Incomplete Re-Expression of Neuroendocrine Progenitor/Stem Cell Markers is a Key Feature of β-Cell Dedifferentiation

There is increasing evidence to suggest that type 2 diabetes mellitus (T2D), a pandemic metabolic disease, may be caused by beta-cell dedifferentiation (beta CD). However, there is currently no universal definition of beta CD, and the underlying mechanism is poorly understood. We hypothesise that a high-glucose in vitro environment mimics hyperglycaemia in vivo and that beta cells grown in this milieu over a long period will undergo dedifferentiation. In the present study, we report that the pancreatic beta cell line mouse insulinoma 6 (MIN6) grown under a high-glucose condition did not undergo massive cell death but exhibited a glucose-stimulated insulin-secreting profile similar to that of immature beta cells. The expression of insulin and the glucose-sensing molecule glucose transporter 2 (Glut2) in late passage MIN6 cells was significantly lower than the early passage at both the RNA and protein levels. Mechanistically, these cells also expressed significantly less of the 'pancreatic and duodenal homebox1' (Pdx1) beta-cell transcription factor. Finally, passaged MIN6 cells dedifferentiated to demonstrate some features of beta-cell precursors, as well as neuroendocrine markers, in addition to expressing both glucagon and insulin. Thus, we concluded that high-glucose passaged MIN6 cells passaged MIN6 cells. provide a cellular model of beta-cell dedifferentiation that can help researchers develop a better understanding of this process. These findings provide new insights that may enhance knowledge of the patho-physiology of T2D and facilitate the establishment of a novel strategy by which this disease can be treated.