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Simple Summary: Loss of the cells which secrete insulin, the hormone which controls blood sugar levels, can occur due to the damaging effects of high levels of sugar and fat in the bloodstream, and is a key factor which triggers type 2 diabetes. Protection against this damage is provided by one of the fat and protein complexes which carry the 'good' cholesterol in the bloodstream, a complex which is called high-density lipoprotein. This study looks at the changes in the expression of small pieces of RNA, called microRNA, triggered in insulin-secreting cells by treatment with high density lipoprotein. These small RNA sequences can help to regulate the expression of genes which can contribute to the protective effect of high-density lipoproteins. Delivery of one of these sequences was able to modulate gene expression in cells, but could not provide enough protection against the damaging effects of high sugar and fat. We conclude that the complex changes in numerous microRNA sequences caused by high density lipoproteins cannot be replicated by a single sequence, suggesting that networks of regulatory microRNA sequences are more important than single sequences. The results will inform drug discovery strategies which focus on high density lipoprotein and microRNA. 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. This study 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. Microchip array 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. We 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. [ABSTRACT FROM AUTHOR]