1765-P: Direct ß-Cell Effects of miR-6727-3p, an miRNA Related to Improved ß-Cell Function in Humans

Most people with type 2 diabetes (T2D) have limited improvement in β-cell function with glucose-lowering treatment; but we know little about contributing factors. Plasma miRNAs may reflect or predict treatment response at the level of the β cell. In youth treated with insulin glargine followed by metformin in the Restoring Insulin Secretion Study, we found that miR-6727-3p was positively associated with treatment response. Thus, we sought to determine whether miR-6727-3p has a direct effect on islets to improve insulin secretion and decrease cell death under T2D conditions. C57BL/6 mouse islets were treated for 48 h with 11.1 mM glucose (considered “normal” for mouse islets) or 25 mM glucose + 0.5 mM palmitate (“T2D”) in the presence of 5 nM miR-6727-3p mimic or miR-scramble. Thereafter, we assessed glucose-stimulated insulin secretion (GSIS) and islet cell death. T2D conditions resulted in elevated basal and reduced GSIS (Table). Regardless of condition, miR-6727-3p had no effect to change basal or GSIS. As expected, cell death increased in islets cultured in T2D vs normal conditions, but surprisingly, miR-6727-3p further exacerbated cell death under both conditions. Together, these data suggest miR-6727-3p may not alter β-cell function but that it may be deleterious to β-cell survival. Moreover, higher levels of plasma miR-6727-3p in responders are likely unrelated to treatment response.