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Updated: Jul 22, 2025

Studying the Hypothalamic Insulin Signal to Peripheral Glucose Intolerance with a Continuous Drug Infusion System into the Mouse Brain
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PKCα Isoform Inhibits Insulin Signaling and Aggravates Neuronal Insulin Resistance

Devanshi Mishra1, Ishitha Reddy1, Chinmoy Sankar Dey2

  • 1Kusuma School of Biological Sciences, Indian Institute of Technology-Delhi, New Delhi, Hauz Khas, -110016, India.

Molecular Neurobiology
|July 20, 2023
PubMed

Insights

Protein kinase C alpha (PKCα) overexpression disrupts insulin signaling in neurons. Inhibiting PKCα enhances insulin sensitivity and glucose uptake, offering new therapeutic targets for metabolic and neurodegenerative disorders.

Area of Science:

  • Neuroscience
  • Metabolic Disorders
  • Cellular Signaling

Background:

  • Protein kinase C alpha (PKCα) role in insulin signaling is controversial and tissue-specific.
  • Previous studies linked PKCα overexpression to inhibited insulin signaling in skeletal muscle, but its precise role remains unclear.
  • The function of PKCα in neuronal insulin resistance and diabetes requires further investigation.

Purpose of the Study:

  • To elucidate the role of PKCα in neuronal insulin signaling and insulin resistance.
  • To investigate the molecular mechanisms by which PKCα affects insulin sensitivity in neuronal cells.
  • To explore the potential of targeting PKCα for treating metabolic and neurodegenerative disorders.

Main Methods:

  • Utilized neuronal cell lines (Neuro-2a, SHSY-5Y) and insulin-resistant diabetic mouse brain tissues.
  • Investigated the interaction of PKCα with insulin signaling pathway components, including IRS-Akt, PP2A, AS160, 14-3-3ζ, and GSK3 isoforms.
  • Assessed the effects of PKCα inhibition and silencing on GLUT-4 translocation, glucose uptake, and insulin sensitivity.

Main Results:

  • PKCα was demonstrated to inhibit insulin signaling in neuronal cells via an IRS-Akt pathway, involving PP2A and 14-3-3ζ, independently of AS160.
  • Inhibition or silencing of PKCα improved insulin sensitivity, increased GLUT-4 translocation to the plasma membrane, and enhanced glucose uptake.
  • PKCα differentially regulated GSK3 isoforms, with higher activity exacerbating insulin resistance in a GSK3β-dependent manner.

Conclusions:

  • PKCα plays a significant role in regulating insulin signaling and contributing to neuronal insulin resistance and diabetes.
  • Targeting PKCα presents a promising therapeutic strategy for metabolic disorders and neurodegenerative conditions.
  • The findings provide mechanistic insights into PKCα's contribution to neuronal dysfunction in diabetes.
Keywords:
Alzheimer’s diseaseInsulin resistanceInsulin signalingNeuronPKCα

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