title: Incomplete Re-Expression of Neuroendocrine Progenitor/Stem Cell Markers is a Key Feature of β-Cell Dedifferentiation.
abstract: There is increasing evidence to suggest that type 2 diabetes mellitus (T2D), a pandemic metabolic disease, may be caused by β-cell dedifferentiation (βCD). However, there is currently no universal definition of βCD, and the underlying mechanism is poorly understood. We hypothesise that a high-glucose in vitro environment mimics hyperglycaemia in vivo and that β cells grown in this milieu over a long period will undergo dedifferentiation. In the present study, we report that the pancreatic β 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 β 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) β-cell transcription factor. Finally, passaged MIN6 cells dedifferentiated to demonstrate some features of β-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 β-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.
authors.affiliation: Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Australia.|School of Medicine And Pharmacology, University of Western Australia, Carwley, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Neelankal John
authors.affiliation: Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Australia.|School of Medicine And Pharmacology, University of Western Australia, Carwley, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Morahan
authors.affiliation: Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, Australia.|School of Medicine And Pharmacology, University of Western Australia, Carwley, Australia.
authors.forename: F-X
authors.initials: FX
authors.lastname: Jiang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D054337:Cell Dedifferentiation / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005934:Glucagon / Q000096:biosynthesis; D005947:Glucose / Q000494:pharmacology; D051273:Glucose Transporter Type 2 / Q000096:biosynthesis; D018398:Homeodomain Proteins / Q000096:biosynthesis; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015534:Trans-Activators / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis
chemical_list: D015415:Biomarkers; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein; D005934:Glucagon; D005947:Glucose
keywords: mouse insulinoma 6; neuroendocrinology; β-cell dedifferentiation