J Korean Diabetes Assoc.  2006 Jul;30(4):237-245. 10.4093/jkda.2006.30.4.237.

Rho-kinase and Insulin Signaling

• Kim YB

• KMID: 2177593
• DOI: http://doi.org/10.4093/jkda.2006.30.4.237

Abstract

Insulin's ability to acutely stimulate glucose uptake and metabolism in peripheral tissues is essential for normal glucose homeostasis. Resistance to this insulin effect is a major pathogenic feature of type 2 diabetes and obesity. Although many of the proximal steps in insulin signaling have been identified, the molecular mechanisms underlying insulin resistance under various metabolic states are still unclear. Recent study suggests that Rho-kinase is an important mediator of insulin signaling and glucose homeostasis. Specifically, Rho-kinase directly controls insulin receptor substrate-1, which plays an important role in regulating insulin action. Inhibition of Rho-kinase function results in a decreased insulin response, leading to insulin resistance. Thus, Rho-kinase is identified as a novel regulator of insulin action and glucose homeostasis, and a potential target for new diabetes drugs.

MeSH Terms

Glucose
Homeostasis
Insulin Receptor Substrate Proteins
Insulin Resistance
Insulin*
Metabolism
Obesity
rho-Associated Kinases*
Glucose
Insulin
Insulin Receptor Substrate Proteins
rho-Associated Kinases

Figure

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  Fig. 1 Regulation of Rho.

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  Fig. 2 The structure of Rho-kinase.

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  Fig. 3 Schematic diagram of IRS-1 serine phosphorylation sites by Rho-kinase. The relative positions of the pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains are indicated.

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  Fig. 4 Effects of IRS-1 serine phosphorylation on insulin signaling in CHOIR cells. CHOIR cells were transfected with a WT-IRS-1 or a S632/635A-IRS-1 or a S936A-IRS-1 or a S972A-IRS-1cDNA. After 48 hours, cells were stimulated with insulin (10 nM) for 15 minutes. Cell lysates were subjected to immunoprecipitation with an IRS-1 antibody. p85 and IRS-1 were visualized by immunoblotting with a p85 antibody or an IRS-1 antibody. IRS-1 and IR were visualized by immunoblotting with a phosphotyrosine, a phospho-specific IRS-1 or a total IRS-1 antibody.

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  Fig. 5 A hypothetical mechanism by which Rho-kinase enhances insulin signaling and glucose metabolism. Upon insulin stimulation, Rho-kinase is activated and rapidly phosphorylates IRS-1 on serine residues, which in turn increases the ability of IRS-1 to activate PI 3-kinase, leading to enhanced glucose transport activity and other downstream pathways.

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