682-P: Novel Dual Glucagon and Glucagon-Like Peptide-1 Receptor Agonist LY3305677 Improves Glucose Control, Reduces Body Weight, and Increases Energy Expenditure in Mice
| العنوان: | 682-P: Novel Dual Glucagon and Glucagon-Like Peptide-1 Receptor Agonist LY3305677 Improves Glucose Control, Reduces Body Weight, and Increases Energy Expenditure in Mice |
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| المؤلفون: | Krister Bokvist, Yanyun Chen, Julie S. Moyers, Mezo Adam Robert, Melissa K. Thomas, Tamer Coskun, Min Song, William C. Roell, Valenzuela Francisco Alcides, Hongchang Qu |
| المصدر: | Diabetes. 70 |
| بيانات النشر: | American Diabetes Association, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Agonist, medicine.medical_specialty, FGF21, Peptide analog, medicine.drug_class, business.industry, Endocrinology, Diabetes and Metabolism, Semaglutide, Glucagon, Oxyntomodulin, chemistry.chemical_compound, Endocrinology, chemistry, Internal medicine, Internal Medicine, medicine, Receptor, business, Glucagon-like peptide 1 receptor |
| الوصف: | LY3305677 (LY) is a synthetic peptide analog of mammalian oxyntomodulin with a fatty acyl side chain to extend time action. LY functions are mediated by binding and activation of both glucagon (GcgR) and glucagon-like peptide-1 (GLP-1R) receptors. LY is bound with potent binding affinity (Ki) to human and mouse GcgR (Ki: 17.7 nM and 15.9 nM, respectively) and GLP-1R (Ki: 28.6 nM and 25.1 nM, respectively). LY dose-dependently stimulated insulin secretion in mouse pancreatic islets (EC50: 5.2 nM) and in mice. In oral glucose tolerance tests of diet-induced obese (DIO) and streptozotocin-induced diabetic mice, a single subcutaneous (SC) dose of LY significantly reduced glucose area under the curve by up to 65%. SC injections of LY to DIO mice dose-dependently reduced serum triglycerides and PCSK9 (proprotein convertase subtilisin/kexin type 9) levels and dose-dependently increased FGF21 (fibroblast growth factor 21) levels. In DIO mice treated over 18 days, LY 30 nmol/kg reduced body weight to a greater extent (33%) than semaglutide 60 nmol/kg (12%), and decreased food intake by 50% compared to vehicle. At Day 18, LY 30 nmol/kg group lost 33% of initial bodyweight, which was primarily due to 70% reduced fat mass. LY reduced liver triglycerides by greater than 70% and increased serum ketones by more than 3-fold compared to vehicle, suggestive of increased fatty acid oxidation. LY decreased body weight in both GcgR knock-out (KO) and GLP-1R KO mice, indicating that activation of both receptors contributed to greater weight loss. To assess potential changes in energy expenditure, DIO mice were treated chronically with SC LY (15 nmol/kg), semaglutide (60 nmol/kg), or vehicle. LY, but not semaglutide, increased energy expenditure as compared with vehicle. These preclinical studies indicate that novel dual GcgR and GLP-1R agonist LY may have potential to enhance metabolic health by improving dyslipidemia, hyperglycemia, or obesity. Disclosure Y. Chen: None. H. Qu: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. A. Mezo: None. T. Coskun: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. M. Song: None. W. C. Roell: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. K. B. Bokvist: Employee; Self; Eli Lilly and Company, Sanofi-Aventis Deutschland GmbH, Stock/Shareholder; Self; Johnson & Johnson, Sanofi-Aventis Deutschland GmbH, Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. J. S. Moyers: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. M. K. Thomas: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. F. Valenzuela: None. Funding Eli Lilly and Company |
| تدمد: | 1939-327X 0012-1797 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::fa273a6e8b63606b2790d9ac363a0bf1Test https://doi.org/10.2337/db21-682-pTest |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi...........fa273a6e8b63606b2790d9ac363a0bf1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1939327X 00121797 |
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