FoxO1 Plays an Important Role in Regulating ß-Cell Compensation for Insulin Resistance in Male Mice.
Endocrinology
; 157(3): 1055-70, 2016 Mar.
Article
em En
| MEDLINE
| ID: mdl-26727107
ABSTRACT
ß-Cell compensation is an essential mechanism by which ß-cells increase insulin secretion for overcoming insulin resistance to maintain euglycemia in obesity. Failure of ß-cells to compensate for insulin resistance contributes to insulin insufficiency and overt diabetes. To understand the mechanism of ß-cell compensation, we characterized the role of forkhead box O1 (FoxO1) in ß-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 ß-cell compensation via 3 distinct mechanisms by increasing ß-cell mass, enhancing ß-cell glucose sensing, and augmenting ß-cell antioxidative function. These effects accounted for increased glucose-stimulated insulin secretion and enhanced glucose tolerance in ß-cell-specific FoxO1-transgenic mice. When fed a high-fat diet, ß-cell-specific FoxO1-transgenic mice were protected from developing fat-induced glucose disorder. This effect was attributable to increased ß-cell mass and function. Furthermore, we showed that FoxO1 activity was up-regulated in islets, correlating with the induction of physiological ß-cell compensation in high-fat-induced obese C57BL/6J mice. These data characterize FoxO1 as a pivotal factor for orchestrating physiological adaptation of ß-cell mass and function to overnutrition and obesity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Resistência à Insulina
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Adaptação Fisiológica
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Células Secretoras de Insulina
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Fatores de Transcrição Forkhead
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Insulina
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article