High-density lipoproteins provide protection against the damaging effects of glucolipotoxicity in beta cells, a factor which sustains insulin secretion and staves off onset of type 2 diabetes mellitus. In this study the researchers at the Glasgow Caledonian University examines epigenetic changes in small non-coding microRNA sequences induced by high density lipoproteins in a human hybrid beta cell model, and tests the impact of delivery of a single sequence in protecting against glucolipotoxicity. Human PANC-1.1B4 cells were used to establish Bmax and Kd for [³H]cholesterol efflux to high density lipoprotein, and minimum concentrations required to protect cell viability and reduce apoptosis to 30mM glucose and 0.25 mM palmitic acid. The microchip array services from LC Sciences’ identified the microRNA signature associated with high density lipoprotein treatment, and one sequence, hsa-miR-21-5p, modulated via delivery of a mimic and inhibitor. The results confirm that low concentrations of high-density lipoprotein can protect against glucolipotoxicity, and report the global microRNA profile associated with this lipoprotein; delivery of miR-21-5p mimic altered gene targets, similar to high density lipoprotein, but could not provide sufficient protection against glucolipotoxicity. They conclude that the complex profile of microRNA changes due to HDL treatment may be difficult to replicate using a single microRNA, findings which may inform current drug strategies focused on this approach.