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Palmitate induced insulin resistance by PKCtheta-dependent activation of mTOR/S6K pathway in C2C12 myotubes

X Wang1, W Yu, A Nawaz

  • 1Department of Pathophysiology, Yunyang Medical College, Shiyan, China.

Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [And] German Diabetes Association
|April 30, 2010
PubMed

Insights

Palmitate triggers insulin resistance in muscle cells via the protein kinase C-theta (PKCΘ) and mammalian target of rapamycin (mTOR) pathway, impacting S6K phosphorylation.

Area of Science:

  • Molecular Biology
  • Cellular Metabolism
  • Endocrinology

Background:

  • Insulin resistance in skeletal muscle is a key factor in type 2 diabetes.
  • The precise molecular mechanisms driving palmitate-induced insulin resistance remain unclear.
  • Skeletal muscle insulin sensitivity is crucial for glucose homeostasis.

Purpose of the Study:

  • To elucidate the mechanism of palmitate-induced insulin resistance in skeletal muscle cells.
  • To investigate the role of protein kinase C-theta (PKCΘ) and mammalian target of rapamycin (mTOR) in this process.
  • To identify key signaling pathways involved in palmitate's effects on insulin signaling.

Main Methods:

  • Utilized C2C12 myotubes as a model system for skeletal muscle cells.
  • Examined the effects of palmitate exposure on insulin signaling pathways.
  • Employing genetic deficiency (PKCΘ- and mTOR-deficient cells) and pharmacological inhibition (rapamycin, PKCΘ pseudosubstrate).
  • Assessed protein phosphorylation of key signaling molecules including PKCΘ, mTOR, and S6K.

Main Results:

  • Palmitate inhibited insulin signaling in C2C12 myotubes.
  • This inhibition was associated with increased PKCΘ phosphorylation.
  • Deficiency in PKCΘ or mTOR, or rapamycin treatment, diminished palmitate's inhibitory effects.
  • Palmitate-induced phosphorylation of mTOR and S6K was reduced in PKCΘ-deficient cells or with PKCΘ pseudosubstrate treatment.

Conclusions:

  • Palmitate-induced insulin resistance in skeletal muscle cells is mediated by the PKCΘ/mTOR/S6K signaling pathway.
  • PKCΘ plays a critical role in transmitting palmitate's inhibitory signals on insulin action.
  • Targeting the PKCΘ/mTOR/S6K pathway may offer therapeutic strategies for managing insulin resistance.

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