In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist

Diabetes Obes Metab. 2022 Nov;24(11):2090-2101. doi: 10.1111/dom.14794. Epub 2022 Jul 18.


Aims: To describe the in vitro characteristics and antidiabetic in vivo efficacy of the novel glucagon-like peptide-1 receptor agonist (GLP-1RA) GL0034.

Materials and methods: Glucagon-like peptide-1 receptor (GLP-1R) kinetic binding parameters, cyclic adenosine monophosphate (cAMP) signalling, endocytosis and recycling were measured using HEK293 and INS-1832/3 cells expressing human GLP-1R. Insulin secretion was measured in vitro using INS-1832/3 cells, mouse islets and human islets. Chronic administration studies to evaluate weight loss and glycaemic effects were performed in db/db and diet-induced obese mice.

Results: Compared to the leading GLP-1RA semaglutide, GL0034 showed increased binding affinity and potency-driven bias in favour of cAMP over GLP-1R endocytosis and β-arrestin-2 recruitment. Insulin secretory responses were similar for both ligands. GL0034 (6 nmol/kg) led to at least as much weight loss and lowering of blood glucose as did semaglutide at a higher dose (14 nmol/kg).

Conclusions: GL0034 is a G protein-biased agonist that shows powerful antidiabetic effects in mice, and may serve as a promising new GLP-1RA for obese patients with type 2 diabetes.

Keywords: GLP-1 analogue; antidiabetic drug; antiobesity drug; beta-cell function; drug development; incretin therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate
  • Animals
  • Blood Glucose
  • Cyclic AMP / metabolism
  • Diabetes Mellitus, Type 2* / drug therapy
  • Glucagon-Like Peptide-1 Receptor / agonists
  • HEK293 Cells
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use
  • Insulins*
  • Ligands
  • Mice
  • Weight Loss
  • beta-Arrestins / metabolism


  • Blood Glucose
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Insulins
  • Ligands
  • beta-Arrestins
  • Adenosine Monophosphate
  • Cyclic AMP