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

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.