Beta cell secretion of miR-375 to HDL is inversely associated with insulin secretion

Abstract

Extracellular microRNAs (miRNAs) are a new class of biomarkers for cellular phenotypes and disease, and are bioactive signals within intercellular communication networks. Previously, we reported that miRNAs are secreted from macrophage to high-density lipoproteins (HDL) and delivered to recipient cells to regulate gene expression. Despite the potential importance of HDL-miRNAs, regulation of HDL-miRNA export from cells has not been fully studied. Here, we report that pancreatic islets and beta cells abundantly export miR-375-3p to HDL and this process is inhibited by cellular mechanisms that promote insulin secretion. Small RNA sequencing and PCR approaches were used to quantify beta cell miRNA export to HDL. Strikingly, high glucose conditions were found to inhibit HDL-miR-375-3p export, which was dependent on extracellular calcium. Likewise, stimulation of cAMP was found to repress HDL-miR-375-3p export. Furthermore, we found that beta cell ATP-sensitive potassium channel (K ATP ) channels are required for HDL-miRNA export as chemical inhibition (tolbutamide) and global genetic knockout ( Abcc8 −/− ) approaches inhibited HDL-miR-375-3p export. This process is not likely associated with cholesterol flux, as gain-of-function and loss-of-function studies for cholesterol transporters failed to alter HDL-miR-375-3p export. In conclusion, results support that pancreatic beta cells export miR-375-3p to HDL and this process is inversely regulated to insulin secretion.

miR-375 Promotes Pancreatic Differentiation In Vitro by Affecting Different Target Genes at Different Stages

“…Studies have shown that in human type 2 diabetes and other rodent models with diabetes, the level of extracellular miR-375-3p is affected. Nevertheless, in both humans with type 1 diabetes (T1D) and murine models of T1D, miR-375-3p was consistently found to be upregulated in plasma samples [ 30 ]. The circulating level of miR-375 may reflect changes in β -cells and may be changed in the blood of patients recently diagnosed with T1D [ 12 , 31 ].…”

Exosome-Mediated Differentiation of Mouse Embryonic Fibroblasts and Exocrine Cells into β-Like Cells and the Identification of Key miRNAs for Differentiation

“…Moreover, the overexpression of miR-127 is known to promote mesendoderm generation via nodal signaling [54]. miR-709, a miRNA predominant in pancreatic β-cell-derived exosomes [55], targets different genes in different tissues [47]. For example, in a peripheral nervous system injury, it targets the Egr2, c-Jun, and Sox-2 transcription factors [56], whereas in adipocytes, it mediates glycogen synthase kinase-3β downregulation, which activates Wnt/β-catenin signaling [57].…”

Optimal Time to Ship Human Islets Post Tissue Culture to Maximize Islet Recovery

“…There continues to be an overwhelming need for high-quality human islets for a myriad of research studies attempting to understand and treat diabetes. Human islets are a staple for diabetes investigators working on a wide range of experiments, from developing new diagnostic tools 31 , including new chip technology 32 , to prototypes for encapsulation studies 33 , 34 , alternate transplant sites 35 , 36 , selection of biomaterials for implants 37 , and basic science for the understanding of islet physiology 38 , 39 . As the need for human islets increases with the rise in the number of studies requiring them, islet distribution organizations need to be cognizant of variables that influence islet recovery and function.…”