Characterization of LY3324954 a long-acting glucagon-receptor agonist
Objective: Glucagon is a crucial regulator of glucose and lipid metabolism as well as whole-body energy balance. Thus, modulation of glucagon receptor (GCGR) activity in the context of single-molecule multi-receptor co-agonists has become an emerging therapeutic target against obesity and obesity-as...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-01-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877824002047 |
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| author | William Roell Tamer Coskun Teayoun Kim Libbey O’Farrell Jennifer A. Martin Shelly Nason Jasmin Hernandez-Alamillo Saidharshana Dhantu Daniel J. Drucker Kyle W. Sloop James P. Steele Jorge Alsina-Fernandez Kirk M. Habegger |
| author_facet | William Roell Tamer Coskun Teayoun Kim Libbey O’Farrell Jennifer A. Martin Shelly Nason Jasmin Hernandez-Alamillo Saidharshana Dhantu Daniel J. Drucker Kyle W. Sloop James P. Steele Jorge Alsina-Fernandez Kirk M. Habegger |
| author_sort | William Roell |
| collection | DOAJ |
| description | Objective: Glucagon is a crucial regulator of glucose and lipid metabolism as well as whole-body energy balance. Thus, modulation of glucagon receptor (GCGR) activity in the context of single-molecule multi-receptor co-agonists has become an emerging therapeutic target against obesity and obesity-associated metabolic dysfunction. To better elucidate the role of GCGR-signaling when paired with incretin receptor signaling or on its own, we developed, LY3324954, a GCGR agonist with improved potency and selectivity as compared to the native glucagon peptide. Methods: LY3324954 was administered to DIO mice, rats, dogs, and monkeys to evaluate pharmacokinetic (PK) profile. Biweekly treatments were conducted in lean and DIO mice to characterize LY3324954-effects on glucose homeostasis and energy balance. Single dose studies were also conducted in liver Gcgr-deficient mice to establish receptor specificity. Results: LY3324954 also exhibited extended PK profile in DIO mice, rats, dogs, and monkeys. When administered every 72 h, LY3324954 treatment stimulated transient glucose and insulin excursions in lean mice. In diet-induced obese mice, LY3324954 treatment stimulates energy expenditure, weight loss, and a reduction of adiposity in a dose-dependent manner. Benefit to whole-body lipid homeostasis was likewise observed in these mice. Conclusions: Taken together, these studies characterize a long-acting and potent GCGR-agonist and its regulation of glucose and lipid metabolism as well as whole-body energy balance following both acute and chronic treatment in mice. |
| format | Article |
| id | doaj-art-a43fcb007fdf44d8b7126f4df420df06 |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-a43fcb007fdf44d8b7126f4df420df062025-01-09T06:13:54ZengElsevierMolecular Metabolism2212-87782025-01-0191102073Characterization of LY3324954 a long-acting glucagon-receptor agonistWilliam Roell0Tamer Coskun1Teayoun Kim2Libbey O’Farrell3Jennifer A. Martin4Shelly Nason5Jasmin Hernandez-Alamillo6Saidharshana Dhantu7Daniel J. Drucker8Kyle W. Sloop9James P. Steele10Jorge Alsina-Fernandez11Kirk M. Habegger12Lilly Research Laboratories, Indianapolis, IN, USALilly Research Laboratories, Indianapolis, IN, USAComprehensive Diabetes Center and Department of Medicine - Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USALilly Research Laboratories, Indianapolis, IN, USALilly Research Laboratories, Indianapolis, IN, USAComprehensive Diabetes Center and Department of Medicine - Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USAComprehensive Diabetes Center and Department of Medicine - Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USAComprehensive Diabetes Center and Department of Medicine - Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, USALilly Research Laboratories, Indianapolis, IN, USALilly Research Laboratories, Indianapolis, IN, USALilly Research Laboratories, Indianapolis, IN, USA; Corresponding author. Eli Lilly and Company, Indianapolis, IN, 46285, USA.Comprehensive Diabetes Center and Department of Medicine - Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA; Corresponding author. Department of Medicine - Endocrinology, Diabetes & Metabolism, University of Alabama at Birmingham Birmingham, AL, 35294, USA.Objective: Glucagon is a crucial regulator of glucose and lipid metabolism as well as whole-body energy balance. Thus, modulation of glucagon receptor (GCGR) activity in the context of single-molecule multi-receptor co-agonists has become an emerging therapeutic target against obesity and obesity-associated metabolic dysfunction. To better elucidate the role of GCGR-signaling when paired with incretin receptor signaling or on its own, we developed, LY3324954, a GCGR agonist with improved potency and selectivity as compared to the native glucagon peptide. Methods: LY3324954 was administered to DIO mice, rats, dogs, and monkeys to evaluate pharmacokinetic (PK) profile. Biweekly treatments were conducted in lean and DIO mice to characterize LY3324954-effects on glucose homeostasis and energy balance. Single dose studies were also conducted in liver Gcgr-deficient mice to establish receptor specificity. Results: LY3324954 also exhibited extended PK profile in DIO mice, rats, dogs, and monkeys. When administered every 72 h, LY3324954 treatment stimulated transient glucose and insulin excursions in lean mice. In diet-induced obese mice, LY3324954 treatment stimulates energy expenditure, weight loss, and a reduction of adiposity in a dose-dependent manner. Benefit to whole-body lipid homeostasis was likewise observed in these mice. Conclusions: Taken together, these studies characterize a long-acting and potent GCGR-agonist and its regulation of glucose and lipid metabolism as well as whole-body energy balance following both acute and chronic treatment in mice.http://www.sciencedirect.com/science/article/pii/S2212877824002047GlucagonInsulin secretionGlucose homeostasisDiabetesObesity |
| spellingShingle | William Roell Tamer Coskun Teayoun Kim Libbey O’Farrell Jennifer A. Martin Shelly Nason Jasmin Hernandez-Alamillo Saidharshana Dhantu Daniel J. Drucker Kyle W. Sloop James P. Steele Jorge Alsina-Fernandez Kirk M. Habegger Characterization of LY3324954 a long-acting glucagon-receptor agonist Molecular Metabolism Glucagon Insulin secretion Glucose homeostasis Diabetes Obesity |
| title | Characterization of LY3324954 a long-acting glucagon-receptor agonist |
| title_full | Characterization of LY3324954 a long-acting glucagon-receptor agonist |
| title_fullStr | Characterization of LY3324954 a long-acting glucagon-receptor agonist |
| title_full_unstemmed | Characterization of LY3324954 a long-acting glucagon-receptor agonist |
| title_short | Characterization of LY3324954 a long-acting glucagon-receptor agonist |
| title_sort | characterization of ly3324954 a long acting glucagon receptor agonist |
| topic | Glucagon Insulin secretion Glucose homeostasis Diabetes Obesity |
| url | http://www.sciencedirect.com/science/article/pii/S2212877824002047 |
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