Mitochondrial uncoupling protein UCP2 in synergy with calcium-independent phospholipase A2γ protect INS-1E β-cells against acute palmitate-induced toxicity

not affect glucose-stimulated insulin secretion (GSIS) and does not protect against the harmful effects of palmitate. We have shown that palmitateinduced GSIS impairment is linked to attenuation of glucose sensitivity of mitochondrial respiration and dampening of the coupling efficiency of glucose-stimulatedoxidative phosphorylation [1]. Since these bioenergetic parameters are affected similarly by uncoupling protein-2 (UCP2) activity [2], we hypothesised that UCP2 mediates palmitate-induced defects in oxidative phosphorylation. To test this hypothesis we are performing a mitochondrial respiratory analysis with UCP2-depleted INS-1E cells subjected to bovine serum albumin (BSA)-conjugated palmitate and palmitoleate, added alone or together. Preliminary data suggest that 70% UCP2 knockdown through RNA interference does not significantly affect the glucolipotoxic effects of palmitate on the mitochondrial respiratory response to glucose and the coupling efficiency of oxidative phosphorylation. Palmitoleate remains relativelyharmless inUCP2-depleted cells and still does not protect against palmitate toxicity. These data suggest that UCP2 does not mediate the palmitate-induced defects in oxidative phosphorylation and, consequently, GSIS. We will show the full analysis of this ongoing bioenergetic study, including effects of UCP2 knockdown on fatty acid exposure at low glucose levels. Moreover, wewill evaluate by static and dynamic GSIS experiments if and how UCP2 depletion affects fatty acid effects on insulin secretion.