FoxO1 Plays an Important Role in Regulating [beta]-Cell Compensation for Insulin Resistance in Male Mice

[beta]-Cell compensation is an essential mechanism by which [beta]-cells increase insulin secretion for overcoming insulin resistance to maintain euglycemia in obesity. Failure of [beta]-cells to compensate for insulin resistance contributes to insulin insufficiency and overt diabetes. To understand...

Full description

Saved in:
Bibliographic Details
Published in:Endocrinology (Philadelphia) 2016-03, Vol.157 (3), p.1055-1070
Main Authors: Zhang, Ting, Kim, Dae Hyun, Xiao, Xiangwei, Lee, Sojin, Gong, Zhenwei, Muzumdar, Radhika, Calabuig-Navarro, Virtu, Yamauchi, Jun, Harashima, Hideyoshi, Wang, Rennian, Bottino, Rita, Alvarez-Perez, Juan Carlos, Garcia-Ocana, Adolfo, Gittes, George, Dong, H Henry
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[beta]-Cell compensation is an essential mechanism by which [beta]-cells increase insulin secretion for overcoming insulin resistance to maintain euglycemia in obesity. Failure of [beta]-cells to compensate for insulin resistance contributes to insulin insufficiency and overt diabetes. To understand the mechanism of [beta]-cell compensation, we characterized the role of forkhead box O1 (FoxO1) in [beta]-cell compensation in mice under physiological and pathological conditions. FoxO1 is a key transcription factor that serves as a nutrient sensor for integrating insulin signaling to cell metabolism, growth, and proliferation. We showed that FoxO1 improved [beta]-cell compensation via 3 distinct mechanisms by increasing [beta]-cell mass, enhancing [beta]-cell glucose sensing, and augmenting [beta]-cell antioxidative function. These effects accounted for increased glucose-stimulated insulin secretion and enhanced glucose tolerance in [beta]-cell-specific FoxO1-transgenic mice. When fed a high-fat diet, [beta]-cell-specific FoxO1-transgenic mice were protected from developing fat-induced glucose disorder. This effect was attributable to increased [beta]-cell mass and function. Furthermore, we showed that FoxO1 activity was up-regulated in islets, correlating with the induction of physiological [beta]-cell compensation in high-fat-induced obese C57BL/6J mice. These data characterize FoxO1 as a pivotal factor for orchestrating physiological adaptation of [beta]-cell mass and function to overnutrition and obesity.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2015-1852