Iptakalim, a vascular ATP-sensitive potassium (K_ATP) channel opener, closes rat pancreatic β-cell K_ATP channels and increases insulin release

Sulfonylureas have been the leading oral antihyperglycemic agents, and they presently continue to be the most popular antidiabetic drugs prescribed for treatment of type 2 diabetes. However, concern has arisen over the side effects of sulfonylureas on the cardiovascular system. Here, we tested the hypothesis that iptakalim, a novel vascular ATP-sensitive potassium (KATP) channel opener, closes rat pancreatic β-cell K_ATP channels and increases insulin release. Rat pancreatic β-cell K_ATP channels and heterologously expressed K_ATP channels in both human embryonic kidney (HEK) 293 cells and Xenopus oocytes were used to test the pharmacological effects of iptakalim. Patch-clamp recordings, Ca²⁺ imaging, and measurements of insulin release were applied. Patch-clamp whole-cell recordings revealed that iptakalim depolarized β-cells, induced action potential firing, and reduced K_ATP channel-mediated currents. Single-channel recordings revealed that iptakalim reduced the open probability of K_ATP channels without changing channel sensitivity to ATP. By closing β-cell K_ATP channels, iptakalim elevated intracellular Ca²⁺ concentrations and increased insulin release. In addition, iptakalim decreased the open probability of recombinant Kir6.2FL4A (a trafficking mutant of the Kir6.2) K_ATP channels heterologously expressed in HEK 293 cells, suggesting that iptakalim suppressed the function of β-cell K_ATP channels by directly inhibiting the Kir6.2 subunit. Finally, iptakalim inhibited Kir6.2/SUR1, but it activated Kir6.1/SUR2B (vascular-type), K_ATP channels heterologously expressed in Xenopus oocytes. Iptakalim bidirectionally regulated pancreatic-type and vascular-type K_ATP channels, and this unique pharmacological property suggests the potential use of iptakalim as a new therapeutic strategy for treating type 2 diabetes with the additional benefit of alleviating vascular disorders.