Nature Genetics32, 245 - 253 (2002)
Published online: 3 September 2002; Corrected online: 09 September 2002 | doi:10.1038/ng890
Regulation of insulin action and pancreatic -cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1
Jun Nakae1, William H. Biggs III2, Tadahiro Kitamura1, Webster K. Cavenee2, Christopher V.E. Wright3, Karen C. Arden2
& Domenico Accili1
1
Naomi Berrie Diabetes Center, Berrie Research Pavilion, 1150 St. Nicholas Avenue, Department of Medicine, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA.
2
Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, California, USA.
3
Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Correspondence should be addressed to Domenico Accili da230@columbia.edu
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 -cells results in diabetes arising from a combination of increased hepatic glucose production and impaired -cell compensation due to decreased Pdx1 expression. These data indicate that Foxo1 is a negative regulator of insulin sensitivity in liver, adipocytes and pancreatic -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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