ArticleJournal of lipid research2015
Glucagon receptor antagonism induces increased cholesterol absorption.
Article in Journal of lipid research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
41 citing papers in PubMed, 76 citations in OpenAlex.
- Glucagon receptor antagonist volagidemab in type 1 diabetes: a 12-week, randomized, double-blind, phase 2 trial.Nature medicine · 2022Trial
- Trial
- A first-in-human pharmacodynamic and pharmacokinetic study of a fully human anti-glucagon receptor monoclonal antibody in normal healthy volunteers.Diabetes, obesity & metabolism · 2018Trial
- Metabolic, enterohepatic and gut microbial effects of atorvastatin in healthy men.Endocrine connections · 2026Article
- Elucidation of Mechanism of Action in Drug Invention: Using Stable Isotope Tracers to Unravel Biochemical Kinetics.Pharmacology research & perspectives · 2025Review
- Blockade of glucagon receptor induces α-cell hypersecretion by hyperaminoacidemia in mice.Nature communications · 2025Article
- GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management.Nature metabolism · 2024Review
- Review
- Impaired Fat Absorption from Intestinal Tract in High-Fat Diet Fed Male Mice Deficient in Proglucagon-Derived Peptides.Nutrients · 2024Article
- Glucagon resistance and metabolic-associated steatotic liver disease: a review of the evidence.The Journal of endocrinology · 2024Review
- An orally available compound suppresses glucagon hypersecretion and normalizes hyperglycemia in type 1 diabetes.JCI insight · 2024Article
- Review
- Review
- Review
- Insights into the Role of Glucagon Receptor Signaling in Metabolic Regulation from Pharmacological Inhibition and Tissue-Specific Knockout Models.Biomedicines · 2022Review
- Regulation of α-cell glucagon secretion: The role of second messengers.Chronic diseases and translational medicine · 2022Review
- Role of Glucagon and Its Receptor in the Pathogenesis of Diabetes.Frontiers in endocrinology · 2022Review
- The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror.International journal of molecular sciences · 2021Review
- Glucagon's Metabolic Action in Health and Disease.Comprehensive Physiology · 2021Article
- Pathways of Glucagon Secretion and Trafficking in the Pancreatic Alpha Cell: Novel Pathways, Proteins, and Targets for Hyperglucagonemia.Frontiers in endocrinology · 2021Review
Corrections and comments
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Authors and funding
23 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Glucagon and insulin have opposing action in governing glucose homeostasis. In type 2 diabetes mellitus (T2DM), plasma glucagon is characteristically elevated, contributing to increased gluconeogenesis and hyperglycemia. Therefore, glucagon receptor (GCGR) antagonism has been proposed as a pharmacologic approach to treat T2DM. In support of this concept, a potent small-molecule GCGR antagonist (GRA), MK-0893, demonstrated dose-dependent efficacy to reduce hyperglycemia, with an HbA1c reduction of 1.5% at the 80 mg dose for 12 weeks in T2DM. However, GRA treatment was associated with dose-dependent elevation of plasma LDL-cholesterol (LDL-c). The current studies investigated the cause for increased LDL-c. We report findings that link MK-0893 with increased glucagon-like peptide 2 and cholesterol absorption. There was not, however, a GRA-related modulation of cholesterol synthesis. These findings were replicated using structurally diverse GRAs. To examine potential pharmacologic mitigation, coadministration of ezetimibe (a potent inhibitor of cholesterol absorption) in mice abrogated the GRA-associated increase of LDL-c. Although the molecular mechanism is unknown, our results provide a novel finding by which glucagon and, hence, GCGR antagonism govern cholesterol metabolism.
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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.