The LXR Ligand T0901317 Acutely Inhibits Insulin Secretion by Affecting Mitochondrial Metabolism

Abstract

The role of liver X receptor (LXR) in pancreatic β-cell physiology and pathophysiology is still unclear. It has been postulated that chronic LXR activation in β-cells induces lipotoxicity, a key step in the development of β-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 β-cells. We found that 10 µM T0901317 completely suppressed oscillations of the cytosolic Ca2+ concentration induced by 15 mM glucose. 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.

Approved LXR agonists exert unspecific effects on pancreatic β-cell function

“…In the present study 1 µM T0901317 and GW3965 acutely inhibited SSC in pancreatic β-cells within a few minutes. Evidently, the observed effects were not limited to high concentration of the agonists (T0901317 in [19]), but also occur with lower concentrations of the drugs (T0901317 and GW3965 in this study) that are assumed to be more specific. A genomic pathway is highly unlikely due to the fast onset of the effects seen in patch-clamp experiments and Ca 2+ measurements.…”

“…5b). The drop in [Ca 2+ ] c directly after removal of T0901317 points to ATPdependent SERCA activation after ATP depletion [19]. Accordingly, T0901317 depolarised ΔΨ in LXRα −/− β −/− islet cell clusters under high glucose condition (Fig.…”

“…Details are described in [19]. 20 islets were kept for 30 min at 37°C in incubation medium under conditions as indicated.…”

“…Recently, we made the unexpected observation that 10 µM T0901317 exerts acute effects on SSC in β-cells [19]. Thus, in a first approach we investigated effects of lower concentrations of T0901317 on β-cell function, which are most likely more specific for the LXR, and compared it to another drug which is assumed to be a specific LXR ligand, GW3965.…”

“…Recently, we showed activation of a non-genomic rapid pathway by 10 µM T0901317 that negatively influenced insulin secretion in murine and human pancreatic β-cells [19]. The LXR agonist interfered with stimulus-secretion coupling (SSC) by inhibiting the ATP synthesis probably due to effects on the ROS concentration [19].…”