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Comparative Analysis of Orthosteric and Allosteric GLP-1R Agonists' Effects on Insulin Secretion from Healthy,

Joshua Reed1, Victoria Higginbotham1, Stephen Bain1

  • 1Institute of Life Science, Medical School, Swansea University, Singleton Park, Swansea SA2 8PP, UK.

International Journal of Molecular Sciences
|June 27, 2024
PubMed

Insights

Glucagon-like peptide (GLP)-1 receptor agonists show promise for type 2 diabetes (T2D). Allosteric agonists offer a longer duration of action, and neither type depletes insulin, suggesting a safe and sustainable T2D treatment.

Area of Science:

  • Endocrinology
  • Pharmacology
  • Cell Biology

Background:

  • Type 2 diabetes (T2D) management remains challenging due to prevalent post-diagnosis complications.
  • Glucagon-like peptide (GLP)-1 receptor (GLP-1R) agonists are established T2D therapeutics acting as orthosteric agonists.
  • Novel therapeutic strategies are needed to improve T2D treatment efficacy and safety.

Purpose of the Study:

  • To investigate the in vitro effects of GLP-1R orthosteric and allosteric agonists on glucose-stimulated insulin secretion (GSIS) and cAMP production (GSICP).
  • To compare the efficacy of GLP-1R agonists in INS-1E pancreatic beta cells across healthy, diabetic, and recovered states.
  • To assess the sustainability and safety of GLP-1R agonists by examining intracellular insulin levels.

Main Methods:

  • In vitro analysis of INS-1E pancreatic beta cells.
  • Measurement of glucose-stimulated insulin secretion (GSIS).
  • Quantification of intracellular cAMP production (GSICP) following treatment with GLP-1R agonists.

Main Results:

  • Allosteric GLP-1R agonists demonstrated a longer duration of action compared to orthosteric agonists.
  • GLP-1R agonists did not lead to depletion of intracellular insulin stores.
  • INS-1E cells exhibited variable responses to GLP-1R agonists based on glucose levels and prior drug exposure, differing across healthy, diabetic, and recovered states.

Conclusions:

  • GLP-1R agonists represent a potentially sustainable and safe treatment approach for T2D.
  • The differential response of pancreatic beta cells to GLP-1R agonists highlights the importance of considering cellular state and glucose conditions.
  • Findings provide valuable in vitro insights into pancreatic beta cell responses to T2D drug treatments.
Keywords:
GLP-1RGSICPGSISINS-1E cellsallosteric agonistsdiabetesglucoseinsulinorthosteric agonists

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