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Nat Commun. 2015 May 12;6:7079. doi: 10.1038/ncomms8079.

FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization.

Author information

1
Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612, USA.
2
Department of Molecular Physiology and Biophysics, Vanderbilt Medical School, Nashville, Tennesse 37232, USA.
3
Department of Physiology and Biophysics, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612, USA.
4
Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
5
Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
6
Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
7
Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington 98104, USA.
8
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.

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.

Comment in

PMID:
25963540
PMCID:
PMC4755301
DOI:
10.1038/ncomms8079
[Indexed for MEDLINE]
Free PMC Article

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