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Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without insulin by disrupting a novel diabetogenic pathway
Open accessAbstract
Significance: Subcutaneous injections of insulin sustain life in mammals unable to produce insulin (type 1 diabetes) but do not prevent hyperglycemic and hypoglycemic swings or decrease hemoglobin A1c levels to normal amounts. In mice treated with insulin alone, repeated episodes of transient elevated blood glucose cause long-term damage. We show that in mice with type 1 diabetes treated with insulin, the transient high blood glucose levels require production of glucagon, a hormone that will cause the liver to produce more glucose. Blocking the action of glucagon with an antibody to the glucagon receptor completely normalizes blood glucose and hemoglobin A1c in the complete absence of insulin therapy. Suppressing glucagon action in combination with low-dose insulin would be a superior treatment for type 1 diabetes.
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“It is estimated that as little as 10% of active GLP-1 reaches the general circulation, and only a mere fraction of this reaches the brain63.”
From Transforming obesity: The advancement of multi-receptor drugs (2024) · cites this paper as [63]
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Metadata
- Authors
- Wang, M.-Y., Yan, H., Shi, Z., Evans, M. R., Yu, X., Lee, Y., Chen, S., Williams, A., Philippe, J., Roth, M. G., & Unger, R. H.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- REMD Biotherapeutics, Inc., Camarillo, CA 93012;
- Department of Biochemistry and
- University of Notre Dame (US)
- University of Geneva School of Medicine, 1211 Geneva, Switzerland; and
- VA North Texas Health Care System (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-02-09
- Volume
- 112
- Issue
- 8
- Pages
- 2503-2508
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4345619
- OpenAlex
- W1964812502
- Cited by
- 112
- References
- 36
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 11 · 2023: 6 · 2022: 9 · 2021: 11 · 2020: 6 · 2019: 8 · 2018: 10 · 2017: 15 · 2016: 15 · 2015: 9
- FWCI
- 16.44
- Type
- journal article
- Language
- en
- Update notices
- correction (2015-07-01)
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- REMD Therapeutic INC (OTD-107432)
- Veterans Affairs Merit Review Award (N/A)
- Bristol-Myer Squibb (Contract 101563)
- Diane and Hal Brierley Chair in Biomedical Research (endowment)
- HHS | NIH | National Center for Research Resources (CO6-RR15437)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- type 1 diabetes, glucagon receptor, hyperglycemia, glucagon secretion, insulin deficiency, HbA1c, phosphoenolpyruvate carboxykinase, beta-cell dysfunction, glucose homeostasis
- MeSH terms
- Animals, Antibodies, Monoclonal, Blood Glucose, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Female, Glucagon, Humans, Insulin, Rats, Zucker, Mice, Inbred NOD, Receptors, Glucagon, Paracrine Communication, Mice, Rats
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