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Updated: Jun 6, 2025

Measuring Relative Insulin Secretion using a Co-Secreted Luciferase Surrogate
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Characterization of LY3324954 a long-acting glucagon-receptor agonist

William Roell1, Tamer Coskun1, Teayoun Kim2

  • 1Lilly Research Laboratories, Indianapolis, IN, USA.

Molecular Metabolism
|November 27, 2024
PubMed
Abstract

Insights

A novel glucagon receptor (GCGR) agonist, LY3324954, effectively reduces adiposity and improves lipid metabolism in diet-induced obese mice. This potent and long-acting compound shows promise for treating obesity and related metabolic dysfunctions.

Area of Science:

  • Metabolic research
  • Pharmacology
  • Endocrinology

Background:

  • Glucagon receptor (GCGR) signaling is vital for glucose and lipid metabolism.
  • Targeting GCGR activity is a promising therapeutic strategy for obesity and metabolic dysfunction.
  • Developing potent and selective GCGR agonists is crucial for therapeutic advancement.

Purpose of the Study:

  • To develop a novel GCGR agonist, LY3324954, with enhanced potency and selectivity over native glucagon.
  • To elucidate the role of GCGR signaling in metabolic regulation, independently or with incretin receptor signaling.
  • To characterize the pharmacokinetic and pharmacodynamic properties of LY3324954.

Main Methods:

  • Administered LY3324954 to diet-induced obese (DIO) mice, rats, dogs, and monkeys for pharmacokinetic evaluation.
  • Conducted biweekly treatments in lean and DIO mice to assess effects on glucose homeostasis and energy balance.
  • Utilized liver Gcgr-deficient mice to confirm receptor specificity of LY3324954.

Main Results:

  • LY3324954 demonstrated an extended pharmacokinetic profile across species (mice, rats, dogs, monkeys).
  • In DIO mice, LY3324954 treatment dose-dependently increased energy expenditure, promoted weight loss, and reduced adiposity.
  • Observed improvements in whole-body lipid homeostasis and transient glucose/insulin excursions in lean mice.

Conclusions:

  • LY3324954 is a potent, long-acting GCGR agonist with significant therapeutic potential.
  • Characterized the regulation of glucose and lipid metabolism by LY3324954 in both acute and chronic treatment models.
  • Established LY3324954's efficacy in improving energy balance and reducing obesity-related metabolic dysfunction.
Keywords:
DiabetesGlucagonGlucose homeostasisInsulin secretionObesity

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