title: FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization.
abstract: FoxO proteins are major targets of insulin action. To better define the role of FoxO1 in mediating insulin effects in the liver, we generated liver-specific insulin receptor knockout (LIRKO) and IR/FoxO1 double knockout (LIRFKO) mice. Here we show that LIRKO mice are severely insulin resistant based on glucose, insulin and C-peptide levels, and glucose and insulin tolerance tests, and genetic deletion of hepatic FoxO1 reverses these effects. (13)C-glucose and insulin clamp studies indicate that regulation of both hepatic glucose production (HGP) and glucose utilization is impaired in LIRKO mice, and these defects are also restored in LIRFKO mice corresponding to changes in gene expression. We conclude that (1) inhibition of FoxO1 is critical for both direct (hepatic) and indirect effects of insulin on HGP and utilization, and (2) extrahepatic effects of insulin are sufficient to maintain normal whole-body and hepatic glucose metabolism when liver FoxO1 activity is disrupted.
authors.affiliation: Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612, USA.
authors.forename: InSug
authors.initials: I
authors.lastname: O-Sullivan
authors.affiliation: Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612, USA.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt Medical School, Nashville, Tennesse 37232, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612, USA.
authors.forename: Chong Wee
authors.initials: CW
authors.lastname: Liew
authors.affiliation: Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612, USA.
authors.forename: Jonathan
authors.identifier: 0000000220918113
authors.initials: J
authors.lastname: Liu
authors.affiliation: Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Jihye
authors.initials: J
authors.lastname: Paik
authors.affiliation: Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.affiliation: Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Donna Beer
authors.initials: DB
authors.lastname: Stolz
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.affiliation: Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington 98104, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
authors.affiliation: 1] Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612, USA [2] Medical Service, Jesse Brown VA Medical Center, 820 South Damen Avenue, Chicago, Illinois 60612, USA, USA.
authors.forename: Terry G
authors.initials: TG
authors.lastname: Unterman
mesh_terms: D000818:Animals; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D005947:Glucose