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Cold Spring Harb Perspect Biol. 2014 Jan 1;6(1). pii: a009191. doi: 10.1101/cshperspect.a009191.

Insulin receptor signaling in normal and insulin-resistant states.

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Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.


In the wake of the worldwide increase in type-2 diabetes, a major focus of research is understanding the signaling pathways impacting this disease. Insulin signaling regulates glucose, lipid, and energy homeostasis, predominantly via action on liver, skeletal muscle, and adipose tissue. Precise modulation of this pathway is vital for adaption as the individual moves from the fed to the fasted state. The positive and negative modulators acting on different steps of the signaling pathway, as well as the diversity of protein isoform interaction, ensure a proper and coordinated biological response to insulin in different tissues. Whereas genetic mutations are causes of rare and severe insulin resistance, obesity can lead to insulin resistance through a variety of mechanisms. Understanding these pathways is essential for development of new drugs to treat diabetes, metabolic syndrome, and their complications.

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