Forkhead proteins in insulin action

Type 2 diabetes arises from a combination of impaired insulin action and defective pancreatic beta cell function. Classically, the two abnormalities have been viewed as distinct, yet mutually detrimental processes. Genetic studies of the insulin signaling pathway have led to a critical reappraisal of the integrated physiology of insulin action. These studies indicate that insulin signaling affects beta cell function and regulation of beta cell mass, thus raising the possibility that insulin resistance may be the overarching feature of diabetes in all target tissues. Studies in our laboratory have focused on the mechanism by which insulin affects regulation of gene expression. We have shown that the forkhead protein Foxo1 is an insulin‐regulated transcription factor. Insulin‐dependent phosphorylation inhibits the ability of Foxo1 to stimulate transcription of prototypic insulin‐responsive genes in liver. We have shown that Foxo1 is a key effector of insulin action in several tissues: liver, where it controls insulin inhibition of glucose production; pancreatic beta cells, where it controls proliferation and neogenesis; pre‐adipocytes, where it controls insulin‐dependent adipose differentiation; myoblasts, where it controls myotube formation; and brain, where it controls expression of hypothalamic neuropeptides. Thus, regulation of Foxo1 function can potentially affect insulin sensitivity in vivo by regulating various aspects of fuel metabolism. Inhibition of Foxo1 holds promise as a therapeutic approach to insulin resistance and diabetes.