ArticleThe Journal of endocrinology2015
Glucagon receptor inactivation leads to α-cell hyperplasia in zebrafish.
Article in The Journal of endocrinology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 44 citations in OpenAlex.
- Targeting glucagon signaling in metabolic disorders, functional insights from zebrafish receptor knockouts.Cellular and molecular life sciences : CMLS · 2026Article
- Pancreatic islet α cell function and proliferation require the arginine transporter SLC7A2.The Journal of clinical investigation · 2026Article
- Blockade of glucagon receptor induces α-cell hypersecretion by hyperaminoacidemia in mice.Nature communications · 2025Article
- Article
- Interruption of glucagon signaling augments islet non-alpha cell proliferation in SLC7A2- and mTOR-dependent manners.Molecular metabolism · 2024Article
- Interruption of glucagon signaling augments islet non-alpha cell proliferation in SLC7A2- and mTOR-dependent manners.bioRxiv : the preprint server for biology · 2024Article
- ErbB3 is required for hyperaminoacidemia-induced pancreatic α cell hyperplasia.The Journal of biological chemistry · 2024Article
- Somatostatin signalling coordinates energy metabolism allocation to reproduction in zebrafish.BMC biology · 2024Article
- The Regulation of Metabolic Homeostasis by Incretins and the Metabolic Hormones Produced by Pancreatic Islets.Diabetes, metabolic syndrome and obesity : targets and therapy · 2024Review
- Hyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways.Nature communications · 2023Article
- Evaluation of commercially available glucagon receptor antibodies and glucagon receptor expression.Communications biology · 2022Article
- Zebrafish: A Model to Study and Understand the Diabetic Nephropathy and Other Microvascular Complications of Type 2 Diabetes Mellitus.Veterinary sciences · 2022Review
- Newly discovered endocrine functions of the liver.World journal of hepatology · 2021Review
- Characteristics of the New Insulin-Resistant Zebrafish Model.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Debates in Pancreatic Beta Cell Biology: Proliferation Versus Progenitor Differentiation and Transdifferentiation in Restoring β Cell Mass.Frontiers in endocrinology · 2021Review
- Agonist-activated glucagon receptors are deubiquitinated at early endosomes by two distinct deubiquitinases to facilitate Rab4a-dependent recycling.The Journal of biological chemistry · 2020Article
- Elevated Serum Amino Acids Induce a Subpopulation of Alpha Cells to Initiate Pancreatic Neuroendocrine Tumor Formation.Cell reports. Medicine · 2020Article
- A Primary Role for α-Cells as Amino Acid Sensors.Diabetes · 2020Review
- Global Transcriptomic Analysis of Zebrafish Glucagon Receptor Mutant Reveals Its Regulated Metabolic Network.International journal of molecular sciences · 2020Article
- Functional Genomics in Pancreatic β Cells: Recent Advances in Gene Deletion and Genome Editing Technologies for Diabetes Research.Frontiers in endocrinology · 2020Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
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 (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 α-cells using an α-cell reporter line, Tg(gcga:GFP). Compared to WT fish at 7 days postfertilization, there were more α-cells in gcgra-/-, gcgrb-/-, and gcgra-/-;gcgrb-/- fish and there was an increased rate of α-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 α-cell hyperplasia in response to interruption of glucagon signaling is conserved in zebrafish. The robust α-cell hyperplasia in gcgra-/-;gcgrb-/- larvae provides a platform to screen for chemical and genetic suppressors, and ultimately to identify the stimulus of α-cell hyperplasia and its signaling mechanism.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.