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

J Nakae, WH Biggs, T Kitamura, WK Cavenee… - Nature …, 2002 - nature.com
J Nakae, WH Biggs, T Kitamura, WK Cavenee, CVE Wright, KC Arden, D Accili
Nature genetics, 2002nature.com
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 …
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.
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