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Loxenatide Alleviates High Glucose-Induced Pancreatic β-Cell Senescence via Regulating the PERK/eIF2α Pathway

Junfang Yuan1, Yuzhong Wang2, Defeng Wang1

  • 1Department of Endocrinology, Affiliated Hospital of Hebei University of Engineering, Handan City, Hebei Province, China.

Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme
|September 27, 2024
PubMed

Insights

Loxenatide, a glucagon-like peptide-1 receptor agonist, reverses high glucose-induced pancreatic beta-cell senescence and DNA damage. This peptide enhances insulin secretion and synthesis by modulating the PERK/eIF2α pathway in type 2 diabetes mellitus.

Area of Science:

  • Endocrinology
  • Cell Biology
  • Molecular Medicine

Background:

  • Type 2 diabetes mellitus (T2DM) is linked to pancreatic beta-cell senescence.
  • Glucagon-like peptide-1 (GLP-1) receptor agonists are established treatments for T2DM.
  • The specific effects of loxenatide on beta-cell senescence are not fully understood.

Purpose of the Study:

  • To investigate the role of loxenatide in regulating cellular senescence of pancreatic beta-cells in a high glucose environment.
  • To elucidate the underlying molecular mechanisms, particularly the involvement of the PERK/eIF2α signaling pathway.

Main Methods:

  • Induction of cellular senescence in pancreatic beta-cells using high glucose (HG).
  • Treatment with loxenatide and assessment of cell proliferation, DNA damage, insulin secretion, and synthesis.
  • Analysis of the PERK/eIF2α signaling pathway.
  • Pharmacological intervention using a PERK/eIF2α pathway activator (CCT020312).

Main Results:

  • High glucose induced beta-cell senescence, elevated SASP factors, inhibited proliferation, and stimulated DNA damage.
  • Loxenatide treatment reversed HG-induced senescence, improved proliferation, reduced DNA damage, and enhanced insulin secretion and synthesis.
  • Loxenatide inactivated the PERK/eIF2α pathway by decreasing p-PERK and p-eIF2α levels.
  • Activation of the PERK/eIF2α pathway with CCT020312 abolished the protective effects of loxenatide.

Conclusions:

  • Loxenatide effectively impedes cellular senescence in HG-induced pancreatic beta-cells.
  • Loxenatide promotes cell proliferation, improves DNA damage, and enhances insulin secretion and synthesis.
  • These beneficial effects are mediated through the modulation of the PERK/eIF2α signaling pathway.

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