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

Nakae J, Biggs WH, Kitamura T, Cavenee WK, Wright CV, Arden KC, Accili D
Nat Genet. 2002 32 (2): 245-53

PMID: 12219087 · DOI:10.1038/ng890

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.

MeSH Terms (17)

Animals Blotting, Northern Diabetes Mellitus, Experimental Diabetes Mellitus, Type 2 Forkhead Box Protein O1 Forkhead Transcription Factors Immunohistochemistry Insulin Insulin Resistance Islets of Langerhans Liver Mice Mice, Transgenic Mutation Organ Specificity Receptor, Insulin Transcription Factors

Connections (2)

This publication is referenced by other Labnodes entities:

Links