen for chemical and genetic suppressors, and ultimately to identify the stimulus of ?-cell hyperplasia and its signaling mechanism.

SUBMITTER: Li M

PROVIDER: S-EPMC4598637 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Glucagon receptor inactivation leads to α-cell hyperplasia in zebrafish.

Li Mingyu M Dean E Danielle ED Zhao Liyuan L Nicholson Wendell E WE Powers Alvin C AC Chen Wenbiao W

The Journal of endocrinology 20151101 2

Glucagon antagonism is a potential treatment for diabetes. One potential side effect is α-cell hyperplasia, which has been noted in several approaches to antagonize glucagon action. To investigate the molecular mechanism of the α-cell hyperplasia and to identify the responsible factor, we created a zebrafish model in which glucagon receptor (gcgr) signaling has been interrupted. The genetically and chemically tractable zebrafish, which provides a robust discovery platform, has two gcgr genes (gc ...[more]

PMID: 26446275

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Project description:Glucose homeostasis is determined by a balance between insulin and glucagon, produced by beta and alpha cells of the pancreas respectively. The levels of circulating hormones is partly determined by the mass of these two endocrine cell types. However, in contrast to beta cells, the identity of the signals regulating alpha cell number is not known. Mice with a global deletion of the glucagon receptor (Gcgr-/-) and mice with ablation of prohormone convertase 2 (PC2), the enzyme involved in the conversion of proglucagon into mature glucagon, develop alpha cell hyperplasia. These observations and the fact that Gcgr-/- mice exhibit high levels of circulating glucagon-like peptide-1 (GLP-1) suggested that members of the glucagon family of peptides could be directly involved in the regulation of alpha cell number. In this study we sought to determine whether alpha cells express receptors for Glucagon (Gcgr) and/or the glucagon-like peptide-1 (GLP1r). We examined the expression of these receptors in islets of Gcgr-/-, PC2-/- mice and control littermates, in an alpha (alphaTC1/9) and in a beta (betaTC3) cell line. Gcgr was expressed exclusively by islet beta cells, but not by alpha cells, of the two lines of mice lacking glucagon signaling. Similarly, betaTC but not alphaTC cells, expressed Gcgr. The expression of GLP1r by alpha cells was determined by the genotype and age of the mice. In embryos, GLU+ cells of Gcgr+/+ mice cells express GLP1r during early development, but not in adults. In contrast, alpha cells of Gcgr-/- mice were GLP1r+ throughout life, reflecting the immature state of GLU+ cells when Gcgr is deleted. Unlike alpha cells, beta cells of all mice lines examined initiate GLP1r expression after birth. These results suggest that GLP-1 may affect the maturation of postnatal but not prenatal beta cells. In addition, they also suggest that the incretin could mediate alpha cell proliferation, inducing the development of alpha cell hyperplasia in Gcgr-/- mice.

Dataset Information

Glucagon receptor inactivation leads to ?-cell hyperplasia in zebrafish.

Publications

Glucagon receptor inactivation leads to α-cell hyperplasia in zebrafish.

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