Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival
Objective: It has been thought that the depletion of insulin is responsible for the catabolic consequences of diabetes; however, evidence suggests that glucagon also plays a role in diabetes pathogenesis. Glucagon suppression by glucagon receptor (Gcgr) gene deletion, glucagon immunoneutralization,...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-08-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877816300515 |
| _version_ | 1798043515230355456 |
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| author | Ursula H. Neumann Jessica S.S. Ho Majid Mojibian Scott D. Covey Maureen J. Charron Timothy J. Kieffer |
| author_facet | Ursula H. Neumann Jessica S.S. Ho Majid Mojibian Scott D. Covey Maureen J. Charron Timothy J. Kieffer |
| author_sort | Ursula H. Neumann |
| collection | DOAJ |
| description | Objective: It has been thought that the depletion of insulin is responsible for the catabolic consequences of diabetes; however, evidence suggests that glucagon also plays a role in diabetes pathogenesis. Glucagon suppression by glucagon receptor (Gcgr) gene deletion, glucagon immunoneutralization, or Gcgr antagonist can reverse or prevent type 1 diabetes in rodents suggesting that dysregulated glucagon is also required for development of diabetic symptoms. However, the models used in these studies were rendered diabetic by chemical- or immune-mediated β-cell destruction, in which insulin depletion is incomplete. Therefore, it is unclear whether glucagon suppression could overcome the consequence of the complete lack of insulin. Methods: To directly test this we characterized mice that lack the Gcgr and both insulin genes (GcgrKO/InsKO). Results: In both P1 pups and mice that were kept alive to young adulthood using insulin therapy, blood glucose and plasma ketones were modestly normalized; however, mice survived for only up to 6 days, similar to GcgrHet/InsKO controls. In addition, Gcgr gene deletion was unable to normalize plasma leptin levels, triglycerides, fatty acids, or hepatic cholesterol accumulation compared to GcgrHet/InsKO controls. Conclusion: Therefore, the metabolic manifestations associated with a complete lack of insulin cannot be overcome by glucagon receptor gene inactivation. Author Video: Author Video Watch what authors say about their articles Keywords: Mice, Type 1 diabetes, Insulin, Glucagon, Glucose metabolism, Lipid metabolism |
| first_indexed | 2024-04-11T22:49:53Z |
| format | Article |
| id | doaj.art-a6195303ae054eafa5699dc6e31e513a |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-11T22:49:53Z |
| publishDate | 2016-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-a6195303ae054eafa5699dc6e31e513a2022-12-22T03:58:37ZengElsevierMolecular Metabolism2212-87782016-08-0158731736Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survivalUrsula H. Neumann0Jessica S.S. Ho1Majid Mojibian2Scott D. Covey3Maureen J. Charron4Timothy J. Kieffer5Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, CanadaDepartment of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, CanadaDepartment of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, CanadaDepartment of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, CanadaDepartment of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USADepartment of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, Canada; Department of Surgery, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, Canada; Corresponding author. Department of Cellular and Physiological Sciences, 2350 Health Sciences Mall, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. Tel.: +1 604 822 2156.Objective: It has been thought that the depletion of insulin is responsible for the catabolic consequences of diabetes; however, evidence suggests that glucagon also plays a role in diabetes pathogenesis. Glucagon suppression by glucagon receptor (Gcgr) gene deletion, glucagon immunoneutralization, or Gcgr antagonist can reverse or prevent type 1 diabetes in rodents suggesting that dysregulated glucagon is also required for development of diabetic symptoms. However, the models used in these studies were rendered diabetic by chemical- or immune-mediated β-cell destruction, in which insulin depletion is incomplete. Therefore, it is unclear whether glucagon suppression could overcome the consequence of the complete lack of insulin. Methods: To directly test this we characterized mice that lack the Gcgr and both insulin genes (GcgrKO/InsKO). Results: In both P1 pups and mice that were kept alive to young adulthood using insulin therapy, blood glucose and plasma ketones were modestly normalized; however, mice survived for only up to 6 days, similar to GcgrHet/InsKO controls. In addition, Gcgr gene deletion was unable to normalize plasma leptin levels, triglycerides, fatty acids, or hepatic cholesterol accumulation compared to GcgrHet/InsKO controls. Conclusion: Therefore, the metabolic manifestations associated with a complete lack of insulin cannot be overcome by glucagon receptor gene inactivation. Author Video: Author Video Watch what authors say about their articles Keywords: Mice, Type 1 diabetes, Insulin, Glucagon, Glucose metabolism, Lipid metabolismhttp://www.sciencedirect.com/science/article/pii/S2212877816300515 |
| spellingShingle | Ursula H. Neumann Jessica S.S. Ho Majid Mojibian Scott D. Covey Maureen J. Charron Timothy J. Kieffer Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival Molecular Metabolism |
| title | Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival |
| title_full | Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival |
| title_fullStr | Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival |
| title_full_unstemmed | Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival |
| title_short | Glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival |
| title_sort | glucagon receptor gene deletion in insulin knockout mice modestly reduces blood glucose and ketones but does not promote survival |
| url | http://www.sciencedirect.com/science/article/pii/S2212877816300515 |
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