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Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1.

Type 2 diabetes results from impaired action and secretion of insulin. It is not known whether the two defects share a common pathogenesis. We show that haploinsufficiency of the Foxo1 gene, encoding a forkhead transcription factor (forkhead box transcription factor O1), restores insulin sensitivity and rescues the diabetic phenotype in insulin-resistant mice by reducing hepatic expression of glucogenetic genes and increasing adipocyte expression of insulin-sensitizing genes. Conversely, a gain-of-function Foxo1 mutation targeted to liver and pancreatic beta-cells results in diabetes arising from a combination of increased hepatic glucose production and impaired beta-cell compensation due to decreased Pdx1 expression. These data indicate that Foxo1 is a negative regulator of insulin sensitivity in liver, adipocytes and pancreatic beta-cells. Impaired insulin signaling to Foxo1 provides a unifying mechanism for the common metabolic abnormalities of type 2 diabetes.NOTE: In the AOP version of this article, the name of the fourth author was misspelled as W K Cavanee rather than the correct spelling: W K Cavenee. This has been corrected in the full-text online version of the article. The name will appear correctly in the print version.

Pubmed ID: 12219087


  • Nakae J
  • Biggs WH
  • Kitamura T
  • Cavenee WK
  • Wright CV
  • Arden KC
  • Accili D


Nature genetics

Publication Data

October 30, 2002

Associated Grants


Mesh Terms

  • Animals
  • Blotting, Northern
  • Diabetes Mellitus, Experimental
  • Diabetes Mellitus, Type 2
  • Forkhead Transcription Factors
  • Immunohistochemistry
  • Insulin
  • Insulin Resistance
  • Islets of Langerhans
  • Liver
  • Mice
  • Mice, Transgenic
  • Mutation
  • Organ Specificity
  • Receptor, Insulin
  • Transcription Factors