Pancreatic β Cell Dedifferentiation as a Mechanism of Diabetic β Cell Failure

Abstract

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.

MafA is critical for maintenance of the mature beta cell phenotype in mice

“…Cell plasticity has been intensively investigated in adult pancreatic endocrine cells. Lineage tracing analyses of adult pancreatic cells for various in vivo conditions clearly demonstrate that conversion between different pancreatic cell types occurs in adults through changes in the expression of transcription factors that are critical for endocrine cell differentiation [3][4][5][6][7][8]. These findings are supported by studies reporting that the forced expression of transcription factors convert cell types [9][10][11].…”

Selective and sequential loss of transcriptional factors: A hallmark of β‐cell failure in type 2 diabetes?

“…These results are concordant with the view that MAFA regulates the expression of C/EBP homologous protein, mediated by (dependent on) extracellular signal‐regulated kinase 1/21/2, in glucose‐stimulated β‐cells5. Surprisingly, β‐cell‐specific FOXO1 deletion reportedly induced transdifferentiation from β‐cells to α‐cells under metabolic stress6. These FOXO1‐deficient β‐cells had lost the expressions of PDX1, MAFA and insulin, and instead expressed the progenitor markers neurogenin 3 (NEUROG3), v‐myc avian myelocytomatosis viral oncogene lung carcinoma‐derived homolog (MYCL), nanog homeobox (NANOG) and POU class 5 homeobox 1 (1 POU5F1).…”

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

“…In summary, the plasticity of beta cell identity is a double-edged sword that provides an opportunity to regenerate beta cells from endogenous progenitors, while contributing to their dedifferentiation in diabetes (Jonas et al, 1999;Talchai et al, 2012).…”