Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia
Open accessAbstract
Aims/hypothesis Under normal physiological conditions, glucagon signalling is important in glucose homeostasis. Hyperglucagonaemia or altered insulin:glucagon ratio plays a role in maintaining hyperglycaemia in subjects with type 2 diabetes. It has been reported that glucagon receptor knockout (Gcgr (-/-)) mice develop normally and have lower plasma glucose on a normal diet. The goal of the current research was to further investigate the role of glucagon signalling in metabolic control and glucose homeostasis.Methods Gcgr (-/-) mice were challenged with a high-fat diet (HFD) and with streptozotocin, which induces beta cell damage. They were then analysed for whole-body and serum metabolic phenotypes as well as pancreatic islet morphology.Results In comparison with wild-type mice, Gcgr (-/-) mice exhibited decreased body weight and food intake, reduced plasma glucose levels, and improved oral and intraperitoneal glucose tolerance. Elevated glucagon-like peptide-1 levels and reduced gastric emptying were also observed in Gcgr (-/-) mice, which also had reduced HFD-induced hyperinsulinaemia and hyperleptinaemia, and were resistant to the development of hepatic steatosis. In addition, Gcgr (-/-) mice were resistant to STZ-induced hyperglycaemia and pancreatic beta cell destruction.Conclusions/interpretation This study demonstrates that blocking glucagon signalling by targeted Gcgr gene deletion leads to an improvement in metabolic control in this mouse model.
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Loss of GCGR signaling can normalize glycemia in insulin-deficient conditions, but only if residual insulin is present.
“While lack of GCGR signaling can normalize glycemia under insulin-deficient conditions15,16, this effect is contingent on the presence of residual insulin17.”
From Transforming obesity: The advancement of multi-receptor drugs (2024) · cites this paper as [15]
The Results (page unavailable) report that GCGR-knockout mice remained euglycaemic after streptozotocin treatment, unlike wild-type mice. However, streptozotocin did not detectably reduce insulin levels in the knockout mice, so this study does not establish normalization of glycaemia in insulin-deficient knockout mice or test whether residual insulin is required. (LLM, conf=0.86)
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- Authors
- Conarello, S. L., Jiang, G., Mu, J., Li, Z., Woods, J., Zycband, E., Ronan, J., Liu, F., Roy, R. S., Zhu, L., Charron, M. J., & Zhang, B. B.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Albert Einstein College of Medicine (US)
- Corresponding author
- Zhang, B. B.
- Venue
- Diabetologia
- Published
- 2006-11-28
- Volume
- 50
- Issue
- 1
- Pages
- 142-150
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W1988784323
- Cited by
- 224
- References
- 38
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 12 · 2023: 7 · 2022: 16 · 2021: 15 · 2020: 10 · 2019: 17 · 2018: 17 · 2017: 10 · 2016: 16 · 2015: 17 · 2014: 17 · 2013: 9 · 2012: 14
- FWCI
- 4.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- glucagon receptor, glucose homeostasis, diet-induced obesity, high-fat diet, beta cell destruction, hyperglycemia, insulin/glucagon ratio, glucagon-like peptide-1, gastric emptying, hepatic steatosis, hyperinsulinemia, leptin, type 2 diabetes
- MeSH terms
- Animals, Diabetes Mellitus, Experimental, Dietary Fats, Disease Models, Animal, Glucose, Homeostasis, Hyperglycemia, Male, Mice, Inbred C57BL, Obesity, Streptozocin, Apoptosis, Gene Deletion, Receptors, Glucagon, Mice, Knockout, Insulin-Secreting Cells, Mice
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