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

Nature Genetics volume 32, pages 245–253 (2002)Cite this article

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Abstract

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 β-cells results in diabetes arising from a combination of increased hepatic glucose production and impaired β-cell compensation due to decreased Pdx1 expression. These data indicate that Foxo1 is a negative regulator of insulin sensitivity in liver, adipocytes and pancreatic β-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.

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Figure 1: Generation and metabolic analysis of Insr+/− Foxo1+/−mice.
Figure 2: Analysis of pancreatic β-cell function and gene expression in Insr+/− Foxo1+/− mice.
Figure 3: Generation of transgenic mice expressing a constitutively active Foxo1 driven by the Ttr promoter.
Figure 4: Pancreatic immunohistochemistry in Foxo1 transgenics.
Figure 5: Metabolic characterization of Foxo1 transgenics.
Figure 6: Pancreatic and hepatic function in Foxo1 transgenic mice.

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Change history

  • 09 September 2002

    This was incorrect in AOP version but corrected in print. Changed the spelling of fourth author's last name from incorrect Cavanee to correct Cavenee

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Acknowledgements

This work was supported by grants from the US National Institutes of Health and the Juvenile Diabetes Research Foundation. We thank B. Thorens (Univ. of Lausanne) for the mouse Slc2a2 cDNA and Y. Liu for help with immunohistochemistry.

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Authors and Affiliations

  1. Department of Medicine, Naomi Berrie Diabetes Center, Berrie Research Pavilion, 1150 St. Nicholas Avenue, College of Physicians & Surgeons of Columbia University, New York, 10032, New York, USA

    Jun Nakae, Tadahiro Kitamura & Domenico Accili

  2. Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, California, USA

    William H. Biggs III, Webster K. Cavenee & Karen C. Arden

  3. Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Christopher V.E. Wright

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  1. Jun Nakae
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Correspondence to Domenico Accili.

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Nakae, J., Biggs, W., Kitamura, T. et al. Regulation of insulin action and pancreatic β-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nat Genet 32, 245–253 (2002). https://doi.org/10.1038/ng890

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