Foxo1 plays an important role in regulating β-cell compensation for insulin resistance in male mice

Authors

Ting Zhang, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
Dae Hyun Kim, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
Xiangwei Xiao, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
Sojin Lee, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
Zhenwei Gong, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
Radhika Muzumdar, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
Virtu Calabuig-Navarro, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
Jun Yamauchi, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
Hideyoshi Harashima, Hokkaido University
Rennian Wang, Western UniversityFollow
Rita Bottino, West Penn Allegheny Health System
Juan Carlos Alvarez-Perez, Icahn School of Medicine at Mount Sinai
Adolfo Garcia-Ocaña, Icahn School of Medicine at Mount Sinai
George Gittes, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
H. Henry Dong, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh

Document Type

Article

Publication Date

3-1-2016

Journal

Endocrinology

Volume

157

Issue

3

First Page

1055

Last Page

1070

URL with Digital Object Identifier

10.1210/en.2015-1852

Abstract

β-Cell compensation is an essential mechanism by which β-cells increase insulin secretion for overcoming insulin resistance to maintain euglycemia in obesity. Failure of β-cells to compensate for insulin resistance contributes to insulin insufficiency and overt diabetes. To understand the mechanism of β-cell compensation, we characterized the role of forkhead box O1 (FoxO1) in β-cell compensation in mice under physiologicalandpathological conditions.FoxO1is a key transcription factor that serves as a nutrient sensor for integrating insulin signaling to cell metabolism, growth, and proliferation.Weshowed that FoxO1 improvedβ-cell compensation via 3 distinct mechanisms by increasing β-cell mass, enhancing β-cell glucose sensing, and augmenting β-cell antioxidative function. These effects accounted for increased glucose-stimulated insulin secretion and enhanced glucose tolerance in β-cell-specific FoxO1-transgenic mice. When fed a high-fat diet, β-cell-specific FoxO1-transgenic mice were protected from developing fat-induced glucose disorder. This effect was attributable to increased β-cell mass and function. Furthermore, we showed that FoxO1 activity was up-regulated in islets, correlating with the induction of physiological β-cell compensation in high-fat-induced obese C57BL/6J mice. These data characterize FoxO1 as a pivotal factor for orchestrating physiological adaptation of β-cell mass and function to overnutrition and obesity.