No abstract

Current research indicates that beta cell loss in type 2 diabetes may be attributed to beta cell dedifferentiation rather than apoptosis; however, the mechanisms by which this occurs remain poorly understood. Our previous study demonstrated that elevation of microRNA-24 (miR-24) in a diabetic setting caused beta cell dysfunction and replicative deficiency. In this study, we focused on the role of miR-24 in beta cell apoptosis and dedifferentiation under endoplasmic reticulum (ER) stress conditions. We found that miR-24 overabundance protected beta cells from thapsigargin-induced apoptosis at the cost of accelerating the impairment of glucose-stimulated insulin secretion (GSIS) and enhancing the presence of dedifferentiation markers. Ingenuity® Pathway Analysis (IPA) revealed that elevation of miR-24 had an inhibitory effect on XBP1 and ATF4, which are downstream effectors of two key branches of ER stress, by inhibiting its direct target, Ire1α. Notably, elevated miR-24 initiated another pathway that targeted Mafa and decreased GSIS function in surviving beta cells, thus guiding their dedifferentiation under ER stress conditions. Our results demonstrated that the elevated miR-24, to the utmost extent, preserves beta cell mass by inhibiting apoptosis and inducing dedifferentiation. This study not only provides a novel mechanism by which miR-24 dominates beta cell turnover under persistent metabolic stress but also offers a therapeutic consideration for treating diabetes by inducing dedifferentiated beta cells to re-differentiation.

Inhibition of microRNAs (miRNAs) essential for pancreatic β-cell biology (e.g., ) results in β-cell failure and diabetes in rodent models. Whether the downregulation of miRNAs in pancreatic islets is involved in the development of human type 2 diabetes remains unclear. Here, with the use of an miRNA microarray, we identified a set of miRNAs that were differentially expressed in healthy human islets under glucolipotoxic conditions. A downregulated miRNA,, was preferentially studied because its inhibition causes dramatic β-cell dysfunction and apoptosis. Proteomic profiling and bioinformatics methods identified four target genes, including a Trp53 effector, , that were further confirmed by luciferase reporter assays. We narrowed down the effector of downregulation to PERP owing to its upregulation in islets from diabetic rodents. Indeed, inhibition prevented the β-cell impairment caused by either reduction or glucolipotoxicity. Additional investigations confirmed the modulatory effect of PERP on insulin secretion. Collectively, appears to be an essential regulator of β-cell biology, and its downregulation links PERP enhancement to β-cell dysfunction and apoptosis in glucolipotoxic settings. Our work demonstrates a novel mechanism of glucolipotoxicity-induced β-cell failure mediated through downregulation.

Highlights d FoxO1 acetylation is regulated during the feed-fast cycles d Ets1, a CBP co-factor, is a modulator of FoxO1 acetylation d Ets1 is downregulated during fasting by MEK-ERK pathway d Ets1 suppresses hepatic gluconeogenesis through modulating FoxO1 activity

The presenilin-mediated Notch1 cleavage pathway plays a critical role in controlling pancreatic beta cell fate and survival. The aim of the present study was to investigate the role of Notch1 activation in glucotoxicity-induced beta cell impairment and the contributions of miR-375, miR-30a, and miR-34a to this pathway. We found that the protein levels of presenilins (PSEN1 and PSEN2), and NOTCH1 were decreased in INS-1 cells after treatment with increased concentrations of glucose, whereas no significant alteration of mRNA level of Notch1 was observed. Targeting of miR-375, miR-30a, and miR-34a to the 3′utr of Psen1, Psen2, and Notch1, respectively, reduced the amounts of relevant proteins, thereby reducing NICD1 amounts and causing beta cell apoptosis. Overexpression of NICD1 blocked the effects of glucotoxicity as well as miRNA overabundance. Downregulating the expression of miR-375, miR-30a, and miR-34a restored PSEN1, PSEN2, and NICD1 production and prevented glucotoxicity-induced impairment of the beta cells. These patterns of miRNA regulation of the Notch1 cleavage pathway were reproduced in GK rats as well as in aged rats. Our findings demonstrated that miRNA-mediated suppression of NICD1 links the presenilin/Notch1 pathway to glucotoxicity in mature pancreatic beta cells.