High-density lipoproteins (HDL) can protect pancreatic beta cells from the damaging effects of glucolipotoxicity, this leads to sustained insulin secretion and cell survival. This protection is associated with reduced progression to type 2 diabetes. This video examines changes in microRNA expression induced by HDL in a human hybrid beta cell model and tests the impact of modulation of a single sequence in protection from glucolipotoxicity. Human PANC-1 1.1B4 cells were used to establish minimum concentrations required to protect cell viability and reduce apoptosis during the challenge of 30mM glucose and 0.25mM palmitic acid. Microchip array identified the microRNA expression signature associated with HDL treatment, this led to the identification of hsa-miR-21-5p, upregulated by HDL, as a candidate for facilitating HDL protection. Transfection with miR-21-5p mimic altered similar gene targets to HDL treatment, but could not provide sufficient protection against glucolipotoxicity. Researchers conclude that the complex profile of microRNA changes due to HDL treatment are not easily replicated using a single microRNA, this can inform future studies aiming to develop treatment strategies based on this approach.