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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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Rho-kinase as a molecular target for insulin resistance and hypertension

Takeshi Kanda1, Shu Wakino, Koichiro Homma

  • 1Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|November 4, 2005
PubMed

Insights

Rho-kinase activation contributes to insulin resistance and hypertension by impairing insulin signaling. Inhibiting Rho-kinase improves glucose/lipid metabolism and blood pressure in obese rats.

Area of Science:

  • Biochemistry
  • Physiology
  • Pharmacology

Background:

  • Rho-kinase is implicated in hypertension and insulin signaling interference via IRS-1 serine phosphorylation in vascular smooth muscle cells.
  • Insulin resistance is a complex metabolic disorder linked to cardiovascular abnormalities.

Purpose of the Study:

  • To investigate the role of Rho-kinase in the development of insulin resistance in Zucker obese rats.
  • To evaluate the therapeutic potential of Rho-kinase inhibition on metabolic and hemodynamic dysfunction.

Main Methods:

  • Utilized Zucker obese rats as a model for insulin resistance and hypertension.
  • Administered fasudil, a Rho-kinase inhibitor, for 4 weeks.
  • Assessed blood pressure, glucose and lipid metabolism, IRS-1 phosphorylation, and insulin signaling in skeletal muscle and aortic tissues.
  • Employed intravital CCD videomicroscopy to visualize skeletal muscle arteriole function.
  • Investigated the effects of fasudil and Y-27632 on insulin- and TNF-alpha-induced IRS-1 phosphorylation in skeletal muscle cells.

Main Results:

  • Activated RhoA/Rho-kinase was observed in skeletal muscles and aortas of Zucker obese rats.
  • Fasudil treatment reduced blood pressure and corrected glucose and lipid metabolism.
  • Rho-kinase inhibition improved IRS-1 serine phosphorylation and insulin signaling in skeletal muscles.
  • Fasudil restored blunted vasodilations (acetylcholine- and sodium nitroprusside-induced) in skeletal muscle arterioles.
  • Fasudil and Y-27632 prevented insulin- and/or TNF-alpha-induced IRS-1 serine phosphorylation.

Conclusions:

  • Rho-kinase activation is responsible for impaired insulin signaling in insulin resistance.
  • Rho-kinase acts as a critical mediator linking metabolic and hemodynamic abnormalities in insulin resistance.
  • Targeting Rho-kinase may offer a therapeutic strategy for managing metabolic and cardiovascular complications of insulin resistance.

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