Korean J Intern Med.  2010 Jun;25(2):119-129. 10.3904/kjim.2010.25.2.119.

Molecular Mechanism of Insulin Resistance in Obesity and Type 2 Diabetes

  • 1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA. ykim2@bidmc.harvard.edu


Insulin resistance is a major risk factor for developing type 2 diabetes caused by the inability of insulin-target tissues to respond properly to insulin, and contributes to the morbidity of obesity. Insulin action involves a series of signaling cascades initiated by insulin binding to its receptor, eliciting receptor autophosphorylation and activation of the receptor tyrosine kinase, resulting in tyrosine phosphorylation of insulin receptor substrates (IRSs). Phosphorylation of IRSs leads to activation of phosphatidylinositol 3-kinase (PI3K) and, subsequently, to activation of Akt and its downstream mediator AS160, all of which are important steps for stimulating glucose transport induced by insulin. Although the mechanisms underlying insulin resistance are not completely understood in skeletal muscle, it is thought to result, at least in part, from impaired insulin-dependent PI3K activation and downstream signaling. This review focuses on the molecular basis of skeletal muscle insulin resistance in obesity and type 2 diabetes. In addition, the effects of insulin-sensitizing agent treatment and lifestyle intervention of human insulin-resistant subjects on insulin signaling cascade are discussed. Furthermore, the role of Rho-kinase, a newly identified regulator of insulin action in insulin control of metabolism, is addressed.


Insulin resistance; Type 2 diabetes; Glucose transport; Skeletal muscle

MeSH Terms

Blood Glucose/*metabolism
Diabetes Mellitus, Type 2/*metabolism
Insulin Resistance/*physiology
Obesity, Abdominal/*metabolism
Signal Transduction/physiology
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