Essential role of the imidazoline moiety in the insulinotropic effect but not the KATP channel-blocking effect of imidazolines; a comparison of the effects of efaroxan and its imidazole analogue, KU14R

Aims/hypothesis Imidazolines are a class of investigational antidiabetic drugs. It is still unclear whether the imidazoline ring is decisive for insulinotropic characteristics. Materials and methods We studied the imidazoline efaroxan and its imidazole analogue, KU14R, which is currently classified as an imidazoline antagonist. The effects of both on stimulus secretion-coupling in normal mouse islets and beta cells were compared by measuring K_ATP channel activity, plasma membrane potential, cytosolic calcium concentration ([Ca²⁺]_c) and dynamic insulin secretion. Results In the presence of 10 mmol/l but not of 5 mmol/l glucose, efaroxan (100 μmol/l) strongly enhanced insulin secretion by freshly isolated perifused islets, whereas KU14R (30, 100 or 300 μmol/l) was ineffective at both glucose concentrations. Surprisingly, the insulinotropic effect of efaroxan was not antagonised by KU14R. K_ATP channels were blocked by efaroxan (IC₅₀ 8.8 μmol/l, Hill slope −1.1) and by KU14R (IC₅₀ 31.9 μmol/l, Hill slope −1.5). Neither the K_ATP channel-blocking effect nor the depolarising effect of efaroxan was antagonised by KU14R. Rather, both compounds strongly depolarised the beta cell membrane potential and induced action potential spiking. However, KU14R was clearly less efficient than efaroxan in raising [Ca²⁺]_c in single beta cells and whole islets at 5 mmol/l glucose. The increase in [Ca²⁺]_c induced by 10 mmol/l glucose was affected neither by efaroxan nor by KU14R. Again, KU14R did not antagonise the effects of efaroxan. Conclusions/interpretation The presence of an imidazole instead of an imidazoline ring leads to virtually complete loss of the insulinotropic effect in spite of a preserved ability to block K_ATP channels. The imidazole compound is less efficient in raising [Ca²⁺]_c; in particular, it lacks the ability of the imidazoline to potentiate the enhancing effect of energy metabolism on Ca²⁺-induced insulin secretion.