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Role of the forkhead protein FoxO1 in β cell compensation to insulin resistance
Haruka Okamoto, … , ndrew Ward,, Domenico Accili
Haruka Okamoto, … , ndrew Ward,, Domenico Accili
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):775-782. https://doi.org/10.1172/JCI24967.
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Research Article Endocrinology

Role of the forkhead protein FoxO1 in β cell compensation to insulin resistance

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Abstract

Diabetes is associated with defective β cell function and altered β cell mass. The mechanisms regulating β cell mass and its adaptation to insulin resistance are unknown. It is unclear whether compensatory β cell hyperplasia is achieved via proliferation of existing β cells or neogenesis from progenitor cells embedded in duct epithelia. We have used transgenic mice expressing a mutant form of the forkhead-O1 transcription factor (FoxO1) in both pancreatic ductal and endocrine β cells to assess the contribution of these 2 compartments to islet expansion. We show that the mutant FoxO1 transgene prevents β cell replication in 2 models of β cell hyperplasia, 1 due to peripheral insulin resistance (Insulin receptor transgenic knockouts) and 1 due to ectopic local expression of IGF2 (Elastase-IGF2 transgenics), without affecting insulin secretion. In contrast, we failed to detect a specific effect of the FoxO1 transgene on the number of periductal β cells. We propose that β cell compensation to insulin resistance is a proliferative response of existing β cells to growth factor signaling and requires FoxO1 nuclear exclusion.

Authors

Haruka Okamoto, Marta Letizia Hribal, Hua V. Lin, William R. Bennett, ndrew Ward,, Domenico Accili

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Figure 1

Detection of c-Myc–FoxO1 fusion proteins.

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Detection of c-Myc–FoxO1 fusion proteins.
(A) Insr Western blot. We dete...
(A) Insr Western blot. We detected Insr by Western blotting of liver, brain, and muscle extracts of WT mice. L1 mice express Insr in liver and brain, but not muscle. Insr–/– mice do not express Insr in liver while L2 mice are Insr transgenic knockouts with Insr expression limited to liver and β cells (26). (B) FoxO1 Western blot. We performed immunoprecipitations with anti–c-Myc antiserum and Western blotting with anti-FoxO1 antiserum (upper panel). As a control, we show immunoblotting with anti-FoxO1 (middle panel) and antitubulin antisera (lower panel). (C) Pancreatic immunohistochemistry. We performed immunostaining of pancreatic sections from WT, 307, and 305 mice with anti–c-Myc antiserum to detect transgene-encoded FoxO1 (left panels, red). DNA counterstaining with DAPI is shown in right panels. We show representative sections to illustrate the difference between transgene-positive and transgene-negative cells, indicated by the yellow arrows. Magnification, ×40 (top 3 rows); ×100 (bottom row).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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