Pancreatic β-Cell Dedifferentiation As Mechanism Of Diabetic β-Cell Failure

By C. Talchai, S. Xuan, Hua V. Lin, Lori Sussel, D. Accili. Cell, 2012

1,267 citations recorded by the source corpus.

Diabetes is associated with β-cell failure. But it remains unclear whether the latter results from reduced β-cell number or function. FoxO1 integrates β-cell proliferation with adaptive β-cell function. We interrogated the contribution of these two processes to β-cell dysfunction, using mice lacking FoxO1 in β-cells. FoxO1 ablation caused hyperglycemia with reduced β-cell mass following physiologic stress, such as multiparity and aging. Surprisingly, lineage-tracing experiments demonstrated that loss of β-cell mass was due to β-cell dedifferentiation, not death. Dedifferentiated β-cells reverted to progenitor-like cells expressing Neurogenin3, Oct4, Nanog, and L-Myc. A subset of FoxO1-deficient β-cells adopted the α-cell fate, resulting in hyperglucagonemia. Strikingly, we identify the same sequence of events as a feature of different models of murine diabetes. We propose that dedifferentiation trumps endocrine cell death in the natural history of β-cell failure, and suggest that treatment of β-cell dysfunction should restore differentiation, rather than promoting β-cell replication.

Subfields: Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/6ec20c9988477b091fa17c8ddbc1b5cbb99aff62

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Citations in the corpus

Structure and dynamics of molecular networks: A novel paradigm of drug discovery: A comprehensive review (2012, background): “Type 1 diabetes is primarily related to the dysregulation of insulin secretion of pancreatic ß-cells, where ß-cell dedifferentiation was recently shown to play an important role (Talchai et al., 2012).”