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Endocrinology. 2016 Mar;157(3):1055-70. doi: 10.1210/en.2015-1852. Epub 2016 Jan 4.

FoxO1 Plays an Important Role in Regulating β-Cell Compensation for Insulin Resistance in Male Mice.

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Division of Pediatric Endocrinology (T.Z., D.H.K., S.L., Z.G., R.M., V.C.-N., J.Y., H.H.D.), Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Molecular Inflammation Research Center for Aging Intervention (D.H.K.), College of Pharmacy, Pusan National University, Busan, 609-735 Korea; Division of Pediatric Surgery (X.X., G.G.), Department of Surgery, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Laboratory for Molecular Design of Pharmaceutics (J.Y., H.H.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812 Japan; Department of Physiology and Pharmacology (R.W.), University of Western Ontario, London, Ontario, N6C 2V5 Canada; Institute of Cellular Therapeutics (R.B.), Allegheny Health Network, Pittsburgh, Pennsylvania 15212; and Diabetes, Obesity and Metabolism Institute (J.C.A.-P., A.G.-O.), Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine Mt Sinai, New York, New York 10029.


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 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 β-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.

[Available on 2017-03-01]
[Indexed for MEDLINE]
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