Glucagon Receptor Blockade With a Human Antibody Normalizes Blood Glucose in Diabetic Mice and Monkeys
Abstract
Antagonizing glucagon action represents an attractive therapeutic option for reducing hepatic glucose production in settings of hyperglycemia where glucagon excess plays a key pathophysiological role. We therefore generated REGN1193, a fully human monoclonal antibody that binds and inhibits glucagon receptor (GCGR) signaling in vitro. REGN1193 administration to diabetic ob/ob and diet-induced obese mice lowered blood glucose to levels observed in GCGR-deficient mice. In diet-induced obese mice, REGN1193 reduced food intake, adipose tissue mass, and body weight. REGN1193 increased circulating levels of glucagon and glucagon-like peptide 1 and was associated with reversible expansion of pancreatic α-cell area. Hyperglucagonemia and α-cell hyperplasia was observed in fibroblast growth factor 21-deficient mice treated with REGN1193. Single administration of REGN1193 to diabetic cynomolgus monkeys normalized fasting blood glucose and glucose tolerance and increased circulating levels of glucagon and amino acids. Finally, administration of REGN1193 for 8 weeks to normoglycemic cynomolgus monkeys did not cause hypoglycemia or increase pancreatic α-cell area. In summary, the GCGR-blocking antibody REGN1193 normalizes blood glucose in diabetic mice and monkeys but does not produce hypoglycemia in normoglycemic monkeys. Thus, REGN1193 provides a potential therapeutic modality for diabetes mellitus and acute hyperglycemic conditions.
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In that trial, liraglutide-induced weight loss was accompanied by better glucose control, lower systolic and diastolic blood pressure (−2.8 and −0.9 mmHg vs placebo), improved lipid and cholesterol profiles, and a small heart-rate increase of 2.4 beats/min vs placebo.
“In this study, the body weight reduction induced by liraglutide was associated with improved glucose control, a decrease in systolic and diastolic blood pressure (−2.8 and −0.9 mmHg over placebo controls), along with an improvement in lipid and cholesterol profiles; albeit with a slight increase in heart rate of 2.4 beats/min, in comparison to placebo-treated controls67.”
From Transforming obesity: The advancement of multi-receptor drugs (2024) · cites this paper as [67]
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Experimental — accuracy not yet measuredIn obese subjects without T2D, one year of liraglutide produced about 5.2% placebo-corrected weight loss, with roughly one third losing more than 10%.
“In subjects with obesity without T2D, following one year of treatment with liraglutide, ~5.2% placebo-corrected weight loss was achieved, with approximately a third of subjects reaching weight loss of >10%67.”
From Transforming obesity: The advancement of multi-receptor drugs (2024) · cites this paper as [67]
The DIO mouse-study Methods and Results describe short-term treatment with REGN1193, not a one-year liraglutide trial in people without T2D. The References section mentions liraglutide only in a cited title. Searches for the 5.2% placebo-corrected loss and the proportion losing more than 10% found no passage reporting those outcomes in our copy; page numbers were unavailable. (LLM, conf=0.76)
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- Authors
- Okamoto, H., Kim, J., Aglione, J., Lee, J., Cavino, K., Na, E., Rafique, A., Kim, J. H., Harp, J., Valenzuela, D. M., Yancopoulos, G. D., Murphy, A. J., & Gromada, J.
- Affiliations
- Regeneron (United States) (US)
- Corresponding author
- Okamoto, Haruka
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2015-08
- Volume
- 156
- Issue
- 8
- Pages
- 2781-2794
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2169046916
- Cited by
- 100
- References
- 58
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 6 · 2023: 14 · 2022: 16 · 2021: 11 · 2020: 8 · 2019: 8 · 2018: 10 · 2017: 13 · 2016: 4
- FWCI
- 7.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Regeneron Pharmaceuticals
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- glucagon receptor, monoclonal antibodies, hyperglycemia, diabetes mellitus, hyperglucagonemia, glucagon-like peptide-1, FGF21, diet-induced obesity, ob/ob mice, Macaca fascicularis, glucose tolerance, hypoglycemia
- MeSH terms
- Animals, Antibodies, Monoclonal, Blood Glucose, Diabetes Mellitus, Experimental, Female, Fibroblast Growth Factors, Humans, Hypoglycemic Agents, Macaca fascicularis, Male, Mice, Inbred C57BL, Mice, Obese, Mice, Transgenic, Obesity, Receptors, Glucagon, Mice, Antibodies, Monoclonal, Humanized
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