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  • Review Article
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The role of FOXO1 in β-cell failure and type 2 diabetes mellitus

Nature Reviews Endocrinology volume 9, pages 615–623 (2013)Cite this article

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Abstract

Over the past two decades, insulin resistance has been considered essential to the aetiology of type 2 diabetes mellitus (T2DM). However, insulin resistance does not lead to T2DM unless it is accompanied by pancreatic β-cell dysfunction, because healthy β cells can compensate for insulin resistance by increasing in number and functional output. Furthermore, β-cell mass is decreased in patients with diabetes mellitus, suggesting a primary role for β-cell dysfunction in the pathogenesis of T2DM. The dysfunction of β cells can develop through various mechanisms, including oxidative, endoplasmic reticulum or hypoxic stress, as well as via induction of cytokines; these processes lead to apoptosis, uncontrolled autophagy and failure to proliferate. Transdifferentiation between β cells and α cells occurs under certain pathological conditions, and emerging evidence suggests that β-cell dedifferentiation or transdifferentiation might account for the reduction in β-cell mass observed in patients with severe T2DM. FOXO1, a key transcription factor in insulin signalling, is implicated in these mechanisms. This Review discusses advances in our understanding of the contribution of FOXO1 signalling to the development of β-cell failure in T2DM.

Key Points

  • Hyperglycaemia induces oxidative, endoplasmic reticulum and hypoxic stress, and increases cytokine levels in β cells

  • Metabolic stress leads to apoptosis, failure to proliferate, uncontrolled autophagy and dedifferentiation of β cells

  • FOXO1 inhibits β-cell replication by upregulating expression of cell-cycle inhibitors and suppressing PDX1 transcription

  • FOXO1 inhibits β-cell neogenesis by interacting with Notch signalling and suppressing transcription of NEUROG3, the gene that encodes neurogenin-3

  • FOXO1 protects β cells against oxidative stress by upregulating expression of antioxidant enzymes

  • FOXO1 prevents dedifferentiation and maintains β-cell identity by suppressing expression of neurogenin-3

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Figure 1: The mechanisms that underlie β-cell failure in T2DM.
Figure 2: Involvement of FoxO1 in Notch signalling and β-cell proliferation.
Figure 3: The effects of metabolic and oxidative stress on FoxO1 signalling.

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  1. Metabolic Signal Research Centre, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15, Showa-machi, Maebashi, 371-8512, Gunma, Japan

    Tadahiro Kitamura

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Kitamura, T. The role of FOXO1 in β-cell failure and type 2 diabetes mellitus. Nat Rev Endocrinol 9, 615–623 (2013). https://doi.org/10.1038/nrendo.2013.157

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