Insulin signaling, resistance, and metabolic syndrome: insights from mouse models into disease mechanisms

    1. Shaodong Guo
    1. Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Scott & White, Central Texas Veterans Health Care System, 1901 South 1st Street, Bldg. 205, Temple, Texas 76504, USA
    1. Correspondence should be addressed to S Guo; Email: sguo{at}


    Insulin resistance is a major underlying mechanism responsible for the ‘metabolic syndrome’, which is also known as insulin resistance syndrome. The incidence of metabolic syndrome is increasing at an alarming rate, becoming a major public and clinical problem worldwide. Metabolic syndrome is represented by a group of interrelated disorders, including obesity, hyperglycemia, hyperlipidemia, and hypertension. It is also a significant risk factor for cardiovascular disease and increased morbidity and mortality. Animal studies have demonstrated that insulin and its signaling cascade normally control cell growth, metabolism, and survival through the activation of MAPKs and activation of phosphatidylinositide-3-kinase (PI3K), in which the activation of PI3K associated with insulin receptor substrate 1 (IRS1) and IRS2 and subsequent Akt→Foxo1 phosphorylation cascade has a central role in the control of nutrient homeostasis and organ survival. The inactivation of Akt and activation of Foxo1, through the suppression IRS1 and IRS2 in different organs following hyperinsulinemia, metabolic inflammation, and overnutrition, may act as the underlying mechanisms for metabolic syndrome in humans. Targeting the IRS→Akt→Foxo1 signaling cascade will probably provide a strategy for therapeutic intervention in the treatment of type 2 diabetes and its complications. This review discusses the basis of insulin signaling, insulin resistance in different mouse models, and how a deficiency of insulin signaling components in different organs contributes to the features of metabolic syndrome. Emphasis is placed on the role of IRS1, IRS2, and associated signaling pathways that are coupled to Akt and the forkhead/winged helix transcription factor Foxo1.

    • Received in final form 30 October 2013
    • Accepted 22 November 2013
    • Made available online as an Accepted Preprint 26 November 2013
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