Imeglimin Ameliorates β-Cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway

Diabetes. 2022 Mar 1;71(3):424-439. doi: 10.2337/db21-0123.


The effects of imeglimin, a novel antidiabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets. Imeglimin upregulated the expression of endoplasmic reticulum (ER)-related molecules, including Chop (Ddit3), Gadd34 (Ppp1r15a), Atf3, and Sdf2l1, and decreased eIF2α phosphorylation after treatment with thapsigargin and restored global protein synthesis in β-cells under ER stress. Imeglimin failed to protect against ER stress-induced β-cell apoptosis in CHOP-deficient islets or in the presence of GADD34 inhibitor. Treatment with imeglimin showed a significant decrease in the number of apoptotic β-cells and increased β-cell mass in Akita mice. Imeglimin also protected against β-cell apoptosis in both human islets and human pluripotent stem cell-derived β-like cells. Taken together, imeglimin modulates the ER homeostasis pathway, which results in the prevention of β-cell apoptosis both in vitro and in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cell Line
  • Cell Proliferation / drug effects
  • Endoplasmic Reticulum / drug effects*
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Stress / drug effects
  • Glucose / pharmacology
  • Homeostasis / drug effects
  • Humans
  • Hypoglycemic Agents*
  • Insulin Secretion / drug effects
  • Insulin-Secreting Cells / physiology*
  • Insulin-Secreting Cells / ultrastructure
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / physiology
  • Pluripotent Stem Cells
  • Protein Phosphatase 1 / genetics
  • Protein Phosphatase 1 / physiology
  • Transcription Factor CHOP / deficiency
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / physiology
  • Triazines / pharmacology*
  • Triazines / therapeutic use


  • Ddit3 protein, mouse
  • Hypoglycemic Agents
  • Triazines
  • Transcription Factor CHOP
  • Ppp1r15a protein, mouse
  • Protein Phosphatase 1
  • Glucose
  • imeglimin

Associated data

  • figshare/10.2337/figshare.16654780