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Studying the Hypothalamic Insulin Signal to Peripheral Glucose Intolerance with a Continuous Drug Infusion System into the Mouse Brain
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Insulin Signalling: The Inside Story.

Barry I Posner1

  • 1Department of Medicine, McGill University Hospital Research Institute, Montreal, Quebec, Canada.

Canadian Journal of Diabetes
|September 12, 2016
PubMed
Summary

Insulin receptor kinase (IRK) activation, essential for insulin signalling, is maintained within endosomes. Peroxovanadium compounds activate IRK by inhibiting phosphatases, demonstrating IRK internalization is central to insulin response regulation.

Keywords:
endosomal acidic insulinaseendosomesinsulin receptorinsulinase endosomique acidephosphorylationphosphotyrosine phosphataserécepteur de l'insulinetyrosine kinase

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Endocrinology

Background:

  • Insulin receptor (IR) activation initiates signalling via its tyrosine kinase (IRK) domain.
  • IRK activation, though initiated at the cell surface, is sustained and amplified after internalization into the endosomal system (ENS).

Purpose of the Study:

  • To investigate the role of endosomal insulin receptor kinase (IRK) activation in insulin signalling.
  • To elucidate the mechanism of action of peroxovanadium compounds (pVs) in activating IRK.
  • To identify factors within the endosomal system that regulate the duration and intensity of insulin signalling.

Main Methods:

  • Utilized peroxovanadium compounds (pVs) to activate IRK in the absence of insulin.
  • Investigated the effects of endosomal acidification and substrate recruitment on IRK activity.
  • Examined the role of IRK-associated phosphotyrosine phosphatases (PTPs) in regulating IRK dephosphorylation.

Main Results:

  • Peroxovanadium compounds (pVs) were found to activate IRK, mimicking insulin's effect and eliciting a full insulin response.
  • Activation of the endosomal IRK alone was sufficient to drive insulin signalling.
  • pV action was attributed to the inhibition of IRK-associated phosphotyrosine phosphatases (PTPs).
  • Endosomal factors including substrate recruitment, acidification-induced insulin dissociation, insulin degradation, and PTP activity modulate IRK signalling duration and intensity.

Conclusions:

  • Insulin receptor kinase (IRK) activation is both necessary and sufficient for insulin signalling.
  • Internalization of IRKs into the endosomal system is a critical regulatory step for insulin signalling.
  • Inhibition of IRK-associated PTPs by pVs highlights a key mechanism in modulating insulin signal duration and intensity.