Metabolic syndrome

known as insulin resistance syndrome

has become a major public health problem worldwide. It is represented by a group of interrelated disorders

including obesity

hyperglycemia

hyperinsulinemia

hyperlipidemia

and hypertension. Metabolic syndrome is a high-risk factor for type 2 diabetes mellitus and cardiovascular diseases. As the most important hormone in the body in control of energy homeostasis

insulin and its signaling cascade normally control cell growth

metabolism and survival through activation of mitogen-activated protein kinases (MAPK) and phosphotidylinositide-3-kinase (PI3K)

of which activation of PI-3K-associated with insulin receptor substrate 1 and 2 (IRS1

2) and subsequent Akt→Foxo1 phosphorylation cascade

which has a central role in control of nutrient homeostasis and organ survival. Inactivation of Akt and activation of Foxo1

through suppressing IRS1 and IRS2 in different organs following hyperinsulinemia

metabolic inflammation

and over nutrition

may provide the underlying mechanisms for metabolic syndrome. Targeting the IRS→Akt→Foxo1 signaling cascade will likely provide a strategy for therapeutic intervention in the treatment of type 2 diabetes and its complications in humans. This review discussed how a deficiency of insulin signaling components in different organs contributes to the feature of the metabolic syndrome. Emphasis will be placed on the roles of IRS1

IRS2

and associated signaling pathways that couple to Akt and the forkhead/winged helix transcription factor FOXO1.