Vitamin D receptor-targeted treatment to prevent pathological dedifferentiation of pancreatic ß cells under hyperglycaemic stress.

Dedifferentiation has been identified as one of the causes of ß-cell failure resulting in type 2 diabetes (T2D). This study tested whether increasing vitamin D receptor (VDR) expression prevents dedifferentiation of ß cells in a high-glucose state in vitro. Culturing a mouse insulinoma cell line (MIN6) in a high-glucose environment decreased VDR expression. However, increased VDR following vitamin D3 (VD3) treatment improved insulin release of early-passage MIN6 and insulin index of db/- (heterozygous) islets to levels seen in normal functional islets. Treatment with VD3, its analogues and derivatives also increased the expression of essential transcription factors, such as Pdx1, MafA and VDR itself, ultimately increasing expression of Ins1 and Ins2, which might protect ß cells against dedifferentiation. VD3 agonist lithocholic acid (LCA) propionate was the most potent candidate molecule for protecting against dedifferentiation, and an e-pharmacophore mapping model confirmed that LCA propionate exhibits a stabilizing conformation within the VDR binding site. This study concluded that treating db/+ islets with a VD3 analogue and/or derivatives can increase VDR activity, preventing the pathological dedifferentiation of ß cells and the onset of T2D.

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

There is increasing evidence to suggest that type 2 diabetes mellitus (T2D), a pandemic metabolic disease, may be caused by ß-cell dedifferentiation (ßCD). However, there is currently no universal definition of ßCD, and the underlying mechanism is poorly understood. We hypothesise that a high-glucose in vitro environment mimics hyperglycaemia in vivo and that ß cells grown in this milieu over a long period will undergo dedifferentiation. In the present study, we report that the pancreatic ß 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 ß 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) ß-cell transcription factor. Finally, passaged MIN6 cells dedifferentiated to demonstrate some features of ß-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 ß-cell dedifferentiation that can help researchers develop a better understanding of this process. These findings provide new insights that may enhance knowledge of the pathophysiology of T2D and facilitate the establishment of a novel strategy by which this disease can be treated.