The LXR ligand T0901317 acutely inhibits insulin secretion by affecting mitochondrial metabolism

Abstract

The role of liver X receptor (LXR) in pancreatic b-cell physiology and pathophysiology is still unclear. It has been postulated that chronic LXR activation in b-cells induces lipotoxicity, a key step in the development of b-cell dysfunction, which accompanies type 2 diabetes mellitus. In most of these studies, the LXR ligand T0901317 has been administered chronically in the micromolar range to study the significance of LXR activation. In the current study, we have evaluated acute effects of T0901317 on stimulus-secretion coupling of b-cells. We found that 10 mM T0901317 completely suppressed oscillations of the cytosolic Ca2+ concentration induced by 15mMglucose. Obviously, this effect was due to inhibition of mitochondrial metabolism. T0901317 markedly depolarized the mitochondrial membrane potential, thus inhibiting adenosine triphosphate (ATP) production and reducing the cytosolic ATP concentration. This led in turn to a huge increase in KATP current and hyperpolarization of the cell membrane potential. Eventually, T0901317 inhibited glucose-induced insulin secretion. These effects were rapid in on-set and not compatible with the activation of a nuclear receptor. In vivo, T0901317 acutely increased the blood glucose concentration after intraperitoneal application. In summary, these data clearly demonstrate that T0901317 exerts acute effects on stimulus-secretion coupling. This observation questions the chronic use of T0901317 and limits the interpretation of results obtained under these experimental conditions.