Human β-Cell Dedifferentiation and Diabetes

Abstract

β-cell dedifferentiation in humans is considered as a mechanism underlying β-cell failure, which is characterized by the loss of their differentiated identity and reversion to a fetal-like state. In humans, significant increases in the hormones-negative/Chromogranin A-positive endocrine cells were detected in islets from T2D individuals, which were accompanied by decreased expressions of the β-cell identity transcription factors (NKX6.1, MAFA, etc.) and reactivation of the progenitor marker, NEUROGENIN 3, and dramatic inductions of the dedifferentiation marker, ALDH1A3 and BACH2. The observation of increased dysfunctional dedifferentiated β-cells in non-diabetic patients with chronic pancreatitis or pancreatic ductal adenocarcinoma as well as in non-diabetic aged subjects proposed that β-cell dedifferentiation is not only a major mechanism of pancreatogenic diabetes and age-related diabetes but also an initial trigger for human β-cell failure before hyperglycemia occurs. Indeed, the finding that the ratio of dedifferentiated β-cells is inversely related to HOMA-β and 2h-C Peptide in subjects without a diabetes history further supports the contribution of β-cell dedifferentiation to β-cell failure in humans. Considerable efforts have been made and are still required to identify targets and pathways (in)dependent of hyperglycemia that trigger dedifferentiation in human β-cells. These findings hold promise for the development of effective therapeutic strategies aimed at preventing or reversing this process, thereby maintaining or restoring functional β-cell mass.