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.
Nakae
Jun
J
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.
Biggs
William H
WH
Kitamura
Tadahiro
T
Cavenee
Webster K
WK
Wright
Christopher V E
CV
Arden
Karen C
KC
Accili
Domenico
D
D000818:Animals; D015152:Blotting, Northern; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007150:Immunohistochemistry; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance / Q000235:genetics; D007515:Islets of Langerhans / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009928:Organ Specificity; D011972:Receptor, Insulin / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D014157:Transcription Factors; D011972:Receptor, Insulin