miRNA-642a-3p protects β cells from glucolipotoxicity.

The incidence of type 2 diabetes mellitus (T2DM) is tightly linked to obesity. High levels of circulating glucose and saturated free fatty acids (FFAs), known as glucolipotoxicity (GLT), is implicated in β cell dysfunction and/or death. This study aims to identify miRNAs capable of protecting β cells from GLT-induced cell death (GICD). A library of 2,080 human miRNA mimics was transfected in β cells followed by exposure to GLT. We identified 45 miRNAs capable of protecting β cells from GICD and selected miR-642a-3p for further studies. RNA-seq revealed that miR-642a-3p restored the expression of β cell identity genes and modulated pathways associated with cell survival and lipid metabolism. Moreover, we showed that transfection of β cells with miR-642a-3p protected them from GLT-induced changes in insulin secretion. Compared with the control, hypercaloric-fed mice showed a trend toward decreased expression of GLT-protective miRNAs. Notably, we demonstrated that miR-642a-3p expression was downregulated in human islets isolated from T2DM patients compared with non-diabetic controls. Importantly, in obese patients, the expression of GLT-protective miRNAs in plasma-derived extracellular vesicles was increased in non-diabetic patients. Overall, we have identified a potential dual role for miR-642a-3p as both a biomarker and a facilitator of β cell survival and function, offering a novel theranostic tool for the management of diabetes and/or obesity.