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Metformin prevents endoplasmic reticulum stress-induced apoptosis through AMPK-PI3K-c-Jun NH2 pathway

Tae Woo Jung1, Myung Won Lee, Yong Jik Lee

  • 1Institute of GMS (Genetic Diagnosis & Molecular Medical Science) Research Center, Dr. Lee's OB & GYN Clinic, Seoul, Republic of Korea. ohayo2030@hanmail.net

Biochemical and Biophysical Research Communications
|December 6, 2011
PubMed

Insights

Metformin protects pancreatic beta cells from endoplasmic reticulum (ER) stress-induced death by activating AMP-activated protein kinase (AMPK) and phosphatidylinositol-3 (PI3) kinase. This mechanism regulates the JNK pathway, offering potential therapeutic benefits for type 2 diabetes.

Area of Science:

  • Cell Biology
  • Endocrinology
  • Pharmacology

Background:

  • Type 2 diabetes mellitus is linked to endoplasmic reticulum (ER) stress, which impairs pancreatic beta cell function.
  • ER stress can lead to decreased insulin synthesis and secretion, contributing to hyperglycemia.

Purpose of the Study:

  • To investigate the protective effects of metformin on ER stress-induced pancreatic beta cell dysfunction and apoptosis.
  • To elucidate the molecular pathways, including AMP-activated protein kinase (AMPK) and phosphatidylinositol-3 (PI3) kinase, involved in metformin's protective action.

Main Methods:

  • Utilized NIT-1 cells (a mouse pancreatic beta cell line) exposed to ER stress-inducing agents.
  • Administered metformin and assessed its effects on cell viability, function, and apoptosis.
  • Employed AMPK and PI3 kinase inhibitors to determine pathway involvement.
  • Analyzed the phosphorylation status of c-Jun NH2-terminal kinase (JNK).

Main Results:

  • Metformin demonstrated direct protection against ER stress-induced dysfunction and death in NIT-1 cells.
  • The protective effects were mediated by the activation of AMPK and PI3 kinase.
  • Inhibitors of AMPK and PI3 kinase abolished metformin's protective effects.
  • Metformin decreased the phosphorylation of JNK in ER-stressed cells.
  • The protective mechanism was independent of the unfolded protein response and apoptotic protein inhibitors.

Conclusions:

  • Metformin protects pancreatic beta cells from ER stress-induced apoptosis through the AMPK-PI3 kinase-JNK pathway.
  • These findings suggest metformin's potential therapeutic role in managing ER stress-mediated pancreatic beta cell destruction in type 2 diabetes.

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