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Akt activation protects pancreatic beta cells from AMPK-mediated death through stimulation of mTOR

Ying Cai1, Qidi Wang, Zhidong Ling

  • 1Diabetes Research Center, Brussels Free University, VUB, Partner of the Juvenile Diabetes Research Center for Beta Cell Therapy in Europe, Laarbeeklaan 103, B-1090 Brussels, Belgium.

Biochemical Pharmacology
|April 2, 2008
PubMed

Insights

Sustained AMP-activated protein kinase (AMPK) activation triggers apoptosis in pancreatic beta cells. Akt activation, via mTOR and protein synthesis, promotes beta cell survival against AMPK-induced cell death.

Area of Science:

  • Cell Biology
  • Metabolic Signaling
  • Endocrinology

Background:

  • AMP-activated protein kinase (AMPK) activation induces apoptosis in pancreatic beta cells, particularly under glucose limitation or with AICAR treatment.
  • The role of Akt and its downstream target mTOR in counteracting AMPK-mediated apoptosis in beta cells remains unclear.

Purpose of the Study:

  • To investigate whether Akt activation can prevent AMPK-induced apoptosis in pancreatic beta cells.
  • To determine if mTOR activation mediates the survival signals downstream of Akt in these conditions.

Main Methods:

  • Utilized expression of constitutively active Akt and mTOR targets (S6K, eIF4E) in pancreatic beta cells.
  • Administered AICAR to activate AMPK and rapamycin to inhibit mTOR.
  • Assessed apoptosis rates and cellular protein synthesis activity.

Main Results:

  • Constitutively active Akt increased mTOR activity and prevented apoptosis induced by AMPK activation.
  • Akt-mediated survival was blocked by rapamycin, indicating mTOR dependence.
  • Activating mTOR targets S6K or eIF4E reduced apoptosis, with combined expression mimicking active Akt's protective effect.
  • Protective effects correlated with enhanced cellular protein synthesis.

Conclusions:

  • Akt-mediated survival in pancreatic beta cells under sustained AMPK activation requires mTOR signaling.
  • Activation of mTOR targets involved in protein translation is sufficient for Akt-mediated beta cell survival.
  • This pathway highlights a critical mechanism for beta cell protection against metabolic stress.

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