Energy depletion and not ROS formation is a crucial step of glucolipotoxicity (GLTx) in pancreatic beta cells

We have shown previously that genetic or pharmacological deletion of K ATP channels protect against beta cell dysfunction induced by reactive oxygen species (ROS). Since it is assumed that glucolipotoxicity (GLTx) causes ROS production, we aimed to evaluate whether suppression of K ATP channel activity can also prevent beta cell damage evoked by GLTx. We used an in vitro model of GLTx and measured distinct parameters of stimulus-secretion coupling. GLTx gradually induced disturbances of Ca 2+ oscillations over 3 days. This impairment in Ca 2+ dynamics was partially reversed in beta cells without functional K ATP channels (SUR1 −/− ) and by the sulfonylurea gliclazide but not by tolbutamide. By contrast, the GLTx-induced suppression of glucose-induced insulin secretion could not be rescued by decreased K ATP channel activity pointing to a direct interaction of GLTx with the secretory capacity. Accordingly, GLTx also suppressed KCl-induced insulin secretion. GLTx was not accompanied by decisively increased ROS production or enhanced apoptosis. Insulin content of beta cells was markedly reduced by GLTx, an effect not prevented by gliclazide. Since GLTx markedly diminished the mitochondrial membrane potential and cellular ATP content, lack of ATP is assumed to decrease insulin biosynthesis. The deleterious effect of GLTx is therefore caused by direct interference with the secretory capacity whereby reduction of insulin content is one important parameter. These findings deepen our understanding how GLTx damages beta cells and reveal that GLTx is disconnected from ROS formation, a notion important for targeting beta cells in the treatment of diabetes. Overall, GLTx-induced energy depletion may be a primary step in the cascade of events leading to loss of beta cell function in type-2 diabetes mellitus.