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

InSug O-Sullivan, Wenwei Zhang, David H. Wasserman, Chong Wee Liew, Jonathan Liu, Jihye Paik, Ronald A. DePinho, Donna Beer Stolz, C. Ronald Kahn, Michael W. Schwartz and Terry G. Unterman ()
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InSug O-Sullivan: Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago College of Medicine
Wenwei Zhang: Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago College of Medicine
David H. Wasserman: Vanderbilt Medical School
Chong Wee Liew: University of Illinois at Chicago College of Medicine
Jonathan Liu: Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago College of Medicine
Jihye Paik: Dana Farber Cancer Institute
Ronald A. DePinho: Dana Farber Cancer Institute
Donna Beer Stolz: Center for Biologic Imaging, University of Pittsburgh
C. Ronald Kahn: Joslin Diabetes Center, Harvard Medical School
Michael W. Schwartz: Diabetes and Obesity Center of Excellence, University of Washington
Terry G. Unterman: Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago College of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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. 13C-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.

Date: 2015
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DOI: 10.1038/ncomms8079

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